Dante's Informative Posts

...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

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

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)

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

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

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

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

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

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)

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

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)

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

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

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

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

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

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

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

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:

1. which patients will respond well to a particular therapy
2. which patients are likely not to benefit from therapy
3. 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?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1. Introduction
2. Review of Subjects Safety on Clinical Trial
3. Overall Safety Evaluation
4. 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

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"

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.