Dante Resources, Inc. Blog

Dante's Informative Posts

2010-08-26T14:51:00.002-04:00

...will be back in September 2010.

Enjoy the rest of a safe and sunny summer.

From the desk of Dante Resources, Inc.

Lixiviant Product Development and FDA Regulation

2010-07-19T10:44:00.003-04:00

Lixiviants, the science, the biotechnology and intended use, are well-known to the industry. Lixiviant biotechnology dates back to the time of Egyptian slaves who used lixiviant-like ingredients and processes to clean clothes and preserve food. The word lixiviant comes from Latin - "lix" - lye. The process is based on basic science where adjusting "pH" of solutions releases insoluble materials from soluble. In 2010, several companies inquired about FDA testing requirements, preclinical and clinical trial guidance pertaining to lixiviant product development.

Lixiviants fall into a category that is FDA regulated through GRAS, "generally recognized as safe". All GRAS ingredients allow for safe use for food contact areas such as but not limited to counter tops, cooking utensils and food containers. This applies to all contact, tactile or ingested GRAS substance, detailed processes for the quality management and development leading to successful marketed products. GRAS is a list which provides safety guidance and recommendations, issued by FDA, pertaining to "how to use, the use of certain ingredients, compounds, chemicals and otherwise that preserve, protect, sustain food, clothes and surfaces". Lixiviant ingredients, found on GRAS, are "generally recognized as safe" by industry standards of testing, invitro and invivo. FDA emphasizes that although ingredients are suggested to be acceptable to the environment, vegetation, animals and humans, on touch or consumption, testing is recommended to determine and ensure safety and effectiveness.

Testing required, such as but not limited to:

mutagenicity
toxicology
reproductive
organ
carcinogenicity
otherwise.

FDA recommends testing, invitro and invivo, preclinical and clinical testing in tissue culture (mammalian cells), bacteria, animals, rodents to canine and human clinical trials to assess safety. It is recommended that although one formulation may test "ok" by safety standards, any change to the process, ingredient, sequence of ingredient addition, formulation, concentration, pH, new patent, new product, new intended use, must be re-tested to ensure safety and effectiveness. Similar to drug development CMC requirements.

It is essential for the consumer, the development company and the investor to ensure safety, product consistency, batch to batch, lot to lot, stability, shelf life, all constituents that apply to drug CMC development. All participants must consider consumer health, safety, risk and benefit. FDA with the Department of Labor, Public Health, Occupational Safety requires safety testing which must be addressed proactively when considering lixiviant-like products. Hazards may not be immediately apparent and thus must be researched in depth during development. As always, data results, preclinical testing and clinical trials must be conducted with FDA GCP. QC (quality control) of data and documentation must be accurate and consistent. Development, intended use must be in compliance with FDA and industry standards.

Development of Antibody-Based Therapeutics

2010-07-16T12:15:00.003-04:00

The antibody-based therapeutic market continues to demonstrate an impressive growth and expansion within the pharmaceutical arena. Since 2000, the monoclonal antibody market has grown in the number of approved clinical submissions to FDA as well as expansion in therapeutic indication and focus. Currently the top therapeutic indications and market focus are oncology, autoimmune, infectious disease and AIID. Brand products or products in discovery and in clinical development or on the regulatory pathway to clinical submission are generated by large pharma in the past. Since 2000, more companies, large and small will be in the market and discovery modes involving therapeutic monoclonal antibody-based products.

The market forecast for antibody-based products will continue to rise between 2010-2011. AIID emerging discovery is gaining dominance over R&D oncology targets and treatments. The science is unique and discriminates itself from other therapeutic modalities such as devices, small and large molecules, synthetics, otherwise. Successful strategies for clinical development require integration of relevant knowledge pertaining to target antigen properties, antibody design, affinity, isotope selection, isolation, characterization, PK/PD properties, biophysical, biochemical characterization, cross-reactivity, sensitivity and specificity analyses. The first product in this class of therapeutics was approved by FDA in 1986, Muromonab-CD3, a T cell CD3 Receptor, for Transplant Rejection. Since the first approval by FDA, there are numerous approved products successfully marketed and demonstrating predicted "intended use" directives. The clinical development plan is generic, however specific to each product on its way from discovery to the clinic. R&D, characterization, preclinical, clinical, regulatory, submission, via PMA, 510(k) is the general path. Quality management plans and systems are essential and often reviewed first by FDA before substantive content is considered. Use quality control measures to ensure data and documentation accuracy and consistency, adhere to process, procedures and ensure regulatory compliance for success.

Humanitarian Device Exemption (HDE) Regulation - FDA 510(m)(2)

2010-07-14T10:55:00.003-04:00

The long awaited final guidance, issued July 8, 2010 by CDRH/ODE, for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators and FDA Staff is now available to interested parties. The last updated draft was issued August 5, 2008 and a previous regulation was issued July 18, 2006. This document supersedes all others. The guidance provides application and clinical submission information pertaining to Humanitarian Device Exemption for Humanitarian Use Devices (HUDs) authorized by FDA 510(m)(2) and sets forth additional requirements for Pediatric Device Safety and Improvement.

An HDE is an application guided by 21 CFR 814.3(n), for medical devices for intended use that will benefit "in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4000 individuals in the US per year". The HDE is similar to the premarket (PMA) approval application, but does not require effectiveness requirements as described in the guidance. Medical HUDs cannot be sold for profit and only can be used for its intended use under the approved direction of an IRB, except in certain emergencies described in the guidance. The guidance provides distinction on when a HUD can be "used" vs "investigational use" / "clinical investigation".

FDA Considerations:

FDA will approve or deny HDE applications 75 days from the date of receipt
a 30 day filing period starting at the file date, will be used by FDA to determine "completeness"
if the file is not complete, a RTF, a refusal to file will be issued and the file returned to the submitter
if the file is incomplete and a RTF is issued with a request for additional information, the clock re-starts, the 75-day period is reset
the review time for amendments, supplements and additional reports is 75 days
HDE amendments, supplements and additional reports are subject to the same regulations as PMAs
there are no user fees due FDA for the filing
QRS regulation applies and is focused on manufacturing processes relevant to the safety of the device
an exemption from QRS regulation may be requested and considered.

An HDE may be regulated by CDRH or CBER or both. The first step, when considering a clinical application or a clinical submission for HUD or HUD "Exemptions" is to determine which review division and center the file will be submitted. QC must be used to ensure fileability, completeness of components and to ensure quality of data and documentation, ensure previous submitted consistency in file content and regulatory compliance.

HUDs and HDEs are meaningful to patients who fall into a "special" small, treatable and/or diagnosed disease and/or emergent situation. These applications, as well can be used as strategic "planning" tools. contactus@danteresources.com or danteresources@yahoo.com

How to Manage and Prepare a 501(k) for Clinical Submission

2010-07-08T12:44:00.005-04:00

In the last several months, a number of medical device product companies and manufacturers have contacted me with a similar question. The question pertains to approval in Europe, Australia, Japan, Canada and how that relates to a US approval, and secondly, what type of 510(k) to prepare in the US? Is there a fast track to approval in the US since they have device, detection and diagnostic non-US CE Marks of approval to market in non-US countries? There is much debate with IVDMIA status, STED Pilot Programs and LDT clinical submissions, which does not exist with Traditional, Abbreviated and Special 510(k) types of clinical submissions. The answer is to understand and assess where you are, where you want to go, and plan the most expeditious way to get there while conducting activities in accordance with FDA CDRH guidance and requirements. Assess the status of the device, this means to assess the status as it relates not only to guidance and regulatory requirements, but to assess the integrity and quality of data and documentation, statement, label, claim, completeness of application and submission, intended use, omission, missing data and documentation, translation, standard for development and quality review systems, compliance to the Federal Register and otherwise.

Each medical device product will be reviewed according to its intended use and if it relates to an unmet medical need or emergent or life threatening serious need, but beware, these applications are not easily regulated and approved and will be reviewed with regulatory rigor.

Yes, there are 3 types of PMA 510(k)s that may be submitted to FDA, Traditional, Special and Abbreviated. The Special and Abbreviated regulatory paths were developed under "The New 510(k) Paradigm" to help streamline the 510(k) review process at FDA. The Special 510(k) and Abbreviated 510(k) regulatory methods can only be used if certain criteria are met. The Traditional regulatory path can be used under any circumstances. Information required at the time of filing can be found in 21 CFR 807 Subpart E.

A 510(k) PMA Notification does not require a "form" to complete for submission. There is no form. The 510(k) concept is based on substantial equivalence (SE) to a legally marketed (predicate) device(s). All 510(k)s must provide a comparison between the device to be marketed and the predicate device or devices already marketed.

A most important consideration is the predicate device. A company must identify a predicate device as a component of their clinical submission. That predicate device will be used as a source comparison to your device at the time of clinical submission and regulatory review. The choice of the predicate device is crucial and I strongly recommend that the 501(k) number of the predicate device be identified in the clinical submission - be transparent, be clear, be open. Choose a device for your comparator, that is similar to your device. You may claim SE to more than one predicate. The predicate device of choice will and must be recently cleared and approved by FDA. There is additional guidance at http://www.fda.gov/ pertaining to "How to Find a Predicate Device".

Additional Steps to Aid in Management and Preparation:

Locate Guidance Documents
Locate Design Control Requirements 21 CFR 820.30
Locate QS Regulation
Locate Content and Format for the "Type" of clinical submission to be filed.

Components of a Traditional 510(k), for example:

Form FDA 3601
PRS Cover Sheet
Form FDA 3674
Cover Letter
TOC
Indications for Use
510(k) Summary 21 CFR 807.92 or 510(k) Statement 21 CFR 807.93
Standards Data Report Form FDA 3654
Truthful and Accuracy Statement 21 CFR 807.87(k)
Class III Certification and Summary 21 CFR 807.94.

Items required under 21 CFR 807.87 required for a PMA Notification are numerous, please visit the Federal Register and create a checklist of submittable, required components as it pertains to each device to ensure complete submissions and to minimize potential RTFs - Refusal to File.

FDA CDRH 513(g) Medical Device Classification and Clinical Submission

2010-07-07T10:38:00.004-04:00

The FDA CDRH 510(k) submission is the most common regulatory pathway to filing for most medical devices in the US. The 510(k) clinical submission is designed to demonstrate that a medical device product under clinical development is at least as safe and effective or substantially equivalent (SE) to a predicate device, already approved and legally marketed and follows safety surveillance. The information collected, compiled and presented in a 510(k) medical device clinical submission includes but is not limited to the following data and documentation:

preclinical
nonclinical
clinical
performance
comparative
supportive
supplemental
competitive
predicate
intended use
QRS
QA
QC
SOPs
label
inserts
instructions for use
brochure
WIs
QMP
DMP
CDP
protocol, process, procedure
safety
efficacy
previously submitted regulatory data and documentation US, non-US
previously approved clinical submission US, non-US
literature
briefing documents
CE Mark - Europe
ROW and Country-Specific "Notified Body" Opinions
IRB
software, hardware, array, platform, otherwise
other.

Within FDA/CDRH, 2 offices for medical device evaluation exist, the Office of Device Exemption (ODE) and the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD).

Under FD&C Act, Section 513(g), a sponsor, manufacturer, submitter or person may request a medical device classification for clarity and decision, when a question arises pertaining to a regulatory path to filing or simply "how to submit". The FDA guidance in such cases will evaluate and examine each medical device product case by case and come to a decision as a result of filing a 513(g) clinical submission.

Section 513(g) of the Act:

"Within 60 days of the receipt of a written request of any person for the information respecting the class in which a device has been classified or the requirements to a device under this Act, the Secretary shall provide such person a written statement of the classification, if any, of such device and the requirements of this Act applicable to the device".

Section 513(g) Clarity and Classification Inquiries - to determine regulatory / clinical submission path:

determine whether a medical device is subject to FDA regulations
determine whether a medical device is exempt from the 510(k) requirements of the Act
determine whether a 510(k) is needed for a modification to the respective device
determine the regulatory path for the medical device.

Determination of medical device classification provides important decision making information for future manufacturers, investors, co-development partners, strategic alliances, strategic partners, marketing partners, and otherwise. This guidance provides valuable information pertaining to the appropriate and applicable standards of a successful clinical submission, regulatory timelines, development costs, resources, helps to estimate "realistic" time to submission, "realistic" time to market, regulatory strategy for successful, comprehensive, "real-time" product commercialization.

As always, ensure quality, accuracy, consistency of data, documentation, format, presentation, statement and previously submitted filings. Lead submissions, manage issues, QC, QC, QC, monitor, monitor, monitor CROs and all outsourced resources and contracts. Ensure on time quality, compliant and complete contracted deliverables. Go to http://www.danteresources.com/ for expert gate keeper clinical development and submission leadership, resources, teams, quality management and services. Visit our live interactive seminar/webinar page.

Differences in EU and US 510(k) Market Approval

2010-06-28T18:38:00.006-04:00

Often asked by sponsor pharma and medical device manufacturers - is there a difference in clinical criteria and regulatory submission requirements? Differences in Class II and Class III medical device 510(k) regulatory clearance processes do exist. In particular is the process pertaining to issuance for a 510(k) medical device CE Mark. The EU CE Mark process requires medical device demonstration of safety only, and not efficacy and relies heavily on non-governmental opinion leaders or "Notified Bodies (NBs)" to regulate acceptance criteria, regulatory process, approval registration and post-approval post marketing surveillance for safety. In contrast, approval in the US of a new moderate to high risk Class II or Class III medical device requires demonstration of both safety and efficacy and is more regulated by a central governmental agency, CDRH/FDA. European Union Member Countries most often utilize CE review and approval from NBs, particularly because there is a huge savings in clinical development and clinical submission costs and thus time, with shorten timelines to registration and marketed medical device. Remember, EU approval is based only on data and documentation relating to safety and thus the NBs are often seen and chosen as a quick outlet to success and market CE approval. NBs can issue the CE Mark, they are independent, commercial organizations which implement regulatory control, monitor performance and safety of EU approved Class II or Class III medical devices.

NBs:

review
monitor
audit
critique medical device design
assess safety
verify quality systems
review clinical submission data and documentation
guide regulatory process
approve medical devices
issue CE Marks
establish EU post marketing safety surveillance programs
regulate country-specific requirements and governance.

A medical device sponsor or manufacturer is free to choose an NB within the European Union. Within the European Union, there are more than 50 active NBs to date currently reviewing CE applications and registrations.

In the US, a 510(k) application is submitted to CRDH/FDA. The medical device must be safe and efficacious. The 510(k) application typically requires prospective, randomized, controlled clinical trials. To receive clearance from CDRH/FDA, clinical trial results must demonstrate safety, performance and efficacy, significantly demonstrate acceptable intended use. Clinical trials supporting a Class II or Class III medical device 510(k):

includes ~800 patients
multi-center
randomized
controlled
comparative.

A typical clinical trial including 800 patients with the above bulleted design criteria will cost the medical device sponsor or manufacturer 10M-20M, 24 months to perform, 6-8 months to prepare and submit depending on literature, references and supported by previously submitted "global" supplemental and supportive data from CE Marks, if applicable.

In the next post - more information on SE clearance from FDA/CDRH.

International Clinical Trial Site Inspections by FDA

2010-06-21T16:01:00.013-04:00

A question often asked by pharmaceutical sponsors pertains to criteria for assigning inspections at foreign clinical trial sites - what triggers an onsite inspection by FDA CDER? International clinical trial sites will be audited if there is insufficient domestic data supporting a US clinical submission and non-US data becomes primary data and not supplemental or supportive for a drug marketing approval. Inspections are announced by FDA CDER when foreign clinical trial data is submitted for a US marketing application and inconsistencies in domestic and international clinical trial data and documentation are discovered on review. Inconsistencies between domestic and international data will trigger serious issues pertaining to unreported, under-reporting of AEs, data validity, data integrity and quality.

When conflicting data is identified by FDA CDER and when those results are pertinent to decision-making actions impacting resolve, FDA will arrive onsite, announced or unannounced. Refusal to file will be one action taken by FDA, other investigative actions involving suspicion of fraud, clinical, financial or otherwise, scientific misconduct, significant human subject protection violation - penalties, fees, loss of license, imprisonment, other enforcements will be swift and rigorous.

Facts:

There is a rise is the number of foreign clinical investigators and clinical trial sites inspected in the last 6 years, with 2010 inspections already exceeding those published in 2009
Clinical inspections by FDA CDER are highest in Europe, South/Central America and Africa, with Asia and the Pacific Rim second, while Eastern Europe was last.

In the last 2 years, non-US clinical site inspections by country:

Canada 117
U.K. 92
Germany 54
France 54
Russia 36
Italy 35
Sweden 31
South Africa 30
Belgium 26
Poland 22
Netherlands 21
Spain 16
Argentina 16
Finland 15
Denmark 14
Czechoslovakia 13
Australia 11
Brazil 11
ROW country by country less than 10.

www.fda.gov provides lists of clinical investigators who have been disqualified, restricted or provided assurances.

FDA Regulation Regarding Acceptance for Foreign Data for US Marketing Approval

2010-06-21T10:30:00.012-04:00

A pharmaceutical sponsor who relies on foreign data from a clinical study to support an Investigational New Drug (IND) application and clinical submission for US marketing approval must adhere to requirements cited in 21 CFR 312(b). The pharmaceutical sponsor must submit the following information to FDA:

Description of clinical investigator's qualifications
Description of clinical research facilities
Description of clinical trial site
Detailed summary of the clinical study protocol
Finished, complete, ICH compliant final clinical study report (CSR)
Patient Case Report Forms (CRFs) maintained by the clinical investigator at the clinical trial site - FDA will request CRFs, often there is a question as to whether a request by FDA will be made - prepare ahead of time - the compilation, collation, collection and submission of CRFs is time and labor intensive - the submitted file must be properly formatted, quality-controlled and quality-assured by qualified documentation experts
Description of drug product and drug substance including components, formulation, specifications and bioavailability, CMC for starters
If the clinical study is intended to support effectiveness and safety, the data and documentation must be collected, maintained and managed in accordance with 21 CFR 314.26 GCP.

Regarding Good Clinical Practice and foreign data, GCP must be followed to protect clinical study participants and ensure data and documentation integrity and quality. Final clinical study reports must be prepared in accordance with ICH GCP, including review and approval by an Independent Ethics Committee (IEC). FDA directs the review, inspection efforts and acceptance of foreign clinical study data for marketing approval under the Proposed Rule for Human Subject Protection published June 2004. The rule may be viewed at www.fda.gov/OHRMS/DOCKETS.

Under special consideration, FDA may consider foreign clinical study data to support a marketing approval on its own merit. The criteria for such a marketing application and clinical submission are cited in 21 CFR 314.106(b). Under 21 CFR 314.106(b), foreign clinical study data used to support a marketing application and clinical submission on its own merit must comply with the following requirements:

Data and documentation are applicable and consistent with US medical practice and population demographics and statistical considerations
Clinical investigators are qualified
Data and documentation are of high quality
Data and documentation are valid without FDA inspection
Data and documentation are ICH compliant
Data and documentation are collected under GCP
Data and documentation are complete, quality-controlled and quality-assured
Data and documentation are quality managed
Data and documentation are collected by qualified clinical research associates (CRAs)
Data and documentation are adequately monitored in accordance with GCP
FDA may and will inspect the clinical trial site (facility) to ensure validity of data and documentation.

Clinical Submission Approval under FDA Section 505(b)(1)

2010-06-17T10:39:00.002-04:00

A clinical submission filed under FDA Section 505(b)(1) is an NDA, is required to demonstrate clinical meaningful treatment benefits and statistically significant safety and efficacy objectives and endpoints, is a new chemical entity, with a new indication. The new investigational drug will be administered to the patient in a new formulation, with a new dosage form, new dose strength and is patented. The pharmaceutical company and/or manufacturer seeks market exclusivity for the NDA. Approval of the NDA under Section 505(b)(1), is granted by FDA only after an extensive Phase 1, 2, 3 clinical development program. When all 3 clinical phases are complete, the pharmaceutical company and/or manufacturer, submits an NDA including all results from all studies, nonclinical, preclinical, CMC, clinical, bioanalytical, pharmacologic and pharmacokinetic to FDA. The NDA is filed, reviewed for filing completeness and then sent to the appropriate division at FDA for review. The regulatory "clock" begins for the file.

An NDA is the culmination of 10-15 years of discovery, R&D, clinical development and by the time an NDA is approved by FDA, the pharmaceutical company and/or manufacturer, has invested numerous years and many millions for the approval. Post-marketing, post-approval is the next step and requires a 12 - 36 month commitment to monitor and assess new drug attributes such as risk, benefit, safety, effectiveness, SAE reports and otherwise. At the time of approval of an NDA, FDA grants a period and right of exclusivity to the submitter for the newly approved drug. The approved drug and patent(s) are protected for up to 20 years from the date of the first filing of the patent application.

