Thursday, April 29, 2010

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,, 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.

Wednesday, April 28, 2010

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.

Tuesday, April 20, 2010

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.

Sunday, April 18, 2010

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).

Wednesday, April 14, 2010

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.

Monday, April 12, 2010

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...

Sunday, April 11, 2010

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.


  • 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.

Wednesday, April 7, 2010

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...

Sunday, April 4, 2010

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.