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/.