Under the Hatch-Waxman Act, a new drug application and clinical submission process will fall into one of two categories depending on drug profile and background. The two categories are NDAs and ANDAs (Abbreviated) New Drug Applications. Under FDA Section 505(b), a new drug application and clinical submission is further divided into Sections 505(b)(1) and 505(b)(2). An ANDA is further delineated with respect to Bioequivalence requirements and is submitted as a 505(j) application and clinical submission. The 505(j) drug moiety is not a new chemical. Pharmaceutical companies and/or manufacturers filing under Section 505(j) must follow the "generic" approval process for drug application and clinical submission.

NDAs and ANDAs require QC and QA to ensure fileability, quality content, accurate, consistent data and documentation and a successful clinical and regulatory approvability outcome with FDA and otherwise. NDAs and ANDAs are submitted in a CTD (Common Technical Document) presentation and format. CTD content, completeness and format must be quality-controlled and quality-assured to ensure regulatory compliance and reviewer friendly dossier navigation. For expert clinical submission service and consultation contactus@danteresources.com, danteresources@yahoo.com.

Clinical Submissions That Qualify for 505(b)(2) Approval

2010-06-16T11:07:00.003-04:00

The purpose of FDA Section 505(b)(2) of the Hatch-Waxman Act is intended to promote and approve investigational medications that are safe and efficacious, novel therapeutics, while saving cost, time, resources and avoiding unnecessary duplication of clinical efforts and patient exposure, human testing. Clinical submissions for investigational medications that qualify for 505(b)(2) application and approval are, but are not limited to:

Change in dose
Change in dosage form
Change in excipient
Change in formulation
Change in the route of administration
Change in mechanism of action
Change in prescription combination drug
Change in physical, chemical structure
Change in regimen
Change in protocol
Change in origin or parent compound
Change in how derived, natural, recombinant, proteomic, genomic, for examples
Change in OTC combination drug
Change in delivery, transdermal, capsule, device, inhalation, for examples
Change in strength
Change in active ingredient
Change in therapeutic indices or indications.

Approving 505(b)(2) clinical submissions and medications have been challenged by pharmaceutical companies, drug manufacturers, citizen groups and physicians, from a competitive view and challenging to FDA and worldwide regulatory agencies pertaining to accelerated review.

The 505(b)(2) process allows the applicant to utilize previously submitted information from an already approved medication. As well, the applicant is allowed to use literature, post-marketing prescribing safety information, SAE reports and FDA's prior findings of safety, effectiveness, tolerance, pharmacologic and pharmacokinetic of an approved medication at filing. Remember, for the NDA to be considered as a 505(b)(2) candidate for approval, some portion of the information submitted for approval must come from sources other than studies performed by the applicant. If the applicant has obtained the right of reference to the information, a 505(b)(1) application and clinical submission must be submitted instead. The 505(b)(2) process can no longer be used and in fact, if used, the submitter will receive a Refusal to File. The requirements for 505(b)(1) and 505(b)(2) are basically the same with several differences. The right of reference is the an important, major difference between the two regulatory pathways to approval. For accurate, comprehensive, up to date regulatory and clinical submission consultation contactus@danteresources.com, danteresources@yahoo.com.

Approval Under FDA Clinical Submission - Regulatory Section 505(b)(2)

2010-06-15T12:47:00.003-04:00

Drug products filed with FDA for clinical submission and marketing approval under Section 505(b)(2) are not new products, but are products that already have an active ingredient previously approved by a regulatory agency or is now formulated differently, or has a different route of administration, or will show safety and effectiveness in a different therapeutic indication or demonstrates a different mechanism of action. The appropriate regulatory pathway for either consideration above is to seek marketing approval via FDA 505(b)(2).

The active ingredient has certain information already known about the active ingredient, thus an abbreviated application and clinical submission process that does not require extensive testing via the NDA new drug route of regulatory approval is the chosen path. With a "new" NDA, FDA requires complete extensive clinical trials, Phase 1, 2 and 3. Phase 1 clinical trials involve a small number of healthy volunteers. The basis of the clinical Phase 1 program is to ascertain the pharmacologic and pharmacokinetic activity and tolerance of the drug in humans. The Phase 2 clinical program examines preliminary data in a small number of humans related to the medication's effectiveness, safety, adverse event profile, risk/benefit in patients with a diagnosed disease, a therapeutic indication. The Phase 3 clinical program is extensive, involving a large number, several thousand patients or more participating to evaluate the safety, efficacy and overall risk/benefit ratio for use of this medical product in the general population.

Under the rules in Section 505(b)(2), the applicant can rely on information from clinical studies it did not conduct, but were previously approved by FDA. Thus the 505(b)(2) pathway is considered an abbreviated approach to a "NDA", cost effective, with reduced time to approval and market. The 505(b)(2) application requires full clinical study reports of investigations of safety and efficacy where at least some portion of the information submitted for approval comes from studies submitted for previous approval. The applicant can rely for example, on literature describing the safety, effectiveness, risk/benefit, adverse event profile. The applicant will have FDA's findings of safety and effectiveness from the previous approved medication. As well, pharmaco-safety data and prescribing information are available and must contribute to the clinical submission 505(b)(2) approval process.

Remember, previously submitted, FDA approved clinical submission data and documentation has been quality-controlled and quality assured. It is a must that new clinical data and documentation submitted in the 505(b)(2) filing be consistent with scientific, clinical and statistical statements, data and documentation previously approved. A quality control or QC review to compare previously submitted materials and "to be filed" new clinical data and documentation is a must. This includes post marketing safety data and documentation. Clinical submission data and documentation, collected worldwide fall into the QC cycle. If QC is not applied or utilized, the end result is a disaster (impacting new and previously approved products) and results in data inconsistency and a Refusal to File with FDA, for starters. For QC review contactus@danteresources.com, danteresources@yahoo.com.

FDA - Inspections, Compliance, Enforcement and Criminal Investigations

2010-06-09T12:18:00.002-04:00

In 2010, a noted increase is observed in warning letters issued to pharmaceutical sponsors regarding Form FDA 483 and Investigational Device Exemptions (IDEs). The warning letters were issued by FDA to inform the the pharma sponsors of objectionable conditions observed during a FDA for cause, onsite investigation at selected clinical sites. The purpose of a 483 inspection is to determine whether the activities of the pharmaceutical sponsor/clinical investigator at clinical investigative sites comply with applicable federal regulations. A trend of increasing serious violations of Title 21, CFR Part 812, IDE was noted by FDA inspectors during unannounced onsite inspections. Inspections by FDA investigators are conducted under a regulatory program designed to ensure that data and documentation contained in requests for IDE and PMA applications, approvals and 510(k) clinical submissions are scientifically valid and accurate. Another objective of the FDA program is to ensure that human subjects are protected from undue safety hazard or risk during the course of scientific/clinical study investigations.

Most common violations issued by FDA during onsite inspections:

failure to obtain FDA approval prior to allowing subject participation in a clinical investigation
failure to ensure adequate monitoring
failure to complete Form FDA 1572
failure to complete Subject Informed Consent
failure to obtain IRB approval
failure to obtain a signed agreement from each clinical investigator that includes sufficient accurate financial disclosure
failure to submit complete and accurate clinical investigator certification and study disclosure statements
failure to qualify clinical investigators
failure to qualify clinical investigation sites.

Numerous violations were observed during inspections relating to adequate, quality and management at the clinical investigation sites. Sponsors are responsible for ensuring proper monitoring of the investigation and collection of data and documentation. Most common "monitoring" violations observed, but not limited to:

Standard Operating Procedures (SOPs)
Clinical Study Monitoring Procedure
Monitoring Visit Reports - omissions, missing laboratory tests, missing evaluations, missing conditioning logs, missing diaries
Monitoring Visit Reports - inc0mplete and inaccurate subject CRF
Monitoring Visit Reports - inaccurate, missing subject notes, copies of evaluations and exams.

The monitoring reports were noted to lack documentation for corrections and/or clarifications for the cited omissions. Immediate response from the pharmaceutical sponsor is required and expected. Within 15 working days of receiving such warning letters from FDA, it is required and expected that the pharmaceutical sponsor provide written documentation of actions taken, or to be taken to correct violations and prevent the recurrence of similar violations in current or future studies for which the pharmaceutical sponsor is involved. A corrective action plan must be submitted. The plan must be comprehensive and include projected dates of completion for each corrective action. Failure to comply and response is not recommended.

Monitor, monitor, monitor. QC data and documentation. QC process, GCP and compliance. QC SOPs and implementation at each investigation site. Review regulatory requirements contactus@danteresources.com, danteresources@yahoo.com.

FDA IVDMIA Rule, PMA, 510(k) Application and Clinical Submission

2010-06-08T10:52:00.003-04:00

Often discussed today, is the delay by FDA on its final rule on In Vitro Multi-Variant Index Assays (IVDMIAs). The delay is mainly due to a request by the Office of Management and Budget. The delay will impact IVDMIA development, regulatory rigor and review, guidance, requirements and clinical submission via PMA, 501(k) and otherwise. In 2007, FDA released a draft guidance to the industry pertaining to governance, compliance, safety, effectiveness, substantial and certifiable equivalence. Since July 2007, numerous discussions, forums, conferences, working sessions with FDA and interested groups have taken place with best efforts to resolve FDA concerns pertaining to high risk to patient safety. The delay of course in the past 3 years have impacted companies that are application and clinical submission ready with go-to-market IVDMIA strategies and final image products and kits.

The delay, uncertainty and concern of FDA has slowed investor participation. Uncertain of regulatory rigor, requirements and thus timelines and costs, investors are shy to invest. ROI is uncertain. Approvals are uncertain. Pre- and post-market guided enforcements, surveillance and commitments by FDA involving IVDMIA are uncertain. Best efforts to release a final rule by FDA with interested parties in 2009-2010 are ongoing. Currently circulating since March 2010, is a "notice of proposed rulemaking" from FDA for IVDMIAs. The process allows a 60 day public comment, review and appeal period followed by a 30 day period for FDA, government response. Interested parties are hopeful for a final rule from FDA June 2010. Not likely. Maybe end of summer 2010, maybe end of year 2010. FDA's concerns are but not limited to:

high risk to patient safety
product effectiveness
product validity
clinical validation
clinical outcome determination
clinical diagnosis
clinical interpretation
product surveillance, pre- and post-market
regulatory enforcements, requirements and guidance
complicated, complex diagnostic array platforms
molecular and proteomic complexity
observation correlations between multivariate data and clinical outcome
IVDMIA considered a unique device, case by case
how to regulate IVDMIA devices to ensure a safe and effective intended use
patient reliance upon IVDMIAs with high risk diagnosis
patient reliance upon IVDMIAs and intended use to make health care decisions when FDA has not ensured that the IVDMIA has been clinically validated.

In the most current draft guidance, FDA emphasizes additional enforcement discretion. FDA considers IVDMIAs of high risk intended use since they include elements that are more complex than standard CLIA/LDTs and include unique interpretation functions that cannot be independently validated by clinicians. FDA seeks to identify and measure IVDMIAs as a discrete category of device. Companies must meet pre- and post-market device requirements under the Federal Food, Drug and Cosmetic Act and FDA regulations, including pre-market review requirements following Class II and Class III devices. Regulatory rigor and review, quality control, quality assurance, clinical interpretation of accurate, normal range determinations, false positive and false negative samples are a must. Quality process and management plans are a must. High quality sample and testing data is a must. For innovative development, application, 510(k), PMA clinical submission, FDA communication, quality data and monitored, project-lead and managed development contactus@danteresources.com, danteresources@yahoo.com.

FDA Form 1572 and Information Sheet Guidance May 2010

2010-06-07T12:40:00.005-04:00

The FDA form 1572 is a form that must be completed by clinical investigators worldwide prior to their participation in FDA-regulated clinical trials. Many clinical investigators, sponsor pharmaceutical companies and monitors still may not appreciate the growing complexities involved in completing the mandatory form, implications
of non-compliance or clinical submission. Last year, FDA issued numerous warning letters due to failure to complete and/or failure to file. Experienced clinical investigators continue to struggle with 1572 issues pertaining to:

satellite clinical sites
dispersion of study functions
qualifications
sub-investigator
co-investigator
legal/regulatory implications
legal contract considerations
appropriate expert standards
country-specific uses
collection of source documentations and process.

Offered at http://www.danteresources.com/ are the following pdf files for your download, information and use. Just released and published in May 2010, FDA offers a comprehensive, 17 page guidance on process, procedure, quality and otherwise for:

FDA Form 1572 - Statement of Investigators - Title 21 CFR Part 312.53(c)
FDA Form 1572 Information Sheet Guidance for Sponsors, Clinical Investigators and IRBs and Frequently Asked Questions.

Available at druginfo@fda.hhs.gov. Published May 2010, US Department of Health and Human Services, FDA, Office of GCP, CDER, CBER, Procedural Recommendations.

Who should read the guidance and understand the form? Clinical trials monitors, clinical investigators, site staff, research center compliance officers, CRC, CRA, QC, QA, IRB, CSTM, Regulatory Affairs Staff, Pharmaceutical Sponsors. Form FDA 1572 issues will trigger a Refusal to File, RTF as well.

FDA Action and Enforcement Involving Medical Product Misbranding

2010-06-03T18:13:00.007-04:00

FDA closely monitors the development, performance, safety and efficacy of drugs, diagnostics, biologics, personalized, combination, traditional, proteomics, genomics and delivery device systems as well as investigating illegal actions involving Internet "website" misbranding of drugs, claims, marketing, sales initiatives, advertising and otherwise. In 2009, for example, FDA coordinated a week long, global effort to uncover such illegal activities. Via the IIWA, FDA issued at least 22 warning letters pertaining to "website" illegal claim and misbranding activities involving:

service providers
domain name registrars
selling products violators
prescription drugs
pharmacies
counterfeit drugs
contaminated drugs
expired drugs
adulterated drugs
unapproved drugs
active ingredient inconsistencies
change of formulation
batch to batch, lot to lot deviations
CMC changes
counterfeit claims
altered medical devices.

Divisions at FDA working in conjunction with FDA's OCI, Office of Criminal Investigation, CDER, Center for Drug Evaluation and Research, Office of Regulatory Affairs, targeted 136 websites who were actively and knowingly engaged in the marketing and sale of unapproved and/or misbranded medical products and drugs. The penalties for such illegal actions are civil and criminal, resulting in imprisonment, fines, immediate company closure, loss of operating licenses and otherwise. The violations trigger immediate loss of service provider and domain name registrars, revocation, suspension and termination. Seizure and elimination of the illegal supply chain, drug, medical products and devices are immediate. The protection is enforced due to the medical risk and danger to patients and consumers trusting false, misleading, misbranded, illegal claims for profit.

The initiative was sponsored by the ICPO, International Criminal Police Organization, the World Health Organization's International Medical Products Anti-Counterfeiting Task Force, the Permanent Forum on International Pharmaceutical Crime and national health and law enforcement agencies from 24 participating countries. Immigration, Customs, Border Protection, US Postal and other government worldwide agencies were involved in the week long effort to curb civil and criminal "misbranding" activities.

Information pertaining to the warning letters issued by FDA pertaining to the information cited above may be found on fda.gov.

Monitor the quality, consistency, accuracy pertaining to branding and labels, claims. Adhere to agency compliance and meet regulatory requirements for all phases of medical product development, preclinical, CMC, clinical, application, implementation, surveillance, clinical submission, pre-approval, approval, post-approval commitments, advertising, marketing, branding, label requirements, claim substantiation and sales.

QC, QC and QC again. Monitor, monitor and monitor again. contactus@danteresources.com.

Proteomic Discovery, Development, Clinical Submission - From Peptides to Biomarkers

2010-06-02T19:36:00.004-04:00

Among new, emerging discoveries, personalized medicine, combination products, delivery systems, translational medicine is the discovery of peptide biomarkers, proteomics. Biomarker discovery is a dynamic area of R&D which is born from natural, native physiological and pathological processes in biological systems. The field of biomarker discovery and development - identification, classification, R&D, clinical development phase, transition and validation is currently under debate. A number of groups such as NIH, National Institute of Health Biomarker Definitions Working Group, Divisions at FDA and other regulatory agencies worldwide are in the process of establishing set criteria for proteomic biomarker development.

There are 3 types of Biomarkers:

Prognostic: capable of providing information on clinical outcome at the time of diagnosis, independent of therapy
Predictive: capable of providing information on the likelihood of response to a given therapeutic modality
Screening: capable of providing information on clinical diagnosis in the general population.

The developmental phases are commonly categorized as Discovery, Transition and Validation.

Estimated timelines for the development of a proteomic biomarker (total duration = 48 months) is provided in months:

Discovery 14
Prototype Assay Development 5
Pre-Validation of Assay 5
Assay Development 7
Clinical Validation 17.
Clinical Validation includes, 5 phases of development - preclinical, Phase 1,2,3,4.
The number of samples that must be collected and tested from discovery through validation into application and implementation increase in size in late phase development. Preclinical, POC, Proof of Concept samples collected and tested are usually small in number in discovery = 10, reaching hundreds in the validation stage, transitioning to thousands by the time of application to FDA and implementation.

Regardless of the type, a biomarker must demonstrate, under routine implementation methodologies and conditions of use how the marker impacts clinical management of a patient with life-threatening or terminal disease, either by improving patient outcome or QoL, Quality of Life or by lowering cost and time of patient care.

The quality, accuracy, reproducibility, consistency and integrity of data must be of high level and must be quality controlled, processed and assured. Quality management plans, SOPs, WIs, GCP, GLP, GMP and otherwise must be developed and meet compliance quality standards. All plans, procedures and processes must be developed in accordance with FDA regulatory requirements, guidance and guidelines for the year of the application/implementation. contactus@danteresources.com, danteresources@yahoo.com.

Personalized Medicine on the Horizon

2010-05-27T12:22:00.005-04:00

Personalized medicine is a broad term that covers a wide variety of therapeutic approaches which include drug/diagnostic combination products arising from discoveries in areas of pharmacogenomics, pharmacogenetics and genetic expression. The largest number of personalized medicine products available is for oncology. However, personalized medicine is already being applied to many other different disease indications. Product development is promising in disease conditions which include autism, autoimmune disease, cardiovascular, CNS disorders, HIV infection, osteoarthritis, osteoporosis, pain, diabetes, Lupus, Crohn, Renaud and others.

Personalized medicine, combination products include the identification of biomarkers and validation platforms. Validation new product platforms and test methods are noted in areas of analytical validation, clinical validation, regulatory validation, compliance validation, validation of clinical utility, validation of benefit.

Monitor, manage, QA, QC and review emerging "cutting edge" data and data concepts. Regulatory scrutiny promises to be challenging in the emerging field of personalized medicine. Data and documentation must be of high quality. Clinical study protocol and design is rigorous and difficult, but rewarding with promising statistically significant and clinically meaningful patient results and benefits. FDA and global regulatory agencies require adherence to quality procedures, processes, data collection, entry, management, reporting, analysis and regulatory, clinical submission. Data must follow industry and regulatory standards according to CFR, GCP, GLP, QMP, DMP, QC, SOPs, WIs and otherwise.

As with all emerging science and clinical R&D, companies participating in a new area of therapeutics face a number of challenging issues, strategic, logistical, tactical, hypothetical and theoretical. Pharmaceutical and diagnostic companies must come together in a rapidly changing field of medicine from different segments of the market, traditional and "cutting edge" and come to a common understanding and "working" approach and must interact with each other. R&D, product development and regulatory clinical submission processes and procedures, formats and otherwise must be managed by experts, statisticians, data managers, safety and efficacy review boards and opinion leaders. Seek experts, contact danteresources.com, danteresources@yahoo.com.

Drug/Diagnostic Combinations - Personalized Medicine

2010-05-25T19:23:00.002-04:00

Current widespread interest, industry, pharmaceutical, device, diagnostic, physician, patient and FDA is now focused on the development of drug/diagnostic combinations, drugs used to treat patients and diagnostic platforms that can provide information about how a patient may respond to treatment with that drug. The combination of drug (Rx) and diagnostic (Dx) is termed personalized medicine. The combinations are numerous and smart.

The personalized medicine approach provides numerous benefits for pharmaceutical and diagnostic companies, but most importantly, to the patient for several reasons. Most drugs are developed in accordance with the traditional development approach, Phase 1,2,3 clinical studies. Patients on clinical trial, must pass strict eligibility criteria to be enrolled and randomized to study treatment drug. Patients are informed of the study protocol design and experimental tests of the clinical trial. Patients are usually allowed participation from 18-65 years of age. Medical history is taken to assure the presence and diagnosis of disease or condition. Patient disease or condition severity is determined by scales, blood, urine, physical exam, EKG, baseline testing parameters. Patients with poorly defined underlying disease or complicated medical histories are still grouped in one category for treatment.

Much data is collected to ensure patient safety and patient well being on clinical trial. However, patients still experience adverse reactions, sometimes severe. Some patients respond to treatment drug and some patients derive no benefit from the treatment drug. The result of the traditional approach to drug development is that not all drugs work equally well in all patients. There are many factors that may affect how a patient may respond to a particular drug. Factors that may affect drug performance or patient risk/benefit, for examples are age, diet, environmental factors, psychological and physiological factors, genetic make-up of the patient, genetic changes via time and otherwise.

Therefore, it is not surprising that there is growing interest in the identification of methods and factors to determine:

which patients will respond well to a particular therapy
which patients are likely not to benefit from therapy
which patients are likely to experience adverse reactions and side effects caused by the therapy.

Hence the advancement of drug/diagnostic combinations or personalized medicine for patients.

Whether the approach to patient therapy is traditional or personalized medicine, quality data and documentation is mandatory. QC early in the planning stages of drug development plans and diagnostic test platforms. Contact http://www.danteresources.com/.

What is "STED"? Is STED Analogous to FDA's CTD?

2010-05-24T19:37:00.009-04:00

STED is the Summary Technical Document format preferred by FDA for international medical device regulatory, clinical submissions. STED is a global pilot, voluntary program for PMA and 510(k) applications. Proposed STED guidelines were developed in the last decade by the Global Harmonization Task Force (GHTF) composed of 5 participating country members. GHTF encourages submitters of medical device applications to participate in this ongoing pilot program to ensure conformity across government regulatory agencies. Participating regulatory agencies who promote international harmonization via STED are the US, Australia, Canada, the European Union and Japan.

Proposed STED guidelines seek to ensure global documentation format conformity pertaining to safety and performance of medical device products. STED , in principle, is similar to the acknowledged and accepted CTD, Common Technical Document, which ensures documentation and format conformity across international country-specific drug regulatory, clinical submissions.

CDRH encourages medical device manufacturer participation in the STED Pilot Program. Data quality is expected to be high level, accurate, concise, quality controlled and quality assured. Pertaining to individual and simultaneous country-specific medical device filing(s), PMA or 510(k), outsource to expert regulatory, clinical consultants to ensure data accuracy, documentation and format consistency. To ensure ROI and filing success with no RTF, Refusal to File, seek QC experts. Contact http://www.danteresources.com/.

Off-Protocol New Experimental Treatments

2010-05-24T11:56:00.006-04:00

Frequently asked by a clinical investigator and/or a patient is how to get information pertaining to "Off-Protocol" experimental, new treatments outside of clinical trial? There are a number of procedures to follow that will allow consent for clinical investigators and patients to obtain new off-protocol experimental treatments. While it is not true that you may always or even eventually get off-protocol treatments, the possibility if not limited to treatments which involve only FDA approved drugs. Off-protocol treatments may involve promising new drugs which have not yet been approved by FDA or other regulatory agencies worldwide.

Off-protocol, out of clinical trial treatments are not recommended. Even if you can get a treatment outside a clinical trial, that does not mean you should follow this type of practice. Indeed for many reasons, reasons pertaining to patient safety and quality control, off-protocol treatments are not advised. If you can find a treatment on clinical trial, I strongly recommend this type of practical participation for the patient. Clinical trial protocols are governed with regulations, guidance and FDA GCP, Good Clinical Practice to ensure patient safety and data quality management.

If an off-protocol treatment is pursued, there are usually considerable reasons for selecting treatment outside of clinical trial.

There might not be an open clinical trial available.
You might not qualify for the clinical trial.
The clinical trial is randomized and "blinded" and you need active drug vs the possibility of being randomized to a placebo treatment arm.
Travel to the clinical trial site is difficult, although usually worked out with the clinical site coordinator whenever possible.
Insurance may cover the off-protocol treatment, and sometimes the reverse is true. This seems to be case-dependent.
Life threatening situations.
Terminal illness.

Let me stress again that it is not my recommendation to seek off-protocol treatments. It is strongly recommenced to seek well controlled clinical trials that adhere to GCP and are governed by FDA guidance to ensure patient safety.

In few instances, off-protocol, outside of clinical trial treatment may make sense. Risk and benefit considerations must be fully investigated before any decisions are made by the patient, by the physician, clinic or otherwise. Quality and GCP must always be followed with patients in general, even with off-protocol treatments, however, it is difficult to monitor, manage and enforce.

Country Specific Orphan Drug Development and Clinical Submission

2010-05-19T21:52:00.004-04:00

Country specific regulatory requirements have been enacted to encourage the development and clinical submission of orphan drugs for off-label and compassionate use regarding patients with life threatening disease. Countries involved in the enactment are Australia, Canada, Germany, Great Britain, France, Netherlands, Switzerland and the US.

Each country participates in ICH. ICH guided, CTD and eCTD clinical submission components, data and documentation presentations, statistical analyses and format are for the most part generic. However, country specific CTD and eCTD clinical submission differences do exist. I strongly recommend early communication with each regulatory agency to ensure country specific CTD and eCTD clinical submission compliance and to agree on a definitive, comprehensive TOC for your orphan drug filing.

A question often asked by pharma pertains to country incentives. Due to the high cost of orphan drug development, yes, there are country specific incentives to encourage the development of orphan drugs. Canada provides incentives for orphan drug development to pharmaceutical companies, clinical investigators, IRBs, interested groups and otherwise. Europe and the US offer the greatest incentives for orphan drug development whereas, Australia and Switzerland provide cooperative incentives with other countries.

In all countries, as always, patient safety is foremost. Orphan drug safety and efficacy filings are reviewed with regulatory rigor by all agencies. Data is assessed for quality, accuracy and integrity irrespective of country. Documentation is reviewed for consistency. High quality data and documentation is standard and expected by FDA and regulatory agencies worldwide.

Emergency Use Authorization of Medical Products - Clinical Submission

2010-05-17T18:38:00.004-04:00

The Emergency Use Authorization (EUA) authority recently granted by Congress under Section 564 of the FD&C Act 21 USC 360bbb-3, permits the FDA/FDA Commissioner to authorize the use of an unapproved medical product or an unapproved use of an approved medical product under emergent situations. Under Section 564, the FDA Commissioner may allow emergency medical measures to diagnose, treat and prevent serious or life-threatening diseases or conditions caused by agents, when there are no adequate, approved and available alternatives. The FDA Commissioner, on a case by case basis, will seek advice from DoD, EUWG, ASPR, CDC, NIH, DHS, DVA and other Federal agencies as needed and appropriate.

Clinical Submission Format and Content - Section 564

paper or electronic
when paper, FDA recommends that a minimum of 3 copies be provided
table of contents
application for authorization may refer to previously submitted data and documentation to FDA
reviewable form
risk/benefit statement
well-organized clinical study reports
proof of safety and effectiveness
well-organized nonclinical study reports
well-organized complete assessments
well-organized analyses
well-substantiated interpretations of clinical and nonclinical safety and efficacy findings
other relevant data and documentation
clinical source data
nonclinical laboratory data
other relevant animal studies
clinical case report tabulations
clinical case report forms
clinical withdrawals
therapeutic failures
lost to follow-up data
adverse event information
all patients who died during study
supporting published literature
supporting references
certified translations of data and documentation.

Data quality is critical and a must. GCP, GLP, GMP and QC/QA statements, SOPs and plans must accompany the clinical submission. Well-controlled data and documentation will facilitate FDA review and authorization. Quality management of data, documentation, processes, procedures and systems is a must.

A quality controlled discussion of Risks and Benefits must include measures taken to mitigate risk and optimize benefit, document uncertainly and limitations, identify data gaps and provide contraindications.

QC, QC, and QC again, data and documentation to ensure accuracy and consistency with current and previously submitted FDA and other regulatory agency clinical submissions.

Data Quality and Validity in Clinical Trials, Presubmission and Clinical Submission

2010-05-13T20:30:00.003-04:00

During development, presubmission and clinical submission, investigational therapies and drugs are tested in a clinical setting with human subjects, providing data and assessments that must be reviewed with regulatory rigor, viewed with public confidence and assessed by pharma and FDA for safety and effectiveness. The importance of informed consent, human subject protection, data integrity and quality in clinical trials and clinical submission has been widely discussed over the last 50 years. It is well accepted that human subjects must not be needlessly exposed to risk in clinical trials that fail to yield data. There is widespread agreement among pharma and FDA that data from clinical trials and clinical submission must be of high quality.

Current processes for assuring data quality and validity were developed individually, by pharma companies, clinical investigators and FDA in response to various problems or crises rather than in a comprehensive quality management framework. Although the current system is successful, it has its flaws and is relatively expensive and time intensive. There is no consensus definition of "quality" as it applies to data from clinical trials and clinical submission. If you doubt that fact, please go to the CFR and check. Many changes pertaining to clinical practice, clinical trials and clinical submission, including the widespread use of automated systems, programming validation, computerized data entry, contract research organizations, increased multinational clinical trials, declarations, WHO and health care delivery systems affect data quality and validity.

Data quality and its validity must be managed, processed and controlled for all phases of clinical development, presubmission and clinical submission data. Approached early and with strict go/no regulatory decisions and data and quality management plans, human subjects are protected and data will be credible, consistent and concise.

Quality Data Pertaining to Clinical Submission - Pharma and FDA

2010-05-09T14:37:00.003-04:00

In my experience, greater communication between the pharma industry and FDA is needed when determining quality and adequate clinical submission data handling and cleanup. Pharma and FDA go to great lengths and great expense to ensure data quality. Industry's efforts ensuring clinical submission data quality includes but is not limited to:

checking source data and documentation in the field
the use of double data entry systems
the use of data process cleanup in-process checks
computerized data quality checks
the use of standard operating procedures for the review of data listings
the use of standard operating procedures to identify data outliers
the use of standard operating procedures to identify data inconsistencies
the use of standard operating procedures to identify data omission
the use of standard operating procedures to determine rate of data error
the use of validation systems to ensure quality data
the use of extensive documentation pertaining to data handling plans
the use of extensive quality management data plans
the use of extensive documentation plans pertaining to data inconsistencies
how to handle agreements when data changes are implemented.

Pharma and FDA both use qualified and experienced clinical submission individuals and teams in order to verify the quality of data.

QC
QA
Auditors
Medical Reviewers, Examiners
Statisticians
Analysis Programmers.

I am certain there is a duplication of effort between FDA and pharma to ensure clinical submission quality data. During an audit for example, FDA reviews all of the clinical submission data and not just the primary endpoints of safety and efficacy. The perception among pharma is that FDA Medical Reviewers and Examiners do not like to find any errors, omissions, or inconsistencies in clinical submission data, even in minor secondary variables and that the application will lose credibility should minor errors occur. Pharma's view is that there is no acceptable error rate. Not completely true! FDA has been proactive in developing regulations and guidelines to ensure quality data pertaining to clinical submission, electronic data formats, eCTD, CTD formats and backbones, nomenclature and terminology, and other related topics. There are obstacles however to joint efforts by FDA and the industry such as inconsistencies among FDA divisions and pharma in terms of computer hardware and software, computer literacy, review standards, integration standards, analysis standards, other related topics. Greater communication early in presubmission and clinical submission strategies and planning between industry and FDA to develop clinical submission data management and data quality measurements and guidelines for your submittable data would eliminate such data perception and help to manage concerns. Develop a communicative partnership with FDA early to ensure a "same page" approach to your clinical submission data and quality measures.

Preparation of a New Drug Marketing Application for Clinical Submission

2010-05-08T13:11:00.005-04:00

Preparation and the size of a New Drug Application (NDA) are determined by the number of clinical trials required to prove a drug's safety and efficacy. A clinical study involving a drug for the treatment of cancer might require only a few hundred subjects, whereas one involving a drug used for the treatment of cardiovascular disease can require more than 10,000 subjects. Other sections of an NDA that require extensive documentation include sections of preclinical pharmacology, toxicology, carcinogenicity, chemistry, manufacturing and controls (CMC) and information pertaining to the eventual drug label.

The scope of presubmission and clinical submission formal meetings between industry pharma sponsors and the FDA are defined in NDA regulation and guidance documents available at FDA or online at fda.gov. Verbal, frequent communication is strongly recommended between the sponsor regulatory functions and review divisions at FDA.

An End of Phase 2 meeting is strongly recommended with FDA. The minutes of the meeting must be documented, agreed and archived at the sponsor location and FDA. As a rule, correspondence with FDA must be periodically reviewed on the path to clinical submission to ensure completeness of submittable requirements. The timing of the End of Phase 2 meeting is strategic to the advancement of sponsor and FDA understanding of the NDA to be filed. Prior to the End of Phase 2 meeting with FDA, a Briefing Document must be prepared by the sponsor. Included in the End of Phase 2 Briefing Document are key considerations pertaining to the overall preclinical and clinical development plans, adverse events of interest, clinical trial study design, statistical analysis plan, a Q&A section pertaining safety and efficacy findings and a proposed overall clinical submission Table of Contents (TOC). Failure to take full advantage of these meetings with FDA will lead to expensive delays. Communicate with FDA often and with transparency.

The key consideration in preparing an NDA is the number of pivotal clinical trials needed to demonstrate safety and efficacy of a new drug in Clinical Phase 3. With a new drug, 2 adequate and well-controlled clinical trials are generally needed to establish the safety and efficacy of the new drug. For oncology or orphan drugs, however, the acceptability of one pivotal clinical trial may be negotiated with FDA. Considerations pertaining to superiority and equivalence clinical trials must be discussed and agreed with FDA as well and will impact the number of subjects included in the overall clinical submission.

Discussion with FDA early in the NDA process will also aid in the determination of time to clinical submission, time to drug approval, time to market, related costs, capacity and resource considerations. Proper tracking of clinical submission requirements become realistic and achievable. Clinical submission leadership and issue management are more focused and transparent.

Presubmission and Clinical Submission Data Collection

2010-05-06T11:07:00.002-04:00

A central issue in data collection is how to identify relevant, high-quality data that are readily available for appropriate decision making and to do so in a cost-effective, timely manner, within realistic, projected managed timelines. What is high-quality data? High-quality data refers to data that can be used without further revisions or data that will produce conclusions and interpretations that would be derived from error-free data, data that are accurate, reliable and ready for use. The key to producing such high-quality data is to engineer data quality into the entire preclinical, clinical trial, presubmission and clinical submission process, early in the program.

The factors critical to the successful retrieval and collection of high-quality data begins far upstream from the clinical trial or the start of your FDA Briefing Document and/or halfway through Clinical Phase 3 on your way to clinical submission. High-quality procedures affect all stages of preclinical, clinical trial, presubmission and clinical submission data.

Lets begin with the clinical protocol. The protocol should have:

clear, specific objectives
objectives that must be in a testable hypothesis form and design
well-defined target population with specific criteria
specific criteria for inclusion and exclusion of study subjects
a study design that is relatively simple, because complexity introduces error
relevant, achievable endpoints, primary and secondary
a detailed schedule of activities and observations
a process and standard of operation that address steps taken to assure and ensure high-quality data.

High-quality data provides FDA with scientifically valid data, statistically significant, clinically meaningful, data with confidence and credible endpoints and objectives, ready for review and decision. The return on investment when assuring and ensuring high-quality data is immediate and immeasurable.

Performance Management, Clinical Submission Data Governance and Quality

2010-05-05T09:40:00.004-04:00

Establishing a standard of operation and a business case for data and clinical submission quality improvement hinges upon the ability to document the pains incurred by identifying errors from day to day. The standard of operation to ensure good quality data and clinical submission are not easy, in fact tedious, but worthwhile and requires leadership and relentless management. The task of segmenting flaws and errors across pharma functions and business units involved with the data and clinical submission is daunting. The impact of data and a clinical submission that lacks quality impacts all pharma and business units from low to high levels of negative perception with FDA and financial projection attributable to "bad data". Reviewing the scale of the data and clinical submission failures based on their corresponding negative regulatory perception, and financial impact will suggest ways to prioritize remediation and "corrective action" and "quality management and change control".

Identifying data and clinical submission flaws, inconsistencies and errors, relies on data quality tools, protocols, processes, procedures and monitoring by an experienced team of quality reviewers and auditors. Data flaws, inconsistencies and errors are not readily seen. So, the process of improving data and clinical submission quality is not an easy task.

However, the challenge in employing the concept of return of investment for justifying the finding of an improvement project to improve quality of data and clinical submission is the ability to monitor, over time, whether the improvements implemented through the project are facilitating positive impacts, for examples, shorter timelines, reduced costs, improved regulatory perception, ease of review, improved credibility with all agencies, enhanced approval perception, reduced time to market, reduced risk management, decreased delays - control surprises.

The New 510(k) Paradigm for Clinical Submission to FDA

2010-04-29T12:03:00.002-04:00

The new 510(k) clinical submission method for medical device and diagnostic kit provides 2 optional approaches to the Traditional 510(k) method for obtaining 510(k) marketing clearance under certain instances:

Special 510(k) clinical submission
Abbreviated 510(k) clinical submission.

The Special 510(k) utilizes certain aspects of the QSR (Quality System Regulation) and the Abbreviated 510(k) relies on the use of guidance data, documents, quality-controlled, assured for accuracy and consistency, special controls, processes and recognized standards to facilitate the 510(k) review. The Traditional 510(k) clinical submission is the original complete submission to FDA in accordance with 21 CFR 807. FDA developed the new paradigm to "streamline" the evaluation of Premarket Notifications under special and abbreviated conditions as warranted and as regulated.

As always, fda.gov, provides a "go to" section where interested parties may find clarity - "Frequently Asked Questions" on the New 510(k) Paradigm.

Clinical Submission of a 510(k) is sent to FDA and logged in by the document Mail Center, the 510(k) is sent to the appropriate reviewing division for the type of device or diagnostic kit. Delivery to the proper review division will be facilitated by completing information on the Cover Sheet and Cover Letter, such as advisory panel Code of Federal Regulations reference and product code. Upon receipt in the proper reviewing division, the reviewer utilizes the Pre-Review Form, Company/Device or Diagnostic Kit Form, as an initial screening tool. The reviewer "will" use the Screening Checklist for Traditional, Abbreviated and/or Special Premarket Notification 510(k) Clinical Submission Form to assure that the 510 (k) is administratively complete. If the file is not complete and comprehensive - a refusal to file, RTF will issued and the file sent back to the submitter. QC the file, QC the contents, QC the Table of Contents for accuracy and completeness. Ensure a successful 510(k) clinical submission filing - utilize QC. QC to ensure that the contents provided to FDA in the Cover Sheet, Cover Letter and the contents of the 510(k) are consistent, concise and accurate.

Clinical Submission of a Premarket Notification Application / 510k

2010-04-28T16:20:00.007-04:00

The Food, Drug and Cosmetic Act 501k requires medical device and diagnostic kit companies, manufacturers, importers and/or exporters to register their product with FDA at least 90 days prior to the intended time to market.

A question often asked by a client is...must I submit a 510k Premarket Notification Application to FDA?

Manufacturers, importers, exporters and otherwise of Class I, II, or III device and/or diagnostic kits are required by FDA to file a 510k. This includes:

Device or diagnostic companies, manufacturers, importers and/or exporters wishing to introduce a new device to the US market
Specification developers that design a device or diagnostic kit and have it manufactured by another company for eventual sale in the US
Companies that are proposing a significantly different design or different intended use for a product that is already sold in the US
Companies that repackage or relabel device or diagnostic kits.

There are 3 types of 510k Premarket Notification Applications:

Traditional 510k clinical submission
Abbreviated 510k clinical submission
Special 510k clinical submission.

Clinical submission of a Premarket Notification Application to FDA by the medical device, diagnostic kit company, manufacturer, importer, exporter or otherwise, must contain specific data and documentation, quality controlled systems, standard operating procedures, quality management plans, detailed for each type of product and its intended use.

What is the first clinical submission step when considering your Premarket Notification Application to FDA?

The first step is to determine the classification of your medical device or diagnostic kit. There are 3 classes, I, II or III with specific criteria that must be met for each class.

Medical Device or Diagnostic Kit Class I, II, III - FDA 510K Application and Clinical Submission

2010-04-28T09:09:00.007-04:00

A definite change in clinical development direction has taken place in the pharmaceutical industry. A shift from the clinical development of NCE drugs to the development of genomics, biologics, biomarkers is on the rise. Interest, today, is focused on the clinical development and application of medical device and diagnostic systems.

Early 2005, a marked increase in the interest of 510K applications was noted and continues to rise in 2010. The 510K approval process for medical device or diagnostic kits, when compared to that of a drug requires less time and investment funding. Medical device or diagnostic kits, may be classified as Class I, II or Class III, a 510K marketing approval is necessary to market the product in the US. Application process and approval in Europe are different. For the US, the clinical submission approval requires compliance to the CFR, Part 820 Quality System Regulations, Good Manufacturing Practices and the other applicable CFR requirements for product type and indications of use.

510K Process - Important Facts:

Establishment involved in the production and distribution of medical device and diagnostic kits intended for marketing or leasing in the US are required to register with the FDA. This process is know as Establishment Registration. Registration provides FDA with the location of manufacturing facilities and importers.
A 510K application is made to FDA to demonstrate that the medical device or diagnostic to be marketed is at least as safe and effective, substantially equivalent.
A 510K application requires demonstration of submission equivalence to another legally US marketed medical device or diagnostic.
The holder of a 510K must have design control data and documentation available for FDA review during a site inspection.
Any changes to medical device or diagnostic specifications or manufacturing processes must be made in accordance with 21 CFR 820 and may be subject to a new 510K.
FDA does not perform 510K "clearance" facility inspections.
The submitter may market the medical device or diagnostic immediately after 510k approval is granted.
The manufacturer should be prepared for an FDA "quality system" 21 CFR 820 inspection at any time after 520K approval.
The CE determination is usually made within 90 days and is made based on the information submitted by the submitter.
The FDA charges a one time fee to review the 510K application.

CDER/FDA Regulations Regarding Foreign Clinical Trial Data

2010-04-20T10:48:00.003-04:00

A pharma sponsor who wishes to rely on a foreign clinical trial data to support US IND and/or NDA application for marketing approval must comply with FDA regulatory rigor and meet specific criteria for data submissions under the auspice of CFR requirements.

21 CFR 312 (b) describes regulatory requirements for FDA acceptance of foreign clinical trial data and "detailed" descriptive procedures for study submission:

Description of investigator qualifications
Description of clinical study site qualifications
Description of research facilities
Detailed summary of the clinical protocol
Detailed description of the clinical trial study
Detailed subject case records, case report forms and source documentation
Investigator subject records
Description of drug product, including components, formulation, drug substance specifications
BA/BE data
Detailed documentation of drug efficacy and effectiveness in accordance with GCP and 21 CFR 314.26.
Detailed documentation to demonstrate clinical trial conduct
Detailed documentation to prove adequate and well-controlled clinical protocol.

CDER/FDA Regulations Regarding Foreign Clinical Trial Data

2010-04-18T10:53:00.002-04:00

In the last 5 years, use and submission by pharmaceutical companies of non-US (foreign) data to FDA is on the rise. FDA sets conditions in the CFR Register under which such data can be used in support of clinical research, clinical submission and marketing application approval in the US. Non-US data must be reviewed for regulatory rigor, quality, statistical confidence, therapeutic value and clinical significance. I strongly recommend that a due diligence review and quality audit be performed on all non-US data and documentation prior to integration and submission to FDA.

CDER/FDA Requirements:

Foreign studies are conducted under a filed IND with FDA
If the studies are not conducted under a filed IND with FDA but meet criteria specified in FDA CFR regulations, exceptions to include non-US may be granted
Foreign data and study documentation, final study reports must meet US IND 21 CFR 312 requirements.

CDER/FDA may accept foreign studies not conducted under a filed IND if the studies are:

Well designed
Well conducted
Performed by qualified clinical investigators
Performed at qualified clinical sites
Conducted in accordance with ethical principles acceptable to the WHO
Conducted in accordance with the Declaration of Helsinki
Conducted in accordance with laws and regulations of the country where the clinical research is conducted
Country-specific regulations meet standards set forth by with CDER/FDA - 21 CFR 312.120(a).

CDER/FDA - Clinical Investigator Responsibilities - Informed Consent Form 1572

2010-04-14T20:03:00.003-04:00

Accurate execution of FDA Form 1572 is critical to FDA regulatory requirements and GCP compliance, as well, will ensure the subject is fully informed of their rights, benefits and risks of the investiagtional drug. It is the responsibility of the sponsor and the clinical investigator to ensure the informed consent accurately explains clinical trial conduct and protocol procedures.

Form 1572 includes names of investigators and sub-investigators who will be participating and/or assisting in the conduct of the clinical investigation. Proper execution of Form 1572 - the investigators make a commitment to:

Follow current clinical protocol
Personally conduct and/or supervise the clinical investigation
Ensure all persons assisting in the clinical trials are informed of obligations
Inform subjects of investigational drugs
Ensure informed consent (21 CFR Part 50) and IRB review, approval and reporting (21 CFR Part 56) are conducted under GCP compliance and FDA regulatory requirements
Report to pharma sponsor all adverse events (21 CFR 312.64)
Inform all clinical site associates of changes to protocol
Maintain adequate and accurate records and make available all records and source documents for FDA/DSI inspection, for cause or otherwise (21 CRF 312.68)
Ensure initial and continuing review by IRB
Report all changes to protocol and clinical research
Report all anticipated or unanticipated problems involving risks and benefits to subjects
Ensure no changes to the clinical protocol in general
Ensure good clinical conduct
Ensure that no changes are made to the clinical protocol without IRB approval except where necessary to eliminate immediate hazards and life-threatening events to subjects
Comply with all FDA regulatory requirements in 21 CFR 312.

CDER Assessment of FDA Regulatory Requirements - Sponsor and Clinical Investigator Compliance with GCP

2010-04-12T19:51:00.002-04:00

How does CDER assess FDA regulatory requirements pertaining to sponsor and clinical investigator compliance with GCP?

Sponsor Responsibilities (21 CFR 312.50-312.58) - General and Specific Responsibilities of Sponsors include:

Select qualified investigators
Provide investigators with the information they need to conduct an investigation properly
Ensure that the investigation is conducted in accordance with the protocol
Maintain an effective IND for the investigators
Maintain an effective IB for the investigators
Maintain an effective communication with the investigators
Ensure that FDA and participating investigators are promptly informed of significant new adverse events or risks with the clinical trial drug
Ensure that FDA and participating investigators are promptly informed of significant changes to the protocol
Ensure that FDA and participating investigators are promptly informed of significant new data, preclinical, clinical, same chemical class or otherwise
Ensure that sponsor and investigators protect subject rights on study.
More to come...

CDER's Role in FDA's BIMO, DSI and GCP Goals

2010-04-11T12:54:00.005-04:00

CDER's role in FDA's Bioresearch Monitoring (BIMO) Programs and Human Subject Protection primarily focus on 4 areas which are Compliance, DSI Manufacturing/Product Quality, Compliance Risk Management/Surveillance and the Division of New Drugs/Labeling Compliance.
In an earlier post, goals of CDER's BIMO were clarified and presented.

What are the goals of CDER's FDA's DSI and GCP divisions?

DSI - For the Review Divisions -

DSI will arrange for routine data audit GCP inspections to determine data quality, data integrity and safety of subjects in pivotal clinical trials and provide the inspection reports to the review division prior to the Division Action Goal Date.

DSI - For the Public -

DSI will investigate complaints related to the conduct of clinical trials, including arranging for directed or "for cause" inspections and take appropriate regulatory action.
DSI will arrange for routine surveillance inspections of IRBs to determine if rights, safety and welfare of human subjects are protected.

DSI - GCP -

Issue assignments to the Office of Regulatory Affairs (ORA) field investigators and participate on inspection when expertise is required.
Evaluate the results of inspections from a scientific and regulatory perspective.
Recommend and implement regulatory actions.
Provide expert advice on program design, policy issues and guidance.
Educate and inform program constituents - communication within CDER, FDA, otherwise.

CDER's Role in FDA's Monitoring and Subject Safety

2010-04-07T19:27:00.006-04:00

Several companies recently requested clarity pertaining to CDER's role in FDA's Bioresearch Monitoring Program and Human Subject Protection. The Center for Drug Evaluation and Research (CDER) consists of the following offices and divisions:

Office of the Center Director
Office of Compliance
Division of Scientific Investigations (DSI)
Division of Manufacturing and Product Quality
Division of Compliance Risk Management and Surveillance
Division of New Drugs and Labeling Compliance.

The Division of Scientific Investigations (DSI) consists of a Director, Deputy Director, Field Investigator, Good Clinical Practice (GCP) Branch 1, GCP Branch 2 and Good Laboratory Practice (GLP)/Bioequivalence and Quality (BEQ).

CDER's Bioresearch Monitoring (BIMO) Inspection Programs consist of :

Clinical Investigators
Sponsor/Monitor/CRO Investigators
IRB/RDRC Investigators
Bioequivalence/Good Laboratory Practice Investigators.

The goals of BIMO:

validity of data from studies in support of pending marketing applications
adherence to FDA GCP/GLP/BEQ regulations
whether the rights and safety of subjects have been protected.

More to come on CDER's role and organization...

Annual Safety Report - Table of Ongoing Clinical Trials

2010-04-04T19:39:00.002-04:00

Annual safety reports all include a table of past, present, ongoing, completed and proposed clinical trials as per FDA requirement and rigor. In some instances, a 6 month safety report is requested and required by FDA. For the 6 month safety report, a table of ongoing clinical trials will suffice. The table will include information for all ongoing clinical trials at the time of the safety report submission and will include information pertaining to each ongoing clinical study:

study number
study subjects treated
study design
study status
study dosing
study type
number of clinical study investigative sites
date of first subject screened
date of first subject randomized
date of first subject enrolled
date of last subject enrolled
date of last subject completed.

A safety "cut-off" date is agreed to between pharma and FDA for the reporting period for the 6 month safety report. Remember to review previously submitted safety materials, submissions, narratives, reports and otherwise to ensure accuracy and consistency of data and documentation and reporting - current, ongoing vs. all previously submitted. Remember, safety of the patient or subject on clinical trial is the primary objective of FDA and supersedes the evaluation of effectiveness and efficacy objectives at all times during, pre-, post-submission...all approvals.

Annual Safety Report Composition and Quality Control

2010-04-04T18:04:00.003-04:00

Annual Safety Reports (ASRs) are required by pharma each year for a drug, device and/or biologic, under clinical development and is triggered by an anniversary date linked to safety timelines, IND, CDP, subject exposure, safety of subjects on clinical trial and serious adverse reports (SARs). The Table of Contents (TOC) is much the same, generic in fact, for clinical development programs with agreed upon expansion, between pharma and FDA. An Annual Safety Report TOC for a inhalation device delivery system for example is presented below.

List of Appendices

List of Abbreviations and Definitions of Terms

Introduction
Review of Subjects Safety on Clinical Trial
Overall Safety Evaluation
Conclusion

Appendix A

Appendix B

Appendix C

Appendix D

Section 2, Review of Subjects Safety on Clinical Trial...

Relation of Safety Information with Dose, Duration and Time of Onset of Adverse Reaction
Reversibility of Serious Adverse Reports (SARs)
Previously Unidentified or Other Increased Frequency of Adverse Reactions
Overdose
Drug Interactions or Other Associated Risk Factors
Special Subject Groups
Pregnancy and/or Lactation
Product Abuse
Risks Related to the Investigational or Diagnostic Procedures of the Clinical Trial
Risks Which Might Be Associated with Insufficient Quality of the Investigational Medicinal Product.

ASR submission supporting text, data and documentation must be referenced, appended and quality controlled and quality assured. The ASR is submitted electronically to FDA and is expected to be received on the anniversary date for the ASR. There must be an appendix which includes a line listing of all suspected SARs (Appendix A) and another appendix (Appendix B) with a summary tabulation of all suspected SARs. It is strongly recommended that the line listing and the tabulation of all suspected SARs are quality controlled for consistency, data, documentation and accuracy vs. ASR intext tables and text.

Pharma Expansions, Mergers and Acquisitions - Clinical Operations - De-centralization vs. Centralization

2010-03-30T10:13:00.007-04:00

Recently and due to expansions, mergers and acquisitions, I was approached by pharma to assess and develop and implement a more centralized clinical operations function. With a pipeline of promising new products and rapid growth, the pharma's clinical operations organization expanded considerably and rapidly, becoming fragmented. This fragmentation generated operational inefficiencies and lethargic performance due to several business models existing under the same roof, serious communication issues, a loss of focused leadership, a de-centralized team, duplication of resources, capacity, responsibilities and accountabilities. Certainly, in addition, lost timelines, target dates and quality were sacrificed in the expansion.

This is now a common issue throughout the pharma industry with current expansions, mergers and acquisitions. The assessment required the development and implementation of a new internal and external re-structure, plan and operational process moving forward. The new structure included a good deal of re-work pertaining to, but not limited to, internal and external functions, outsourced resources, leadership, management and strategic planning.

As the pharma company prepared for its first clinical and regulatory submission to FDA, EMEA, and product launch, there was a great need to identify, process and communication bottlenecks and determine which of its functions required the most improvement in a limited time. Short term, long term objectives. Gaps and stumbling blocks in the pharma company's processes were identified and worked through to improve the pharma company's clinical trials operations, performance and quality, good clinical practice. In-depth assessments, process and quality forensics, data and documentation audits focused on short and long term objectives, outlining the best practices. Opportunities for improvement were assessed and implemented. The implementation plan was agreed upon by all functions, all teams, all CROs, inhouse and outsourced, external. An implementation guide was developed for the pharma and was critical to the execution of the prioritized recommendations. Bridging the gap between corporate leaders and operational staff, team and functions was the main key to improvement. Re-build and revise, budgets, processes, standards of operations, plans, optimize alliances, internal and outsources and maximize efficiency and leadership. Key short term objectives.

Optimize focus groups of operational staff, CRAs, CTMs to solve operational problems as they arise.
Provide a no consequences feedback mechanism from operational staff to corporate leadership thereby opening communication.
Perform a where, when, who and why responsibility trail and train to clarify roles and decision makers.

Phase 4 Clinical Research - Increasing Importance to "Buyers"

2010-03-29T15:48:00.005-04:00

Phase 4 clinical research data provides key groups and decision makers with important information pertaining to the safety and efficacy of a drug once approved by FDA. Data and documentation must find its way to physicians, insurance providers, buyers, opinion leaders, pharma sales force and of course FDA, for purposes of review, promotion, education, prescribing, retail, regulatory rigor, patient safety.

Phase 4 clinical research has increasing importance for distributors when helping consumers understand product labels, PDR, package inserts, product brochures. With increasing consumer demand for drugs, natural products, and otherwise, there is more need for research and in-store nutrition knowledge within the retail sector. Sales, marketeers and retailers must be well informed about the products they distribute and sell. Retailers have an important role in explaining nutrition product labels to consumers. This presents opportunity for natural product suppliers to utilize clinical research, in conjunction with market and outcomes research to train and educate their distributors using their product's clinical trial data and documentation.

Opportunities such a advertising displays, promotional items, leaflets, brochures, manuals, pamphlets, videos, infomercials, and otherwise must be used by distributors so they can market to their consumers. Phase 4 clinical data and documentation must be quality controlled and collected with regulatory rigor and good clinical practice. All promotional information whatever form of media used to educate, disseminate and/or train, must also be quality-reviewed and quality-controlled. Phase 4 clinical research must be transcribed, translated, presented and summarized with quality control, consistency, version control, precision, clarity, consistency of claim, statement, storyline and accuracy. Engage experts in quality. Engage gate-keepers who ensure version control of didactic, Phase 4 clinical research, promotional materials, data and documentation worldwide.

2010-03-29T15:48:00.000-04:00

The Importance of the Sales Team - The Importance of Quality and Communicated Phase 4 Clinical Research

2010-03-28T11:03:00.004-04:00

Key target groups must be involved with drug safety and efficacy throughout the life cycle of the drug once approved by FDA. Key groups are physicians, providers, opinion leaders, sales, buyers and FDA. Sales Team - Although not a target group, the sales force must nonetheless be a priority for any pharma engaging in direct to physician sales. The sales team acts as the spokesperson between the pharma/product and the physicians. Pharma must proactively and continuously keep members of the sales force educated on the benefits (and risks) of the product. The degree of success of the pharma sales team directly influences the revenue, ROI, generated for the pharma and the longevity of the brand in the market.

Sales and marketing groups must be proactively informed with consistent, up to date, quality-controlled, clinical trial data and documentation. Global ongoing Phase 4 clinical trials generate global data and documentation. The data and documentation must be organized and managed by experts who serve as gate-keepers for data and documentation version control. Gate-keepers, who are quality control experts in compliance, quality and regulation, ensure quality review and presentation of accurate and adequate, safety and efficacy data and documentation and must interact with marketeers worldwide. Phase 4 clinical research is of course, worldwide.

Remember, every communication to the physician, the patient, the key groups...abstract, newsletter, data, database, clinical protocol, Phase 4 clinical submission, CSR, CTR, expedited safety report, periodic safety update report, annual report, safety narratives and otherwise must be in compliance with regulatory rigor and FDA, Code of Federal Register (CFR) and must be consistent in data, storyline, presentation, statement, claim, product label, previously submitted clinical submission dossiers and must demonstrate clinical, therapeutic application and statistical significance, worldwide. Monitor the clinical trials, monitor the monitors, monitor the quality of the data, review all source documents, follow good clinical practice. Engage experts.

Phase 4 Clinical Research - The Role of Key Opinion Leaders

2010-03-27T11:08:00.003-04:00

Phase 4 Clinical research data provides current information pertaining to an FDA approved drug in the marketplace and in a real life setting. The drug, once approved by FDA, must be monitored with rigor for safety and efficacy by pharma throughout the life cycle of the drug product. Pharma especially, must closely monitor and adhere to safety surveillance and risk marketing plans agreed to with FDA before granting approval to market. In earlier posts, we spoke of the contribution of physicians and health care providers and their role in the dissemination of clinical research data and documentation to key target groups. Key Opinion Leaders, another target group, as well, have a unique position in the dissemination of clinical data and documentation to interested parties.

Effectively marketed clinical data to Key Opinion Leaders (KOLs) is a critical huge factor in gaining full product support in the marketing arena. KOLs are expert physicians who have influence over medical practice. KOLs are sought out groups of experts who set the pace for industry trends. KOLs will share a wealth of information and insight ranging from clinical science to advertising concepts and provide highly credible exposure for a product in the medical community through speaking engagements, published articles in medical journals and general practice. Engage KOLs in market research and medical symposiums. Engage KOLs with the latest clinical research early and throughout the product's life cycle. Engaging KOLs early in marketing practice and plans will ensure pharma with an invaluable feedback and insight throughout the life of the product and thus increased marketing exposure in clinical practice. KOLs are essential to quality. KOLs are essential to ROI.

Responsibility to Disseminate Clinical Research and Educate Key Target Groups

2010-03-25T15:16:00.004-04:00

Clinical research data from Clinical Trial Phases 1, 2, 3 and 4 provides the most up to date scientific objectives and prescribing information for an approved drug. Pharma must educate all key groups who have a vested interest in the well being of the patient throughout the life cycle of the drug. Dissemination of information to at least the following primary constituents is a must.

Health Care Physicians
Health Care Provider's - A provider's responsibility is to provide health care that is effective, affordable and satisfactory to as many people/patients as possible. When new products have entered the market, health care providers are primarily concerned with clinical research that demonstrates information pertaining to patient tolerability, safety and effectiveness. Clinical trial research is paramount for adequate development of "friendly and patient focused" health plans. In today's medical culture where the paradigm has shifted from the physician to the patient, health care plan companies see the need to become more patient-oriented. This presents huge opportunities for pharma companies to work with in-house and external clinical researchers and spearhead additional types of clinical research.
Buyers, Consumers, Distributors
Key Opinion Leaders
Sales and Marketing
FDA.

Responsibility to Disseminate Clinical Research and Educate Key Target Groups

2010-03-25T09:22:00.009-04:00

Questions often asked - Can clinical research be used to disseminate and educate key target groups? Who is responsible for the dissemination of product information once the drug is approved by FDA? The answers are yes and the responsibility of pharma primarily as per post-marketing commitment plans with FDA, respectively.

It is the responsibility of pharma to continue to investigate, elucidate and clarify safety and efficacy benefits and risks for the life cycle of the drug once approved by FDA. Clinical research provides the most up to date scientific intelligence pertaining to drug mechanism of action, safety, tolerability and effectiveness. Clinical research assists key target groups and decision-makers, physicians, health care agencies, health care providers, health care payers, patients, buyers, M&A, key and expert opinion leaders, shareholders, stockholders, sales and marketing, FDA and regulatory agencies worldwide and otherwise to make clinically and meaningful decisions.

It is essential for the pharma industry to educate and disseminate, well monitored, well audited, integrated, summarized quality data and documentation to relevant and appropriate communities and interested parties.

Physicians - It is ideal, especially for pharma companies that health care professionals base their prescribing decisions on supporting evidence provided by quality clinical submission, regulatory approved data, statements and documentation. Prescribing code reinforces that professional exchanges with the medical community are designed to benefit patients and medical practice. The more robust the clinical evidence, data and documentation, the better the case for that drug to be prescribed. Now more than ever, during the post approval period and life cycle of the drug, there is, as well, a good opportunity to more define the product's ROI - return on investment, with continued clinical research.

More to come...

Health Care
Health Care Payers
Key Opinion Leaders
Sales and Marketing
Buyers, Patients, Distributors, Consumers
FDA.

The Importance of Phase 4 Clinical Research

2010-03-24T20:29:00.003-04:00

Often the question arises - What is the importance of Phase 4 clinical research? In an industry, that is heavily regulated and scrutinized, pharmaceutical brands must not only go through Clinical Study Phases 1, 2 and 3 to validate the drug's safety and tolerability, but as well, testing of the product to monitor its safety and effectiveness in a real-world setting and after the product is approved for marketing is a must and is required by FDA.

Post-marketing clinical research trials, used interchangeably with Phase 4 testing, is a phase that takes place after a product is available on the market for public use and is subsequently used to track a product's safety and tolerability in a real-world setting. Marketers in the pharma industry know that the clinical research needed to market and sell a drug product is quite different than research needed to gain FDA approval.

In addition to post-marketing surveillance, Phase 4 clinical studies are also helpful in developing a marketing strategy for a product. In fact, post-marketing research gives insight into questions and concerns raised earlier in Pre-Clinical and Clinical Phases 1,2 and 3. Not only does Phase 4 research allow pharma companies to monitor for real-time effectiveness, long-term safety and tolerability, but it may also give rise to evidence for possible new indications, new markets for which the drug product had not been initially approved. The value of conducting post-marketing clinical research is required by FDA to continue to ensure patient safety post-submission, post-approval, post-marketing. In my opinion and to ensure data with integrity, monitoring post-marketing clinical studies requires quality control, good clinical practice, quality standards of conduct and operation as well as regulatory rigor. Monitor the monitors. QC/QA the data.

The Necessity of Phase 4 Clinical Trials

2010-03-21T18:18:00.004-04:00

Is there a necessity for Phase 4 Clinical Research and Clinical Trials? Of course, the answer is yes. Before drugs are marketed, drugs are considered clinical candidates. During Clinical Phases 1, 2, and 3, pharma studies are designed to test, determine and validate the overall efficacy and safety of the drug. Clinical Phase 1, 2 and 3 processes can take many years, filled with trials and errors. If FDA's action is to approve the drug after advisement, review and regulatory rigor, the pharma company is required to ensure that unanswered questions, viewed by FDA to be time sensitive, are answered.

Unanswered questions, for examples...

How safe and effective is the drug's use in a diseased population
How safe and effective is the drug's use in a compromised patient
How safe and effective is the drug's use in special patient populations
How safe and effective is the drug's use in a diseased population with varying degrees of illness, mild, moderate, life-threatening
How safe and effective is the drug when used by a patient with more than one illness
How safe and effective is the drug when taking multiple drugs
How does the drug product compare in safety, efficacy and tolerability with other products in its class
What are the risks of the drug
What are the benefits of the drug
Do the benefits outweigh the risks.

A comprehensive Phase 4 post-marketing safety surveillance plan/risk management plan developed by pharma and agreed with FDA is the essence of the Phase 4 clinical program. Phase 4 respective plans are developed to answer questions pertaining to drug performance, safety, efficacy and use. Data from Phase 4 clinical trials is essential to:

Pharma and FDA in order to adequately evaluate patient safety post approval
Pharma who face the daily challenges of answering post-approval questions
FDA who closely monitors safety AE and SAE reporting during the post-marketing period.

More to come...

Post-Marketing Phase 4 Clinical Trials - Pharmaceuticals vs Natural Products

2010-03-17T14:49:00.006-04:00

Recently, a number of questions arose by pharma and industry pertaining to the similarities and/or differences between post-marketing (Phase 4) clinical trials comparing pharmaceuticals vs natural products. First, the main similarity is that all have a definite health benefit and have therapeutic value. Secondly, FDA's "current" approval process is very different for natural products, there is no Phase 1-3 clinical program per se, until of course, FDA "knocks" on your door. It is no surprise that Phase 4, post-marketing clinical research and clinical trials have become the fastest growing area of clinical research today. The stakeholders for the natural products industry remains the same as for pharma, such as but not limited to: consumers, patients, homeopathic, herbal practitioners, physicians, complimentary health professionals, naturophilics, holistics, homeopathics and buyers, with slight differences in one category over the other. Each of these groups must complete clinical Phase 4 trials, with good clinical practice, industry standards of operation, quality control and quality assurance and compliance with FDA regulations. Post-marketing Phase 4 requirements are the same in terms of quality, statistical significance and clinically meaningful results. Data is collected and integrated, summarized, presented, submitted, filed and reviewed by FDA. FDA will act on approvals, approvables or non-approvals. The same process holds true for dietary supplements, cosmeceuticals and neutraceuticals with respect to Phase 4 clinical and regulatory submissions to FDA. In a growing industry that is saturated with "natural" products, clinical research/clinical Phase 4 trials becomes the defining factor in distinguishing a product from its competition, strategically positioning the product against the standard and enhancing the product's characteristics, benefits, attributes and health claims among others.

How to proceed?

Differentiate your product from others
Enhance product sustainability
Increase ROI
Set and achieve workable and attainable clinical goals, endpoints and objectives
Attract consumer and patients by enhanced, quality controlled health claims
"Right" - position the product
Enhance the brand
Proceed with data integrity and consistency
Proceed with data consistency
Ensure FDA compliance and agreement
Ensure FDA compliance with guidelines and regulations
Ensure Good Clinical Practice
Ensure Good Manufacturing Practice
Ensure "correctness" and validity of health claims and benefits
Expect FDA.

Early Stage Drug and Device Development - It takes a team to win!

2010-03-10T15:00:00.004-05:00

Implementation of early stage integration of sales and marketing goals with clinical and regulatory groups early in the development of the drug or device is essential. Implementation of early stage integration of marketing and clinical structures, clinical/regulatory submission teams, whether through new product development groups, joint project management teams, formal communication processes, co-governed portfolio management authorities or otherwise is critical.

In these arrangements, there are definite benefits from some form of pooling of ideas. While portfolio groups and multi-faceted oversight can be challenging, there is ROI. One group, must be in control of the process and although many pharma companies choose sales and marketing to carry the ball, the development must be a function of clinical, regulatory and project teams.

Each group's level of strategic influence will vary in the process, however, the important point is that all functions and strategic groups, are heard. Group input becomes a part of the overall development process which inevitably and favorably impacts costs, timelines, resources, capacity and improves quality, quality control and quality assurance.

Enable group communication, knowledge sharing, coordination and "gate-keeping" of information. It takes a team to win. Group communication unites people from different backgrounds in the development process. Groups with diverse experiences and expertise come together to achieve common goals and objectives on time and cost-effectively.

Sound "gate-keeper" activities and "hands-on" project direction and management early on allows teams and groups to navigate go/no go product profile decisions more effectively. The benefits are real and provides a clearer overall picture of clinical and commercial assets and outlooks, especially when clinical candidates are being developed in parallel.

Time Frames of SAE Reporting - Clinical Trials

2010-03-09T18:34:00.004-05:00

SAE (Serious Adverse Event) Reporting is critical to patient safety and is required by FDA while a drug is under clinical research and development. SAE reporting and time frames are required by FDA and are reviewed and approved by an independent Investigational Review Board (IRB) for each clinical study protocol. SAE Reporting and agreed time frames must be in compliance with FDA patient safety guidelines and developed for each investigational drug, device, dosing regimen and therapeutic indication under study. For example -

Pre-dosing:

Events occurring before taking study drug are not reportable unless related to study procedures.

Dosing during study:

All SAEs are reportable.

Post-dosing (regardless of the drug relationship):

All SAEs are reportable from the first dose of the study drug until 28 days following discontinuance of the study drug regardless of relationship to the drug.

Post-dosing (drug related):

All SAEs that are believed to be drug related must be reported regardless of time elapsed since the last study drug dose, even if the clinical trial is stopped or on clinical hold.

Pregnancy reporting:

Dosing during study/post-dosing - Pregnancy occurring in patients treated with the study drug or which occurs up to 90 days after the last dose of the study drug are reportable as SAEs.
Pregnancy occurring in the female partner of a male patient in a clinical trial whose last dose of study drug was within 90 days of conception is also reportable.

Expedited SAE reporting includes:

AEs which are serious and unexpected and classified as drug related qualify for expedited reporting to the FDA.
Information that may influence the benefit/risk assessment of a study drug or that would be sufficient to consider changes in the study drug regimen, administration or in the overall conduct of the clinical drug investigation and protocol design.

As always, early planning, early reporting is a must with SAEs.

CTD Clinical Submission of Phase 2-3 Trial Data

2010-03-08T11:32:00.004-05:00

Phase 2 - 3 clinical safety data presentation, pooling and integration strategies are developed by the clinical submission team and illustrated in your SAP, statistical analysis plan, for all therapeutic indications to be filed in your clinical submission. On an average, a Phase 2 - 3 clinical program consists of 10-15 studies, conducted simultaneously in the US, Europe, rest of world and are designed to "flush" out AEs, SAEs, dosing regimen, safety and efficacy. The Phase 2 - 3 clinical program reflects the "final marketing image" of the drug to be filed. Phase 2 - 3 integrated safety data, is the clinically meaningful information used to develop the "prescribing" label, package insert, information for the PDR (Physician's Desk Reference) for the drug under investigation. The process of integration, pooling strategy and presentation methodologies for Phase 2 - 3 safety data is analogous and linked to your Phase 1 SAP.

For example, a Phase 2 - 3 clinical program consists of 13 clinical trials - a common pooling strategy for safety data would be as follows -

Pool 1 - 5 clinical studies, double-blind, placebo-controlled, fixed-dose (primary therapeutic indication)
Pool 2 - 3 open-label, long-term exposure studies - (primary therapeutic indication)
Pool 3 - 3 double-blind, placebo-controlled, forced-dose titration studies (primary therapeutic indication)
Pool 4 - 2 special studies, in a different, but related therapeutic indication
Pool 5 - 10 double-blind, placebo-controlled studies, regardless of indication, pooling of Pools 1, 3 and 4.
5 Pools - 13 Phase 2 - 3 clinical studies.

The integrated analyses of clinical safety data includes Adverse Events, clinical laboratory evaluations, vitals signs, physical findings and other observations related to safety and safety in special groups and situations. In the integrated analysis, the Medical Dictionary for Regulatory Activities (MedDRA), is used to classify all Treatment Emergent Serious Events (TEAEs), reported by System Organ Class (SOC) and Preferred Term (PT) as per FDA regulations and data compliance guidelines.

A separate safety integrated and pooled database for Phase 1, 2, 3 Clinical Pharmacology data is submitted to FDA as well at the time of filing. Likewise, statistical analyses, integration and pooling rigor and strategies are developed for the best presentation and evaluation of pharmacology safety data for clinical submission and FDA review.

Clinical/Regulatory CTD Submission - Integrated Pooling of Phase 1 Safety Data

2010-03-07T21:33:00.007-05:00

In order to identify all potential safety signals in your Phase 1 clinical trial program for clinical/regulatory submission, an integrated analysis of the safety data from all studies is recommended. The FDA most definitely recommends "some pooling across all Phase 1 Clinical Studies". There are several approaches. The most common approach is a pooling of single dose exposure trials and a second pooling for multiple dose exposure trials. Due to the heterogeneity of Phase 1 studies often pharma will choose to only pool "like" clinical studies and present fixed dose, parallel group, dose escalation, crossover design, drug-drug and special populations separately, by individual study.

For example, safety data is available at the time of clinical/regulatory submission for 22 completed Phase 1 trials -

7 studies were single dose studies - integrated Pool 1
8 studies were multiple dose studies - integrated Pool 2
5 studies were drug-drug - presented individually
2 studies were special populations - presented individually
15 studies would then be integrated
7 studies presented individually.

Not advised and definitely not advised without FDA communication and consensus. If the Phase 1 clinical program consists of 22 clinical trials, FDA will want all studies pooled. Why? To ensure that all AEs are captured and reported. To ensure patient safety. To ensure a benign safety profile, especially if the drug is a new chemical entity. Early communication and consensus with FDA is a must pertaining to the integration of your Phase 1 data. A RTF - refusal to file will be issued by FDA, without question, if the pooling strategy is not agreed to prior to filing. Always communicate with FDA early on when determining the presentation of your Phase 1 integrated safety data and statistical pooling strategy for clinical/regulatory CTD submission.

Phase 1 Clinical Trial Trends - Staffing by Position

2010-03-02T09:43:00.004-05:00

Overall, because a Phase 1 clinical trial typically requires such a small number of patients compared to Phase 2 and 3, fewer FTEs are required to manage clinical study conduct and performance. In my experience and because of smaller patient numbers, simple resource trends surface relating to how to staff by position, a Phase 1 clinical trial.

In the last years, and on average, pharma typically outsourced 41% of staffing by position related to Phase 1 clinical trial activities, SOPS and tasks in 2006. This number, in the first quarter of 2010, increased to 59%. Clinical staffing by position, whether it be FTEs or outsourced, typically trends and follows a distribution profile - In-house FTEs/Outsourced, unless otherwise specified:

Clinical directors, VP - 100% FTEs
Clinical trial managers - 100% FTEs
Data management - 50%/50%
Medical writing - 100% FTEs
Biostatisticians/bioanalysis - 30%/70%
Regulatory - 100% FTEs
Clinical quality control - 100% FTEs
Clinical quality assurance - 100% FTEs
Clinical trials supplies - 100% FTEs
CMC - 100% FTEs
Contract management - 25%/75%
Drug safety - 50%/50%
Pharmacovigilance - 45%/55%.

A Phase 1 clinical trial can be simply and concisely budgeted with early planning development with respect to the clinical protocol and statistical analysis plan. Due to Phase 1 clinical trial simplicity in design, easily measured endpoints, most commonly, patient safety and tolerance, new chemical entity proof of concept design and small numbers of patients involved - the budget can be exact, the ROI easily achieved, results quickly analyzed. A Phase 1 clinical trial resource distribution profile, staffing by position, as seen above, demonstrates that pharma, at this clinical level of drug development maintains staffing by position in-house. Why? During the Phase 1 clinical trial period of drug development - this is the time for pharma take a go/no go decision with respect to the future development of the drug. The decision must come from pharma and only after careful consideration and review of Phase 1 clinical trial data. I strongly advise that go/no go decisions pertaining to Phase 1 clinical trial continuance or not, remain the responsibility and accountability of pharma. Guidance from FDA recommends the same good clinical practice. Plan early, resource and staff by position accurately and appropriately, follow good clinical practice, design concise clinical protocols and SAPs. The Phase 1 clinical trial is the least expensive trial (or should be) in the clinical drug development process and path to regulatory clinical submission.

Budgeting Impact on Superfluous Clinical Trial Data

2010-02-27T19:03:00.004-05:00

In the previous post, we spoke about superfluous collection of clinical trial data and its impact on clinical trial integrity and quality, extra unnecessary data, increased patient dropouts, increased costs, missed timelines, under-resourced departments, etc. The remedy remember is to involve team players and biostatisticians early on the clinical and regulatory path to design a clear-cut protocol with achievable clinical outcomes that are medically meaningful and statistically significant. In other words, design a SAP, statistical analysis plan, that is precise.

Budgeting - patient recruitment can also help in the reducing unnecessary data collection. At the outset of patient recruitment, pharma must first determine a number of factors about the clinical trial that will influence cost, time and yes, data. The budget, the number of patients recruited and the amount of patient data collected are closely linked. All 3 will be influenced by:

how many patients are needed for the clinical trial
how many patients must be screened to randomize the required number of patients
how many investigator sites will be involved in the clinical study and where will they be located
what percentage of patients is the investigator site capable of recruiting and what percentage must be recruited by the pharma, CRO
is this a pivotal clinical trial seeking results for a new drug application (NDA)
how experienced is the pharma at recruiting patients in the therapeutic area in question
how long is the clinical trial expected to last
how restrictive are the patient inclusion/exclusion criteria outlined in the clinical study protocol
are there alternative therapies already on the market.

Unnecessary Clinical Trial Data Leads to Extra Time and Cost

2010-02-26T12:30:00.004-05:00

Oftentimes, clinical trial teams collect, clean and analyze 5 to 10 or more pages of excess clinical trial data that is never used in the final clinical trial or study reports. Moving too much data through the entire clinical trial process - including collection, data entry, data storage, querying, statistical analysis, report writing and review - leads to extensive increases in clinical trial timelines and increases the probability of data errors. Failing to narrow down the target data for clinical trials early in the study planning phase causes trials to last longer than they would otherwise have to and as well, increases the length of time to clean and quality control and quality audit the clinical trial database. Often, the number of patient visits are too numerous and too long. Thus a poor clinical trial and protocol design, will inevitably lead to more patient dropouts, erroneous data, more patient withdrawals, increased patient non-compliance and failures to follow-up. Quality control and quality audit time increases and leads to unnecessary increases in clinical trial costs, CRO, Investigator, all outsourced and otherwise, not to mention time of employees to monitor clinical trial progress, performance and status. Recent reviewed reports on this subject, estimate the time wasted on the unnecessary data collected and related activities exceeds 2-3 months when all of the additional work and rework, quality control, cleaning and quality audit are combined. As well, may seriously jeopardize the integrity of clinical trial data collected. Solution: Working with biostatisticians early in the clinical trial protocol set up, planning and design to eliminate the collection of extra, unnecessary clinical trial data. Simple. Take the team approach.

Outsourced Manufacturing Suppliers and Quality Regulatory Audits

2010-02-24T19:08:00.005-05:00

Recently I was asked by pharma, how can we ensure that outsourced suppliers are manufacturing product in accordance and compliance with FDA regulations. FDA regulations are clear, whether for drug, device, biologic, vaccine, other, pharma is ultimately responsible for the quality of their product. FDA has new regulations pertaining to quality manufacturing activities (and a new Commissioner) and thus, the industry will be scrutinzed regarding increased regulatory, quality rigor, focused on enforcement of high standards of manufacturing and operations.

What can you investigate before choosing your outsourced supplier for your manufacturing needs:

audit and evaluate business practices and standard of operations
audit and evaluate quality, management and manufacturing systems, in process checks
audit and ask about records, procedures, validation, maintenance, calibration, traceability, processes
audit and review procedures that address actions for non-conforming product and standard deviation
audit and investigate history of product release, training, customer track record, pharma satisfaction, FDA satisfaction/correspondence, complaint actions and responses
audit contracts.

Quality should not be predicted. Quality should be evident by audit. Choose your outsourced manufacturer by audit to ensure quality and adherence to FDA regulations and guidance.

Pros and Cons to Clinical Partnerships and Metric Model Selection

2010-02-20T15:02:00.007-05:00

In the last 5 years and most probably due to the vast number of pharma M&A, easily measured clinical conduct, operations and submission resource solutions have been lost in the chaos. For example, several pharma believe that the CEO of the company must be involved in and focused on the life cycle of the clinical trial and clinical submission. No. Many pharma use elaborate tactical and strategic sourcing plans and metric model selection processes to resource their clinical trial and clinical submission needs and requirements. No. A number of pharma fall to strategic partnerships to reduce their resourcing and outsourcing burdens. No. Many pharma tend to follow complicated collaborative schemes by applying multidimensional performance metrics for improved clinical trial and clinical submission management indices. No. Pharma companies are trying to learn how to avoid 483 observations regarding FDA oversight and resultant compliance and deviation issues. No. Bridging the gap with so many strategic partners can only provide more chaos, create vacuums, isolate people and data, reduce ease of communication.

Classic drug, device, technology development is simple when processes and procedures are clearly mapped out in detail from start to finish and resourced properly by understanding how long it takes to create a SAS program, write a clinical summary of integrated safety and efficacy, review a safety narrative, prepare a patient profile, quality-control (QC) a clinical study report, develop a global integrated database, publish a submission-ready document - only then can pharma accurately and effectively manage resource responsibilities, start, stop dates and accountability, that will lead to a successful, compliant clinical trial and clinical submission.

Keep it Simple. Follow the regulation and guidance. Don't get fooled by elegant ways to short-cut the system or quality. Do it right the first time. Keep the team hands-on, communicate clearly and often, lead the team, manage the issues. Walk the halls.

Strategic Partnerships in Clinical Trials and Clinical Submissions

2010-02-19T14:37:00.002-05:00

Often pharma companies are faced with a huge pipeline of drugs, devices and technologies to develop after M&A. Often after or during a M&A, and as a result of the M&A, there is not enough in-house employees or employees with the specific expertise required to develop and conduct clinical trials and/or prepare and submit a clinical submission to FDA and/or regulatory agencies worldwide. There is no shortage of CROs who participate in resourcing outsourcing needs or even "partner" with the pharma company. These strategic partnership agreements between pharma and the CRO are often created and do benefit both the pharma sponsor and the incoming CRO. The selection of a CRO and more importantly a CRO strategic partner is no an easy process. In fact, if performed correctly, the process of selection very much resembles an audit and takes much time and effort. However, the time and effort spent on selecting a fit for your clinical trial and clinical submission is critical and unmeasurable in value. To ensure a fit with pharma and the CRO is terms of vision, one needs to look closely at CRO metrics such as "pace and intensity, quality and met timelines". Look at the track record of "success" in the particular therapeutic field of development and submission for starters.

Recently, I read a brief summary describing the monetary consequences of not choosing the appropriate CRO or CRO partner. Internal resource burden of not outsourcing efficiently can result in 50% more FTEs. Having to repeat a Phase 2 clinical trial due to erroneous, incomplete, data can amount to $10-$20M. Selecting the wrong clinical partner for your clinical Phase 3 trial will cost the pharma partner $5-$10M. Loss of valuable time to market due to clinical trial delays can result in an extra unnecessary expenditure of $10-$50M. Therefore, selecting the the best partner for your clinical trial and clinical submission is critical and worth due diligence, audit and investigation.

More to come pertaining to the selection of a clinical trial and clinical submission partner.

FDA Expedited Regulatory Submission Review of Device or Device with Drug Product

2010-02-18T11:37:00.003-05:00

FDA from time to time, publishes nonbinding recommendations for device, technology, drug or otherwise, for expedited regulatory review in an effort to benefit patients who fall into a unmet medical emergent, urgent need for therapy, in need of new breakthrough technology and serves the best interest of patients in life-threatening situations or irreversible debilitating disease or condition.

Breakthrough technologies must be demonstrated to lead to a clinical improvement in the treatment or diagnosis of the life-threatening or irreversibility debilitating condition.

The device must provide for a clinically important earlier or more accurate diagnosis or offer important therapeutic advantages in safety and/or effectiveness over existing alternatives. For examples:

superiority over current treatments for advantages on serious outcomes (e.g., morbidity)
ability to provide clinical benefit for those patients unable to tolerate current treatment
ability to provide a clinical benefit without the serious side effects associated with current treatments.

The availability of the device must be in the best interest for patients and that is, the device provides a specific public health benefit or meets the need of a well-defined patient population.

All provisions may also apply to a device that was designed or modified to address an unanticipated serious failure occurring in a critical component of an approved device for which there a no alternatives or for which alternative treatment would entail substantial risk of morbidity for the patient.

FDA is open to demonstrations of real benefit for the safety and well-being of patients who have compassionate and life-threatening pleas. Regulatory submission documentation and dossier for the device, device with drug must be pristine, demonstrate clinically meaningful and statistically significant benefit, quality-controlled data and provide a remarkable and superior benefit/risk statement.

Devices Appropriate for Expedited FDA Regulatory Review

2010-02-17T19:16:00.003-05:00

FDA considers a device or combination product containing a device appropriate for expedited regulatory review if the device or combination product:

is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition and
addresses an unmet medical need, as demonstrated by one of the following:

the device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology
no approved alternative treatment or means of diagnosis exists
the device offers significant, clinically meaningful advantages over existing approved alternative treatments
the availability of the device is in the best interest of patients.

Under "special " considerations, pharma manufacturers who are working with a Federal Agency in the development of medical devices to address a national security issue should include a letter in the premarket regulatory submission from the Federal Agency, likely, Department of Defense, Department of Homeland Defense, identifying the specific device or device type and indicating that commercial availability is of particular importance to our national security. The letter of course, must be printed on official agency letterhead and signed by an individual with appropriate authority for making the request.

More information to come pertaining to the definition of "breakthrough", "clinically significant therapeutic advantages" and "public health benefit on device availability".

Preparing a CTD, eCTD Project Planner for your Clinical Submission

2010-02-16T16:45:00.003-05:00

In preparing a CTD, eCTD Project Planner for your next Clinical Submission, pharma companies, submission team members, project leaders, managers, regulators and planners must include and integrate communication, correspondence, Q&A, End of Phase 2 Briefing Document discussions, meeting minutes, agreements and commitments, Beginning of Final Marketing Image (FMI) Phase 3 Briefing Document discussions, meeting minutes, agreements and commitments and records of all teleconferences past and current. Communication and resulting deliverables with FDA, now become required regulatory components of the pharma's CTD, eCTD TOC (Table of Contents) and Backbone and must be completed with quality and submitted at the time of filing. If the filing is not complete with FDA requirements as discussed and agreed to with pharma - a RTF, a Refusal to File will be issued when received by FDA. Communications can include but are not limited to CTD, eCTD:

content
clinical studies
statistical analyses
file naming conventions
navigational QC process
folder specifications
module numbering (2.7.1, 2.7.2, 2.7.2.2, 2.7.2.2.1) conventions
module numbering granularity
how to present AEs of interest
hyperlinking conventions
CDISC versions
WHO dictionary versions
MedDRA versions
FDA Guidelines and Guidances at the time of filing
how to handle inter-module and intra-module dependencies
and otherwise.

It is wise to begin the process of Project Planner Preparation by creating a "generic" project planner and then "customize" the planner in accordance with FDA agreements.

QC all components of the CTD, eCTD clinical submission including hyperlinks, FDA correspondence, module numbering and otherwise to ensure quality, consistency and accurate navigational direction. Navigational QC is an activity that not only "checks" to ensure the accuracy and integrity of your hyperlinks from data to supporting source documents but ensures that the link is "active" and "live" (blue and not black print) when the dossier is submitted to FDA on filing.

Creating a Project Planner for your eCTD Submission

2010-02-14T20:04:00.003-05:00

Pharma companies have awareness and knowledge with respect to "what it takes" to file an eCTD for their drug with FDA. To aid in the overall project planning and eCTD organization and to ensure that the file is complete when you press "send" to FDA - a Project Planner is strongly advised to help manage the overall file and deliverable. Creation of a user friendly, accurate, Project Planner for an eCTD submission, pharma functions, CROs and team members must consider the following "initial" points:

task involved
resources required
capacity required
team composite
team leadership
issue management
process and procedure
function responsibility
CRO responsibility
team accountability
CRO accountability
estimated hours per task
estimated number of drafts per task
estimated overall timeline per task
estimated "start/"stop" dates per task
therapeutic indication and claim
new chemical entity
brand
generic
typical or atypical eCTD organization, backbone structure
special SAEs and how to handle and adjudicate
interlinking data and documentation to legacy and previously submitted materials to FDA
estimated date of "expected" eCTD filing
estimated date of "realistic" eCTD filing
correspondence and agreements with FDA pertaining to the eCTD Submission Table of Contents.

Creating a proper Project Planner that realistically addresses task and time is not a one day event. It takes team integration and communication, starting with initial, simple questions and resources while taking into consideration results from preclinical and clinical studies and how to handle serious adverse events of interest.

Above are initial points to consider. More to come...

Compliant and Correct SOPs for Clinical/Regulatory Trial, Study and Submission

2010-02-11T11:27:00.004-05:00

Clinical and regulatory FDA and country regulations are not open to interpretation, however, both guidelines and guidances are negotiable with credible, literature and data based reason and rationale. Once SOPs are written, project leaders must ensure team and company compliance. Adherence to SOPs is critical to data, documentation and company integrity. FDA will not only review the long list of SOPs on audit, but will as well look for a record for proof of implementation, usability, enforcement and a tracking record of compliance throughout the company, project by project, clinical study by clinical study, clinical and regulatory submissions, one by one.

Points to Consider for SOPs:

areas where SOPs are useful (times when they are unnecessary)
appropriate outline for each SOP
what should not be included in company SOPs
training on SOPs to ensure team understanding and why the need for the procedure
when an SOP needs to be updated and why
standards for archiving SOPs
FDA access to your SOPs
involve FDA in your SOP compliance program - communicate.

Once a year, a pharma company must review/audit SOPs and related procedures in order to assess QC/QA issues and concerns before FDA does so, unannounced and for cause. Proactive, internal pharma audits must be routine and could be prompted much like an alert to generate an annual safety report. In this way, everyone, the team and the company are on board and the attention to SOPs and related activities become a scheduled company practice.

Clinical Trials and Neutraceuticals

2010-02-10T13:20:00.002-05:00

Clinical trials in humans can be expensive. For neutraceutical clinical trials to be successful and cost-effective, trial objectives must be focused. Animal study data, documentation and results can provide this unique added focus to better enhance the development of a clinical study protocol that is "likely" to generate a positive outcome.

There are several possible approaches for neutraceutical product development. A balanced approach of doing some preclinical testing before, during and after the clinical phase of R&D is prudent and recommended. Remember that each product is different and thus there is no set rule in development. Several "approaches", that safely and conscientiously consider both animal testing and human clinical trials is strongly recommended. The clinical trials can be, for examples, a small pilot clinical study in humans or a proof of concept clinical study in humans. Either would provide useful, hopefully positive outcome information that will be used in future clinical development considerations.

Whether animal or human, testing or clinical study, respectively, remember to apply GLP and GCP as per FDA regulatory rigor and guidance - and quality control all data and documentation early, often and always.

Neutraceutical - Animal Testing vs. Human Clinical Trials

2010-02-09T22:45:00.007-05:00

Some companies may question the need for spending money on animal testing if they are committed to investing in neutraceutical clinical trials. Perhaps it is less than ethical to test neutraceuticals on animals when human research is equally possible for potentially harmless natural health products. No. There is still plenty of research that is possible only in lab animal testing and not at all in humans. For examples, where there are specific safety concerns for the neutraceutical clinical trial patient/subject and/or where the manufacturing process is likely to alter the ingredient dramatically, it is required by FDA to perform basic, extensive safety testing in animals - before marketing, before human clinical trials.

Even when animal studies are not FDA required, invitro and invivo efficacy and safety studies both offer advantages of screening several ingredients and doses of the same ingredient rapidly and more efficiently in the lab than would be possible in human clinical trials. More importantly, some animal testing models are available that can elucidate mechanisms of actions which are difficult to reveal in simple human neutraceutical clinical trials, Proof of Concept, Phase 1,2 or otherwise. As well, pharmacokinetic and bioavailability markers can be more efficiently and more effectively elucidated in animal studies.

Follow FDA, good laboratory practice, good manufacturing practice and QC when conducting animal studies. If requested by FDA, data and documentation integrity must be met.

Selecting Health Claims for Neutraceutical Clinical Trials

2010-02-08T18:55:00.005-05:00

Determining the primary question to be asked in a neutraceutical clinical trial is critical to its success. Ask a wrong question, design the protocol incorrectly and you end up with the wrong answer, no answer, an answer that has no market or regulatory value or even worse, negative data that stays with the neutraceutical for a lifetime.

How does one interpret R&D critical decisions regarding claim selection/definition and design a neutraceutical clinical trial that works?

Simple. Look at what happens in conventional, traditional, drug development - the regulatory process and path provides lessons for planning effective and safe neutraceutical clinical trials. As well, consider all R&D decisions from the point of view of the investigator, regulatory advisement and more importantly, the subject/patient/consumer and sponsor's interests. Follow FDA and pharma standards in clinical design and clinical conduct. Follow good clinical practice and quality control of data and documentation.

How Natural Products Can Provide the Basis for New Clinical Candidates

2010-02-07T10:55:00.002-05:00

Recently, I was asked about preclinical and clinical development and considerations pertaining to phytochemicals, neutraceuticals, natural products and specifically, potential "antitumor properties" and new therapeutics.

Phytochemicals have potent antitumor properties. There is increasing focus of "designer" targeted therapeutic anticancer agents, the broad spectrum of activity of natural products across multiple signaling pathways remains inadequately explored. The chemical diversity, structural complexity, affordability, lack of substantial toxic effects and inherent biologic activity of natural products makes them ideal candidates for new therapeutics. Natural products not only disrupt aberrant signaling pathways leading to cancer but also synergize with chemotherapy and radiotherapy.

Yes, there is a wealth of scientific, research on phytochemicals, nutraceuticals, bacterial and algae secretory by- and end-products as potential, potent therapeutics in cancer, CNS, and otherwise. Much of the early R&D focuses on mechanism of action of key natural products and there is an abundance of early, promising preclinical data for their efficacy as single agents of in combination with standard therapies. Much of the early work in the area of phytochemicals, neutraceuticals and natural "active" products originate at research institutes and academia. Good science, however, preclinical (and clinical) testing, quality controlled testing, regulatory rigor, data and documentation will be needed to build a "true" therapeutic agent. Safety and efficacy must be measured by quality controlled standards as set forth by FDA compliance and regulatory guidance. Product quality and consistency is a must. Consumer or patient/subject safety is the first concern.

Neutraceutical Clinical Trials and Regulatory Submission

2010-02-04T10:31:00.002-05:00

Today, neutraceutical companies are increasingly dedicated to clinical trials and quality-controlled data and outcome endpoints; however, two types of preclinical research - "Formulation & Analytical Development" and "Animal Pharmacology & Toxicology" - are important, although the investment can seem costlier than the results.

Lets discuss F&AD first:

Most companies find a novel compound from countries, India, China, Japan, Poland, Russia, for examples, that they want to market as a neutraceutical globally. The neutraceutical company performs some relevant inhouse laboratory testing and obtain data to substantiate certain health and pharma benefits. The question: Is your neutraceutical ready to make that same claim in most countries? The answer: No.

To be able to market and make the claim worldwide, the finished product must have quality and consistency, and achieve FDA regulatory GMP CMC-like standards. Ingredient certificates of analysis (CoA) provide details on the ingredient itself; however, formulation and production steps ranging from granulation to tablet formation can impact the compound. Further, novel delivery systems and dosage forms also affect an ingredient's bioavailability and stability.

On a global level, innovation in novel neutraceutical dosage forms has been slow, although some actives have been converted into forms suitable for the food and beverage formulation (and FDA).

The net-net - if a finished product is not standardized as it leaves the production lines, demonstrating shelf stability, product consistency, batch to batch, lot to lot, safety and efficacy - your product will not be well accepted by the consumer, the market, the FDA and will not be allowed import/export from country to country.

Quality control of testing claims - data, process and documentation is a must.

Is my Neutraceutical Ready for Clinical Trial and Regulatory Submission?

2010-02-02T10:23:00.005-05:00

Several neutraceutical clients recently asked me "When will their product be ready for clinical trials and subsequent regulatory submission? The need to know is twofold - one, FDA rigor and requirements, and two, to support marketing claims and increase perception and value of the neutraceutical in the eye of the FDA regulatory reviewer and the product consumer. Clinical trials generate data and documentation that must be collected and cleaned via SOPS for GLP, GMP, GCP and QC. The data must still be quality controlled and quality assured, consistent in statements, patient/subject outcomes and endpoints and marketing claims.

A clinical trial is considered "gold" in the dietary supplement industry yielding immediate marketing value. Other forms of data to support claims for a health ingredient or dietary supplement are not so compelling to the bottom line. Why? Consumers do want to know whether a neutraceutical, and there are many competing for the same claim, works on them and not just in animals, in theory and/or on the "bench". Companies, in the past, relied heavily in the absence of clinical trial data on consumer perception, testimonials and endorsements. However, that does not speak to the product's finished quality.

So, when is your neutraceutical ready for clinical trials?

Preclinical testing is next and prior to clinical testing and trials. The preclinical testing phase is similar to that of a regulated drug, device, biologic, vaccine, etc.
The preclinical testing includes:

formulation development
analytical development
animal pharmacology
animal toxicology.

Clinical trials are next in line. At this point, when the preclinical data is collected, QC, summarized and reviewed, and is "deemed" good - the neutraceutical is clinical trial "ready".

Preclinical and Clinical testing results become major factors when considering the acquisition of a neutraceutical product and thus must be quality assured with due diligence review.

Neutraceuticals - Due Diligence - FDA Regulatory Scrutiny - Investor ROI

2010-01-30T13:56:00.005-05:00

As FDA closes in on neutraceutical regulation and clinical and regulatory submission and rigor - investors, with today's economic environment require more due diligence pertaining to the product, prior to investment. Due diligence, is performed by a group of experts who examine all data, documentation, manufacturing, formulation, efficacy and safety claims, QC/QA, FDA requirements of the respective neutraceutical. In the case of FDA - someday soon, neutraceutical companies and neutraceutical products will be regulated to some degree. For the interested investor, ROI is important, however, as well, directly relates to product QC/QA, product development, formulation, manufacturing and a twist on advertising, marketing - and consumer safety essential.

Recently, I was asked to perform a quick due diligence on a neutraceutical product. What did I examine at first blush?

clinical and medical claims
clinical and medical use
product claims
product revenue
product formulation
miss-use or abuse issues
disclaimers
proprietary product documentation
confidentiality/non circumvent agreements
SEC documentation
private or public company profile
financial documentation
financial disclosure
revenue stream
purchase invoices
"the need"
"the perception"
P&L
shipment considerations
publication, abstract, literature, advertising, marketing, infomercial, brochure, statements
manufacturing license
manufacturing process and agreements
GRAS list for import and export of product substance
CMC - chemistry, manufacturing and controls
"rights" to active ingredient
product line of the company
FDA correspondence
claim substantiation
claim longevity
claim integrity
clinical studies to support claims
consumer safety
consumer adverse reports pertaining to product use
endorsements
testimonials
data
documentation
company history and background information
company operations and staff
Officers of the company, CEO, CFO, COO, CSO, CMO, etc.

The "quick" due diligence performed for the neutraceutical in question was essentially a snapshot of a QC/QA, "check-list audit" process and procedure that would be required by FDA for a drug, device, biologic, vaccine, technology - similar, indeed.

The need for due diligence is clear for the FDA and the investor. The process, procedure and audit type is dependent on the neutraceutical and the claim. Whether FDA or investor, quality is a must. Ensurance of subject/patient and/or consumer safety is critical.

Neutraceutical - How close to Pharmaceutical FDA Rigor?

2010-01-29T14:14:00.002-05:00

Recently, I was asked to review with FDA rigor and "investor" interest and due diligence, several NCEs for various therapeutic indications, all in areas of unmet medical needs, inhalation devices, state of the art and several neutraceutical products.

For this blog, lets focus on neutraceuticals -

Interesting enough, FDA is closing in on neutraceuticals. These are products that are generating revenue on the market, manufactured by top pharma manufacturing facilities, formulated and contain active substances which in addition to the primary product "marketed" claim - lowers cholesterol, while building muscle and correcting hormonal balance - as well demonstrates efficacy or benefits in other areas, for example CNS - demonstrates a sense of well being in patients diagnosed with bipolar, schizoaffective, psychosis, etc. These are products that have not traveled the clinical and regulatory pathway with FDA rigor.

At some point in life cycle of the neutraceutical and because of the "apparent" medical benefit of the neutraceutical, FDA will step in and demand that the formulation, the product, become quality-controlled and assured and regulated. FDA will want the neutraceutical company to submit a clinical and regulatory submission and product filing.

It will happen - it is just a matter of time. In the last two years, across my desk, four neutraceutical companies in business for at least 10+ years have been contacted by FDA to provide a clinical development and submission plan for filing.

If you are a neutraceutical company, stay tuned - it will happen to you. If it does, FDA will want to see in a realistic time frame, your intent to comply with their request for FDA rigor. I will speak about how to comply and the components of the filing in the next several blogs. I will as well, provide a brief checklist on due diligence from an investor's point of view as well.

Clinical and Regulatory Biostatistical Submission Data Display - The Proper Use of Graphs

2010-01-27T16:32:00.003-05:00

The design of a good graphic display for clinical and regulatory submission data must show the FDA reviewer the data and encourage the reviewer to think about the substance and storyline as described in the Clinical and Regulatory Development Plan and the Statistical Analysis Plan. What are you trying to convey to the FDA reviewer - don't be afraid to show it in a well designed graphic display.

Good Clinical and Regulatory Submission Graphs should:

emphasize data and storyline and not methodology, technology or "tricky" analytics that beat up the data for clinical and statistical significance
not distort what the data has to say
be closely integrated with statistical and verbal descriptions of the dataset and database
present many numbers in a small space
make large datasets and databases, integrated or otherwise, coherent
reveal the data in many levels of detail.

Just as good medical writing is a result of frequent communication between the medical writer, SAS programmer, clinical safety and efficacy and the QC team member - the same holds true with the development and creation of a good analytical graph - there must be frequent communication between the SAS programmer, analyst, QC, clinical safety and efficacy - for whom? - for the benefit of the FDA reviewer.

With regard to clinical and regulatory submissions - there is the overall submission team and additionally, there are submission subteams that must be responsible for the clear presentation of submission data from their respective areas of expertise.

"It takes a team to win".

Clinical And Regulatory Submission Data - Design of Good Graphic Display

2010-01-26T18:07:00.003-05:00

For good graphic design for clinical and regulatory submission data strive for quality by focusing on the following points to consider:

a well designed presentation of interesting data is a matter of substance and storyline, of biostatistics and of design
complex ideas should be communicated with clarity, QC, precision and efficiency
graphics should give the team reader and FDA reviewer the greatest number of ideas in the shortest amount of time while using the least print in the smallest place - pertaining to data density and presentation for clinical and regulatory submissions - the adage is "give the FDA reviewer a lot of white space on a page"
the true data must be shown and used - for only then will the data display a precise biostatistical point
most graphs, and therefore most data, when presented with clarity are multivariate - well thought out design and display of accurate, clear data even multivariate in nature will present well.

"The data must be true" - yes, and the first step to accomplish a graph of excellence is to use QC early in the collection of the data to be included as points in the graph.

Clinical and Regulatory Submission Biostatistical Display

2010-01-25T15:09:00.003-05:00

Graphs communicate. There is both an art and a science to the accurate and appropriate choice of clinical and regulatory submission visual display of biostatistical display.

The Purpose of Graphs

A good graph will:

save the user time - information is sifted and refined
gain user attention - easy and pleasing to the eye to generate reader motivation
show relationships and permit study of the data
the user should be able to look for regularities and irregularities with in the data
study data points and their spatial relationships to each other may reveal meanings not otherwise observed
in deciding whether to use a chart or a graph - the form which best shows the relationships should be used
suggest new ideas - a good graph might reveal connection that otherwise would not be perceived
make efficient use of information - display fundamental relationships by way of visual convention.

Three things will happen with a good graph:

the graph will be studied
the graph will be accepted
the graph will be remembered.

Remember, clinical and regulatory submission data points are the building blocks of a graph and as such a QC (SOP) procedure must be developed and utilized to ensure accuracy in data entry, programmatic presentation and graphics. Graphs are most often "double" program validated first, followed by a second, final data QC step.

Regulatory and Compliance - Inhaler Drug Device and Delivery Systems - FDA

2010-01-22T18:23:00.005-05:00

When considering a inhalation device or delivery system for your drug, here are important points to consider with respect to device or delivery system design, flexibility, user-ease, single or multidose compartmentalization, drug stability, lock-out measures to counter patient abuse, miss-use and street value. As per FDA and by guidance, guideline and requirement, FDA will expect the following attributes to be thoroughly investigated, controlled, tested and achieved with quality and statistical significance - results, data and documentation included in your regulatory submission and filing.

High efficiency of delivery
High accuracy of delivery
Dose reproducibility
Dose feedback
Coordination independence
Flow independence
Orientation independence
Support all populations, elderly, pediatric, compromised, etc.

Transfer of Clinical and Regulatory Submission Data and Documentation for QC

2010-01-19T22:18:00.003-05:00

Clinical and regulatory data and documentation presented for QC must be version-controlled, protected and transferred from one site to another, one location to another, worldwide, with proper security via standard process, procedure and acceptable media.

For QC to be effective, clinical and regulatory submission data and documentation must be transferred via acceptable media:

floppy disk
paper
CD
DVD
DLT
shared secured, password protected drives
FTP servers - secured, password protected
a validated, process-controlled documentum tool
a validated, process-controlled publishing tool
a validated submission-ready template
pharma servers - proprietary and protected.

Clinical and regulatory submission data and documentation for QC must not be transferred at any time or under any circumstance via unacceptable media:

email
excel spread sheet
fax
telephone
blackberry
power point slides.

According to QC and GCP (Good Clinical Practice) guidance, clinical and regulatory submission data and documentation must be securely transported and version-controlled. Any media that allows modification to the data and documentation, before, during or after transport is unacceptable according to ICH, GCP, SOP, FDA standards. A QMP (Quality Management Plan) SOP outlining the process, procedure and transport of clinical and regulatory data and documentation is recommended. Adherence to the SOP is strongly advised without deviation.

Clinical and Regulatory CTD Submission QC - Why QC?

2010-01-17T20:55:00.004-05:00

Why QC your clinical and regulatory submission - data, documentation, summary module, CTD?

The result of effective QC -

The final product, your clinical and regulatory submission is credible, accurate and consistent with previously submitted documents and data worldwide - with QC review - inaccurate data and global inconsistencies are caught and corrected
Highly complex, complicated, summarized clinical integrated submission data and documents are inherently prone to errors and inconsistencies - with QC review - these errors are caught and corrected
SAS programmed integrated data, tables, listings, graphs and figures, summarized clinical and regulatory submission "storyline" statements, interpretations and conclusions appear sensible, however, clash after many team reviews - with QC review - inconsistent statements, interpretations and conclusions are caught and corrected
Module to Module data and documentation errors arise in CTDs - with QC review - intermodular and intramodular errors are caught and corrected
Clinical Summary to Nonclinical Summary to CMC Quality Summary - summary to summary inconsistencies arise during the course of submission - with QC review - summary inconsistencies are caught and corrected.

The QC team are "gate-keepers" of all data and all documents and track errors, statements, interpretations, corrections, versions, etc., so the final data, documents, clinical and nonclinical, CMC summaries, CTD Modules are clear, consistent and accurate and are QC final with respect to QMP, SOP, ICH, CFR, FDA compliance and quality standards.

The QC team provides a unique opportunity as gate-keepers - the team reviews all data and documentation in the clinical and project submission process while building your CTD. The process of QC is independent of pharma functions and CROs - a clear advantage.

QC Provides ROI and Prevents Clinical/Regulatory Submission Pitfalls

2010-01-16T13:07:00.002-05:00

The utilization of QC (quality control) pertaining to your clinical/regulatory submission, program, project, data and/or documentation, daily and routinely, is a must and the results are - ROI (return on investment), dramatic reductions in costs, avoidance of pitfalls leading to erroneous data and process and agreed upon timelines are met.

QC objectives, plans and benefits (to mention a few):

easy to forecast QC pitfalls when not utilizing QC
each data, table, listing, graph, figure and/or document must have a QC plan tailored to catch errors and provide accuracy with current and previously submitted clinical and regulatory submissions and filings
easy to forecast areas of significant QC findings and where and how data, statement, format and documentation errors are more likely to be found
easy to resolve QC findings
easy to track QC findings
easy to implement QC findings
easy to follow-up the implementation of QC findings throughout your clinical/regulatory submission when dealing with hundreds of thousands of data points
easy to demonstrate "streamlining" time, cost, manpower, version, template, effort, data, statement, clear and present presentation, accuracy, consistency pertaining to your data and documentation as a result of QC
easy to follow the plan and reap the benefits of quality-controlled data, statement, format, template and documentation pertaining to your clinical/regulatory submission.

Appropriate QC planning and utilization is a must. For example, a waste of QC time is to QC a draft version of a clinical study report, clinical study appendix, a safety narrative, a SAS programmed table, a clinical summary of safety and efficacy, a summary of bioanalytics, a summary of clinical pharmacology, a clinical overview, a subject patient profile, a database listing, a database - to mention a few components, "too early" in the writing and development stages - QC must be performed on the appropriate version, a mature version, a near final version.

The first QC round must be utilized for gross QC (procedure/objectives found in the QC plan) - the second QC round must be focused on QC resolution of the findings, correction, implementation, tracking and finalization.

Two rounds of QC is optimal for most data and documentation.

A third round of QC may be needed if time is tight, the length of the document is too long, for some reason, exceeds the recommended number of pages and/or the document is heavily populated with data. Time, length and data density issues occur due to miss-managed project, writing and SAP (statistical analysis plan) - and are items that must be controlled by the pharma/CRO teams prior to the start of QC - so that QC is effective.

The Benefits of QC - Clinical/Regulatory Submission

2010-01-15T20:54:00.002-05:00

The benefits of quality control of clinical/regulatory submission data and documentation is obvious, speaks to ROI - return of investment and ensures fileabilty of the dossier.

The obvious benefits are, to mention a few:

fast track FDA review
fast track approvals
less Q&A, post-file
less Q&A with advisory committees
less Q&A with expert panels
less Q&A post-approval
clinical submission content is credible
cost effective
time effective
on time team review
timelines are keep, fast tracked
provides, well-controlled data and documents
ensures confidence in the accuracy of data and documents
ensures confidence in the accuracy of current and previously submitted clinical submissions and filings
provides user-friendly data and documents to the end user - FDA, Worldwide
coming in under budget.

QC is different than QA. Often pharma mistakes the two tasks, both are necessary, both are essential, both are important points to consider in the early planning stages of clinical/regulatory submissions.

International Regulatory Guidance - EMEA ICH E9

2010-01-13T21:26:00.003-05:00

The international regulatory guidance pertaining to the creation and development of the Global Integrated Database (GIDB) for clinical submission is EMEA ICH E9. When creating the GIDB and Integrated SAP (Statistical Analysis Plan), while utilizing the guidance provided in EMEA ICH E9 - it is important to develop a strong:

methodological approach
statistical analysis plan that will demonstrate significance pertaining to objectives and endpoints
appropriate and version specific and accurate tools for programming TLGFs (Tables, Listings, Graphs and Figures) - SAS Version 9.1 and 8.2, current and previous version, respectively
standardized, validated program of analysis
QMP - Quality Management Plan
"Change" Plan - how to manage
GIDB Mapping Plan
GIDB Coding Plan
GIDB CDISC
GIDB Dictionaries, MedDRA, WHODRL, etc.

The guidance will "suggest" the creation of two SAPs for the GIDB - one developed for the programming, presentation and pooling strategies for safety data and one for efficacy data. It is important to communicate with FDA early in the development of each GIDB SAP to agree on the programming, presentation and pooling strategies pertaining to clinical submission data. Communication with FDA concerning the GIDB can begin as early as the End of Phase 2 Clinical Studies or at the beginning of the Clinical Phase 3 Program when the "final marketing image" of the investigational drug is clear and decided and the dosing, safety and efficacy objectives and endpoints are final.

Clinical Submission Global Integrated Database (GIDB)

2010-01-12T20:58:00.002-05:00

With respect to the final QC controlled and QA clinical submission GIDB and "locking the database" - is a "Database Lock Form" required?

The answer is - yes. Remember, at the clinical study level, when a database is locked, a "Database Lock Form" is required. The same holds true at the submission level with the GIDB Lock.

The Database Lock Form will include:

Sponsor name
Project name - usually the name of the investigational drug
Database - GIDB - Global Integrated Database
Version
Statement - "After checking all items relative to the data management activities, the clinical manager and the data manager (pharma, CRO, consultant or otherwise, in-house or outsourced) indicate that the database is final and request it to be locked."
Signed and dated by the clinical manager
Signed and dated by the data manager
Signed and dated by the biostatistician that wrote the SAP (GIDB) - the person performing the "Lock"
Time and date of the GIDB Lock.

There are no changes allowed to the GIDB after the time, date and signatures are received and the Database Lock Form is fully executed on the "same day".

Make no mistake in the process, procedure, time, date or otherwise - it will invalidate the GIDB - now, the clinical submission GIDB has serious data integrity issues - sometimes reparable with GCP correction and communication with FDA, sometimes irreparable, sometimes - "a do over - the GIDB has to be created from the start" - first data point, first clinical study. Serious cost, timeline delays, quality management issues, perception of FDA - not good.

More to come from the Desk of Dante pertaining to the Clinical Submission GIDB - important points to consider.

GIDB - Global Integrated Database - Clinical/Regulatory Submission

2010-01-11T12:01:00.003-05:00

A point to consider which is often asked and debated by pharma when considering the development, structure and SAP (Statistical Analysis Plan) of the Clinical/Regulatory Submission GIDB (Global Integrated Database). The GIDB is an integrated database which captures all data from Clinical Studies, Phases 1,2,3. The GIDB includes all data for clinical safety and clinical efficacy. FDA will often expect several "GIDBs" - one for safety and one for efficacy. The GIDB for efficacy will include data for Clinical Studies, Phase 2 and 3. The GIDB for safety will include data for Clinical Studies, Phases 1,2,3 - yes, FDA will expect, a GIDB for Phase 1 as well.

It is expected by FDA to "have some pooling across all studies" for Phase 1 safety. Most pharma disagree with the Phase 1 GIDB because they feel that Phase 1 studies are too heterogeneous in design and captures information for safety and tolerability, not detailed , much like a POC study.

However, the FDA explanation and reasoning is that even in Phase 1 an AE (adverse event) may appear and for FDA that is their main concern to make sure ALL AEs are captured, reported, reviewed and researched - the ultimate goal is not to approve a drug - it is patient safety.

Make sure you correspond with FDA, verbally and in writing as to this requirement. It is a point of consideration to the overall filing - it can trigger a RTF (Refusal to File) if FDA requested a Phase 1 GIDB and the pharma company did not include one in the filing.

Careful negotiation with FDA pertaining to the content and the TOC of the GIDB, the pooling is important. The GIDB must carry the "storyline" of the clinical submission and should be equivalent to the eventual message in the label of the drug. With careful planning and clear statistical strategy, one can negotiate with FDA how to present the data in the best way for clarity, however, don't fall short on the importance of including all safety data at all stages of clinical development. Under-reporting for any reason is not tolerated by FDA.

The Difference between TGA and EU CTD Filings

2010-01-09T10:37:00.006-05:00

A client of mine just asked me several days ago, a drug was purchased from a company that was in distress, the "price was right". The drug was just approved in the EU. The client wanted to submit the same CTD dossier to TGA (Australia).

The client is correct on one hand and needs advice on the other. In my experience to handle sections with "identical" content for TGA, EU, FDA, others - consider first that nothing is a cut and paste, nothing is identical, nothing is exactly the same from one submission to another. Second, to save time, map similar sections from one document to another, perform a cut and paste activity from one document to another and modify as needed. A QC must be performed to deem this documentation QC final and QA certified.

The answer to the larger question - yes, TGA is happy to use the CTD documentation from EU for their review, however, there are certain sections that must be, by requirement expanded. One of these sections is clinical laboratory data, ECG and otherwise. Another difference between EU and TGA, is "narratives" - narratives (several types) may be included in Module 1 for TGA, not so with EU. So, here are two examples, the former pertaining to expansion of data and the latter pertaining to a change in content location. The point, whether minor and major - there are differences.

Communication with TGA is a must to understand fully the target TOC, the arrangement and the exact organization for the format and the entire clinical submission. Always request correspondence, minutes to the meeting, TC or face to face - this information becomes critical at the time of filing and RTF and completeness. QC the clinical submission - all Modules - for accuracy and consistency across all data and documents.

Medicines for Children - EU Pediatric Regulation - EMEA

2010-01-08T18:08:00.002-05:00

In the previous communication, information pertaining to EU PIP was provided to the readers. A bit more about the PIP Regulation - yes, it is new - entered into force in the EU on 26 January 2007.

The objective of the Pediatric Regulation is to improve the health of children in EU by:

facilitating the development and availability of medicines for children aged 0 to 17 years
ensuring that medicines for use in children are of high quality
ethically researched
authorized appropriately
quality-controlled
quality-assured
improving the availability of information on the use of medicines for children

without:

subjecting children to unnecessary clinical studies and clinical trials
delaying the authorization of medicines for use in adults.

The Pediatric Regulation dramatically changes the regulatory environment for pediatric medicines in EU.

In the next communication, I will provide opinion and key aspects of the changes impacting the regulatory environment for pediatric medicines in EU.

PIP EU - Pediatric Investigational Plan - Clinical/Regulatory Submission

2010-01-08T15:54:00.004-05:00

Due to recent legislation in the EU governing the development and authorization of medicines for use in children, a PIP now needs to be written and an opinion adopted, prior to clinical/regulatory submission of a MAA - Marketing Authorization Application.

The preparation of a PIP presents the unique challenge of concisely presenting information on the disease to be treated in children and current knowledge of the drug being developed, together with assembling a convincing rationale for the pediatric development program being proposed.

PIPs can be developed, prepared and submitted in most therapeutic areas, applicable to pediatrics.

In several ways, the PIP is more complicated than most clinical/regulatory submissions. Therefore, it is strongly advised that all pharma sponsor functions be proactively involved. Literature based information, post-marketing information, safety surveillance information and otherwise as well as previously submitted and approved filing for the adult in all indications, if applicable, are readily available to the writing and QC teams at development start of the PIP.

Acceptance and use of the PIP clinical/regulatory submission in the EU is in its first year and I believe just in the recent past, the first approval was awarded, so the SOPs, the structure and content are still under scrutiny and is currently monitored and reviewed with rigor.

From the Desk of Dante and Dante Colleagues.

Clinical Documentation - Medical Writers and QC (Quality Control)

2010-01-04T15:33:00.004-05:00

A clinical development program/CTD clinical submission for drug, biologic, device, vaccine, gene-product, stem cell, monoclonal and otherwise, require a range of documentation, regulatory, non-regulatory, clinical, non-clinical, major and minor, all require process and procedural adherence, all require QC (quality control) of data, all require QA (quality assurance) of guidance completeness and compliance. All require tracking and monitoring. All require project management for realistic timelines, resource and capacity. All require dedicated medical writers.

The range of documents required for a clinical development program which by normal progression populates your CTD (Common Technical Document) Clinical Submission includes but is not limited to the following -

CSP (Clinical Study Protocol)
CSR (Clinical Study Report)
CTR (Clinical Trial Report)
CTD Module Summaries
Informed Consent Form
Narratives
Subject Patient Profiles
PIP (Pediatric Investigative Plan)
RMP (Risk Management Plan)
Manuscripts
SmPC (Summary of Product Characteristics)
USPI (United States Package Insert)
Posters
PSUR (Periodic Safety Update Report)
ASR (Annual Safety Report)
IB Investigator Brochure
IMPD (EMEA Product Dossier)
CTA (Clinical Trial Application)
IND (Investigational New Drug Application)
NDA (New Drug Application)
GIP (General Investigative Plan).

It is imperative to have your clinical development team and your clinical submission team work together at the beginning of your clinical development program (CDP) through to filing to ensure efficiency and quality.

It is imperative that expert medical writers and QC work together in the early document development stage, preparing thoughts and clear structured statements. Thoughts and statements that are real and can be supported by data.

By organizing the medical writers and QC teams early in the development of your documentation, it will streamline the later stages of the CTD and streamline all documentation.

Using the same teams, medical writers and QC and keeping those teams together until the filing of the dossier will ensure overall efficiency, consistency and accuracy.

When does QC begin? Which documents should be QC? At the beginning of the clinical program and all documentation, respectively.

What is the benefit of having early medical writing and QC teams? - The benefit and result can be easily measured in metrics pertaining to ROI (return on investment) -

# of document revisions are reduced
# of QC cycles are reduced
# of document drafts are reduced
# of team reviews are reduced
time to filing is reduced
costs of the CDP and CTD are reduced
impact on employee manpower is reduced
impact on pharma organization is reduced
CRO outsourcing, timelines, efforts, materials, consultants, tasks are reduced.

Global Project Team Leadership and Task Management for Clinical Submission

2010-01-02T19:09:00.004-05:00

Global Project Management occurs across all sponsor functions and all vendors.

The "gate-keeper" role of a global clinical submission project leader is to lead the team and manage the functions, the issues, the changes, the processes, the procedures, especially monitor and QC the data and the documentation. "On-time" timelines and targets will be achieved if the practice of leadership, management and communication are performed religiously, thoroughly, completely, logically, logistically and concisely. Find the weakest link, whatever and where ever and "support" the link.

Global Project Leadership and Management for Clinical Submission occurs across all sponsor functions and all vendors, all tasks, all deliverables, all responsibilities, all accountabilities, all teams, contributing to the filing and the eventual submission -

Regulatory
Clinical
Nonclinical
CMC
Data Management
Statistics
Programming
Project
Publishing
Quality Control
Quality Assurance
Contributing Functions
Outsourced, Contractors, Consultants, Vendors
All Data
All Databases, study level and global integrated
Experts, Advisory Committees, Opinion Leaders
Adjudicators
Timelines, Tracking, Milestones, Monitoring, Communication, FDA Correspondence
Pharmacovigilence.

Did I miss anyone, any team, any task, any function?

Data Management for Clinical Studies

2009-12-30T16:56:00.002-05:00

The management of data at the clinical study level is the foundation of what will eventually become one of the many building blocks of your clinical submission to FDA. Considerations that must be processed and planned by regulation and guideline regarding FDA, EMEA, ICH, TGA, DEC, other, must be current in compliance and compatible and equivalent to pharmaceutical industry standards. Engage experts to manage your data - it is impossible to do otherwise and achieve the integrity of data and accuracy that is required by regulation. At the Clinical Study Level, there are steps in "handling" data, from CRF development to Database Lock to Database and Program Transfers at the end of the clinical study.

Here are important steps and points to consider, and without question, each step and/or action must be recorded, processed and managed by quality management data plans specific for the task - all of the following require "Standard Operating Procedures (SOPs)". On FDA Audit, for sure, these plans must be available for review by the agency. Each respective plan must include data handling versions specific for each task, as reviewed below.

CRF Development.
Database Setup - "Oracle" is the choice and CDISC versions 2.0 and 3.1 are used by pharma at this writing and are compliant with regulatory standards and compatible with industry use and FDA review.
Data Validation.
Data Coding - The management of data for clinical signs and symptoms, AE coding using MedDRA Version 9.1 or previous versions. Treatment Coding using WHODRL Version 6.4 or previous versions. Pharmacovigilance database reconciliation.
Quality Control Management Procedures for Interim Data Analysis (IA), Data Entry Audits, Data Review, Data Change, Database Lock and Data/ Program Transfer at the end of the Clinical Study. Data/Program Tranfers can be formatted in .sas., csv., txt., xml, other - the format must be agreed upon by the pharma, all CROs, FDA and WW agencies slated for submission.
Quality Control (QC) Plans to ensure accurate, compliant data. Expert QC teams work with raw data captured in the CRF, DCFs, listings, PPs, other source data documentation to ensure correct management and accuracy of data until the database is locked and the data is transferred to the sponsor or to the next step - the clinical submission team.
End of Clinical Study Data Management.
Data Tools - Clinical Data Management "Systems" that are used by the industry and compatible and compliant with FDA 21 CFR Part 11 Guidance. For example, "Capture System", Version 5.5, Editor "Clinsight".
Audit Trail Systems and SOPs to capture all data changes, database actions and data and procedural change and standard deviations.

Expert data management teams work onsite and offsite and integrate with the sponsor, the CROs, the monitors and clinical study site personnel, CRC, CRA, PIS, sub-PIs, from the first data point - and from CRF development to end of study transfer of data and programs. Monitor and Track Data. Develop Plans. Adhere to Plans. Record Changes. Manage Change. Lead the team and manage the plans.

SAS Programming Points to Consider in Clinical Submission

2009-12-27T09:30:00.002-05:00

Remember, there is SAS programming performed at two levels in a clinical submission.

One: There is programming which occurs at the clinical study level. At the completion of all clinical studies, each clinical study database is reviewed, cleaned and closed. Each clinical study SAP (Statistical Analysis Plan) will direct the generation and programming of clinical study TLGFs - SAS output of programmed tables, listings, graphs and figures to be incorporated intext and EOT (End of Text) located in the appendix of the CSR.
Two: At the completion of the last pivotal clinical study or before, depending on the MSPP, and according to an Integrated, Global SAP, a GIDB (Global Integrated Database) is created which integrates all data from all clinical studies, in particular for clinical safety, clinical efficacy and clinical pharmacology. SAS programming off the GIDB will serve as the data source of integrated TGLFs that will be used by medical writers and clinical team members to develop CTD Module Clinical Summaries (2.7.1, 2.7.2, 2.7.3, 2.7.4), Clinical Overview (2.5.), ISS (Integrated Summary of Safety) and ISE (Integrated Summary of Efficacy. Note: There is a separate, additional ClinPharm Database at the Global Integrated level of programming.

All clinical study databases and the GIDB must be CDISC compliant for the year the filing is to be submitted to FDA.
It is strongly recommended that Subject or Patient Profiles (PP) are developed and programmed for Clinical Phase 2 and 3 studies. With communication and logic, FDA will negotiate with the sponsor to program PPs only for pivotal Phase 2 and 3 clinical studies, refer to the Integrated SAP as to whether the programmed TLGFs will be pooled in some way, for example, for Phase 2 and 3 clinical studies, data is often combined.
Before creating the GIDB, CSR databases must be validated and checked for quality, accuracy, consistency, completeness, coding, compliance, nomenclature, CDISC version, etc. The GIDB must be harmonized when combining databases from all clinical studies worldwide. Standards, metrics, terms, units, calibrations, measures must be standardized for labs, AEs, medical history, eligibility, etc.
FDA will most certainly ask the sponsor to submit a ISS (Integrated Summary of Safety), which is similar but not exact in content and data presentation to CTD M 2.7.4, the Clinical Summary of Safety.
FDA will most certainly ask the sponsor to submit a ISE (Integrated Summary of Efficacy), which is similar but not exact in content and data presentation to CTD M 2.7.3, the Clinical Summary of Efficacy.
TLGFs for CTD Modules 2.7.3 (CSE), 2.7.4 (CSS) and the ISE and the ISS, respectively, will be programmed in SAS output from the GIDB.
All document summaries, all PPs, all CSRs, all TLGFs, whether at the clinical study level or the GIDB level must be QC. Quality Control of data is essential at the CSR and GIDB levels.
Remember that the ISS, ISE, CTD Module GIDB TLGFs must be compliant and compatible with the clinical submission writing system and "que" and the publishing tool, especially for format considerations.
All GIDB SAS programs are submitted at the time of filing to FDA for Phase 2 and 3 clinical studies and ClinPharm studies.
If requested, Phase 1 SAS programs are also filed at the time of the clinical submission with FDA.

Much more to come...

Clinical Submission - Integrated Statistical Analysis Plan (SAP)

2009-12-26T11:44:00.004-05:00

For your clinical - regulatory filing, FDA requires an integrated SAP. An integrated SAP is a harmonization of data and terms, data coding, data guidelines, data requirements, data CDISC version and data otherwise of all clinical studies for safety, efficacy and clinical pharmacology, performed during the clinical examination and lifetime of the investigational drug. The Integrated SAP must be compliant and up to date with all requirements and guidelines for the year the file is to be submitted to FDA.

It is strongly recommended that at the completion of your Phase 2 studies, a Briefing Document is prepared for FDA that will include the overall Submission "Integrated" SAP and Analysis Plan for the following:

Develop a Integrated Clinical Submission SAP for Clinical Phases 1,2,3
Choose how the Integrated Safety Data will be presented and then develop your Integrated Safety SAPs accordingly - for example, a SAP for Phase 1, a SAP for Phase 2, a SAP for Phase 3, or a SAP for Phase 2 and 3 combined
Develop a separate Integrated SAP for Efficacy - usually pooling Phase 2 and Phase 3 clinical studies
Develop a separate SAP for Clinical Pharmacology
File the SAPs early with FDA as a component of the sponsor's End of Phase 2 Briefing Document
Request a date with FDA to review and comment and discuss the End of Phase 2 Briefing Document especially the SAPs
Make sure to finalize agreements with FDA on the SAP methodology early so preparation for the Integrated Global Database , the GIDB can begin
DO NOT unblind the last Pivotal Phase 3 Clinical Study before finalizing and receiving agreement on the Integrated SAPs for Safety, Efficacy and Clinical Pharmacology
Ask FDA for meeting minutes pertaining to the End of Phase 2 Briefing Document Meeting to ensure comprehension and confirm agreements of what is to be filed pertaining to data presentation, integration and pooling
Review the meeting minutes and debrief notes and all correspondence from FDA - it is important to archive all correspondence from FDA - follow the correspondence and make sure that all items of the correspondence from FDA are addressed - if this is not done - a RTF - REFUSAL TO FILE will be triggered by FDA at the time of filing - the RTF will be issued for "filing an incomplete clinical submission". Ramifications, costs, loss of timelines, submission integrity, questioning perception with FDA and delays are huge and can be easily avoided with properly managing FDA correspondence and follow-up.

Effective Medical Writing for Clinical Submission #6

2009-12-23T18:51:00.002-05:00

For medical writing for clinical submission to be effective, lets review submission reminders and points to consider:

Know FDA and all regulatory requirements and guidelines to ensure a complete and compliant document
Always remember who your end user is - yes, FDA and regulatory agency reviewers, so create a simple, user friendly document
Communicate to FDA and others, planned changes that may be used in a document - if different from the standard requirements and guidelines
Again, provide user friendly documents that are easily navigated
Make sure all bookmarks, hyperlinks, internal (text) and external (linked) to the document are present, correctly linked to content and are active
For the CTD Module 2.5, which is the Clinical Overview and for the Application Summary for a NDA, transparency goes a long way, discuss weaknesses in the subject matter and content as well as strengths - be prepared to address both in support of the benefits (risks) of the drug
Respect document length (# of pages and # of in text and end of text (EOT) tables, listings, graphs and figures), especially the Clinical Overview - the overview must be ~25 pages summarizing data and interpretation - not a regurgitation of tabular and text table data
Ensure appropriate hyperlinking to other CTD Modules 1,2,3,4,5 and/or NDA Sections such as, the ISS (Integrated Summary of Safety) and ISE (Integrated Summary of Efficacy).

All clinical submission documents have a respectful, anticipated and expected length - adhere to the requirements and guidelines when determining the length of all clinical submission documents early in the development of the document. The "recommended" length of each clinical submission document can be found at www.fda.gov.

Effective Medical Writing for Clinical Submission #5

2009-12-20T16:06:00.002-05:00

Yes, there is the document type and the timelines to consider, now lets look a bit more into the review and QC cycles involved in the development process of the document.
Important points to consider:

Clearly define the objectives and the process to be followed during the actual review and QC
Who on the clinical and project submission teams are involved in the review and the QC - of course the medical writer and the QC data controller are involved throughout the lifetime of the document under development
How many review cycles are needed
How many QC cycles are needed
How will the review comments be tracked
How will the review comments be resolved
Who will resolve the review comments
Check to see if the review comments are implemented and implemented correctly
Follow the same considerations for outlining the process for QC comments
For each review and QC cycle, no comment should be left without resolution - this includes, data, text, statement, interpretation, conclusion or an action item
Submission medical writers and QC data consultants must always interact directly with clinical or expert decision makers in resolving comments and QC findings - this to avoid uninformed intermediaries that may not have credible, accurate, decisive resolutions to positioned comments.

In order to move a document ahead, each review and QC cycle must not leave open-ended comments and both medical writer and QC consultant must be able to close out the comment, complete the resolution and implement the change to the document - by using a tracking tool which archives the change, the reason for the change, the source of corrective action, date of change, the version of the document changed and of course the data changed - the comment is then signed off and initialed by the MW and QC. The comment is not to be revisited. The next document will reflect the implemented correction.

Moving the document ahead with Quality is essential. Changes must be tracked and resolved. Lead the team and manage the comments, track the resolutions.

Effective Medical Writing for Clinical Submission #4

2009-12-19T19:48:00.002-05:00

When preparing clinical submission documents two parameters must be considered. One, the document itself and two, document timelines. The latter is in some instances more important and more difficult to achieve. Yes, the document must be completed according to GCP, ICH, FDA and CTD requirements and guidelines. However, the document must be completed with a timeline in mind as well. This timeline is integral to the rest of the clinical submission because the message and content of each document builds on each other as the writing team climbs the clinical submission pyramid, from CTD Modules 3,4,5 being the foundation of the clinical submission pyramid, Module 2, backbone and Module 1, the peak of the pyramid.

Important points to consider with clinical submission document timelines - what the clinical, project submission and medical writing teams must develop and adhere to for each document prepared and written:

Are the document timelines realistic
Implement periodic clinical and medical writing team meetings to ensure that the timelines remain realistic
Implement measures to communicate the progress of each document vs timelines
Ensure that each medical writer and quality data controller gets accurate, quality source documents to develop the document content
Ensure that each medical writer and quality data controller gets accurate quality tables, listings, graphs and figures (TLGFs) to develop the document content
Ensure that each medical writer and quality data controller gets source documents and TLGFs on time for a start date to begin writing - the clock starts
Ensure that each medical writer and quality data controller gets a complete set of source documents and TLGFs
Ensure that each medical writer and quality data controller gets the correct, most up to date version of the source documents and TLGFs
Build in useful, meaningful and appropriate team reviews
Build in useful, meaningful and appropriate cycles of QC
Build in a realistic sign-off final date.

Monitor and project manage each document and each step of document development vs a timeline.

Measure metrics on completion vs progress and impact to the overall timeline of the clinical filing and clinical submission. Lead the people, project manage the documents, control the quality of the data. Keep timelines realistic. Ensure timelines.

Effective Medical Writing for Clinical Submission #3

2009-12-13T12:23:00.002-05:00

Focus, create and develop templates early and communicate processes and procedures to medical writers and all team members. Submission medical writers who are experienced must lead this effort since they have the ultimate responsibility for the overall quality of the final document. The direction is simple and if followed religiously, the final document will be content final, with accurate, consistent data, ready for publish, ready for submission, ready for FDA.

Focus all writers, all teams, nonclinical, clinical, CMC, CP, CRO, Sponsor, Outsourced Submission Teams, etc., early in the development of the submission document pertaining to agreed upon processes and procedures
Adhere to the processes and procedures - do no deviate - if a deviation is considered, quickly inform all team members - the deviation will undoubtedly impact subsequent documents
Work with Outsourced Quality Control consultants early in the process to ensure accurate document versions and data versions across all functions, across all documents
Establish an agreement on a storyline early in the development of the submission document
Do not deviate from the agreed upon storyline once set and communicate the storyline to team members and medical writers - this storyline will be written in numerous documents and cited often in the overall submission - stay with one storyline for consistency and to drive the benefits of the drug to the reviewers at FDA

Create submission documents shells early in the development of the TOC - documents shells, populated with data or not, can provide useful information pertaining to electronic hyperlinks, size of submission, how many programmed tables, listings, graphs and figures per document, how to provide submission document and content crosslinks, etc.

Develop the submission document format, writing styles and submission and publish ready templates early and consistently across all submission NDA Sections and CTD Modules 1-5.

Good medical writing and good, clear, concise content - is a team effort. Communicate. Enforce Quality and Consistency Processes and Procedures. Track and review the progress of each document frequently. Lead the submission team and project manage document issues!
More to come...

Effective Medical Writing for Clinical Submission #2

2009-12-11T14:10:00.004-05:00

Once the clinical submission team establishes (with FDA) a TOC for the clinical filing, responsibilities and accountability's are assigned to medical writers. Who will write which documents? Will the documents be written by the sponsor? Will the documents be written by the pharma's functional areas? Will the documents be written by the CRO? Or will the documents be written by consultants, members of a high level medical writing project/clinical submission team asked to participate (outsourced) by the pharma?

It is strongly advised that writing decisions and assignments do not change mid-stream - adhere to a decision that there is one author - and that author is responsible and accountable for each assigned document from start to finish, submission ready, publish ready through final sign-off.

Simple considerations to establish early...

Who is responsible from each function, if a function task, if a consultant, if a medical writing team?
Who is accountable from each function, if a function task, if a consultant, if a medical writing team?
Establish clear reporting and responsibility lines of communication, for data questions, for issues, for progress, for status!
Clarify writing responsibilities, who will write, who will review, how many reviews?
Clarify who will QC, who will review the QC findings, who will implement the QC findings, who will track the QC findings, how to track the QC findings, how many cycles of QC?
Clarify ownership of the documents as a whole, to ensure consistent, data accurate, submission ready, publish ready, template accurate, storyline correct, documents with continuity and completion endpoints!

In my opinion and historically, since clinical submission documents are frequently complicated with data, hyperlinks and statements, outsourced medical submission writing teams should be engaged by the pharma - these medical writers must be leaders in the respective subject, be proactive (and diplomatic) in soliciting information from sponsor functions, which include but are not limited to, biostatistics, project management, data management, nonclinical and clinical functions, CROs, experts and QC. The medical writer drives the document to completion not clinical or regulatory team participants. The medical writer must work early in the development of the document template with programmers, QC and submission publishers to ensure submission ready and publish ready documents at completion and final sign-off.

More to come...

Effective Medical Writing for Clinical Submission #1

2009-12-10T17:25:00.003-05:00

Effective, which means, cost, time, effort, quality-controlled, quality-assured, consistent, accurate, version correct, data-driven, GCP-driven, process and procedure adherent, medical writing for clinical submission will follow these parameters early in the development of a document to be written...

Consider all documents and components, for examples, appendices, narratives, TLGFs, required for the clinical submission...

a clinical submission for a drug for example has 5 CTD Modules, "what documents and document components are to be written"? Develop a TOC!
a clinical submission will require a format, "what format will be followed"? CTD? Legacy NDA? 505 (b)(1) or (2)? Choose a format!
a clinical submission will require source documents to support the written documents, "what are the source documents, which will be included in the clinical submission"? Develop a TOC that reaches this level of granularity!
a clinical submission will require a team effort between writers, QC, QA, sponsor functions, experts, CROs, etc., "what is the process for file and information transfer between team members onsite and offsite, inhouse and remote"? Develop a process and procedure! Adhere to the process and procedure throughout the clinical submission! Communicate the process and procedure to all team members!

For effective medical writing for clinical submission, these are important points to consider early in the process.

More to come...

Clinical Research Fraud - Prevention

2009-12-08T12:30:00.002-05:00

Here are some tips on "How to Prevent Clinical Fraud" to Pharma Sponsors, Clinical Team Staff and CRAs and others who monitor and/or audit GCP at Investigator Clinical Study Sites...

During the pre-study evaluation, carefully scrutinize clinical sites in the following areas:

interest in the study
stability of the clinical staff onsite
investigator/staff interactions
workload
level of training
conduct GCP training at the start and throughout the study as necessary
emphasize company policy on fraud at the initiation visit
be expert on the protocol particularly with parameters that determine eligibility and primary efficacy
minimize the use of enrollment incentives and pressure to perform and enroll
don't place needless requirements or unreasonable demands on clinical sites
maintain frequent interaction with clinical sites through regular monitoring visits and phone calls.

Good follow-up practices and procedures and early utilization of GCP and quality control measures will undoubtedly provide rigor, expectations of clinical quality and reduce the thought and even the logistics of clinical fraud at the site.

Be involved as a monitor and sponsor. Practice follow-up. Train and insist on integrity and quality control and GCP.

Clinical Trial Fraud - Questionable Miscellaneous Data

2009-12-05T13:11:00.002-05:00

Finally we come to "miscellaneous" data in clinical misconduct and fraud. Miscellaneous data is just that - found everywhere, comment page sections, comment fields, notes, charts, medical history, entry eligibility, etc. There is a trend. If a few miscellaneous data checks are found, for sure, there will be numerous "finds" in data entries and corrections, certainly not according to GCP and Quality Control Audits processes and procedures.

Here are examples of miscellaneous fraudulent clinical data:

Miscellaneous items in subject binders incriminating
Difficult to determine PIs involvement
Reiteration of SC notes
Corrections are rarely initialed
Corrections are rarely dated
CRF Investigator Assessment Page says "not assessed". At a later date, "not assessed" is crossed out and then a reaction is indicated.
No "person obtaining subject informed consent" signature
Documents are dated and are signed by employee with dates before the 1st day of employment at the clinical study site
No GCP training
Medical History page lists 1st item as a surgery which occurred several months after the subject's enrollment into the clinical study
Clinical chart notes indicate "itching/irritation in TX area". Source documents indicate "none".

Inherent in the trend of miscellaneous data fraud is inconsistency and "forgetting" comments written in a variety of sections and pages during an onsite monitoring visit and/or a subject's scheduled visit according to protocol. Fraudulent data often lacks consistency. Look for the lack of consistency. There is a trail.

Clinical Trial Fraud - Lab Information, General Warning Signs of Misconduct

2009-11-30T12:28:00.004-05:00

In my experience, questionable data is readily and easily detected in subject lab information and results. Clinical study staff are trained by education and are expected to know each protocol lab test and understand lab values, IUs and ranges and the proper way to fill out the lab forms. Lab protocols and tests are reviewed extensively during pre-study start Investigator Meetings with staff, monitors and PIs/SCs.

It is my practice as well as my recommendation when reviewing, monitoring and investigating subject lab information and results - do not just log the test...instead, read, read the test and the results, each data entry, read the entire form. A high frequency and incidence of data fraud at the clinical study site will, most definitely, be found in subject lab data.

Where and How?

Panic values on labs coded "1" and no comment is made by PI
Labs not evaluated prior to entrance into the clinical study
Technical units are expressed several different ways by staff and PI/SC.

General Warning Signs of Misconduct - What are these? Easy to identify for a monitor who is clear and present...

High staff turnover
Staff are disgruntled
Staff are fearful
Staff are anxious
Staff are depressed
Staff are defensive
High pressure work environment
Obsession with study payments
Absent PIs
Absent SCs
Absent staff
Lack of GCP training
Unusually fast recruitment.

Monitoring with Quality Control is a full time job and when done correctly, GCP is clear and misconduct and fraud are easily seen in trends and such. Choose and interview your clinical PIs, SCs, staff, CRO and/or consultant CRAs/CRCs and monitors carefully. Train them on GCP and QC and QA. Monitor their visits, reports, correspondence, communication and performance.

As well, there is clinical study data that falls into the "miscellaneous" subject data category - interestingly, not significant to subject outcomes or endpoints, but will point a finger at data trends leading to the identification of clinical fraud. These categories will be highlighted in my next blog pertaining to clinical fraud at the clinical study site.