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Ensuring FDA Compliance in International Clinical Trials


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Detailed review of FDA compliance issues in clinical trials, with an emphasis on impact on international studies.

Published in: Law
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Ensuring FDA Compliance in International Clinical Trials

  1. 1. Ensuring FDA Compliance in International Clinical Trials Michael A. Swit, Esq., Vice President ACI International Clinical Trials Master Class Thursday, February 26, 2009 New York City
  2. 2. Enforcement – Ensures FDA’s Mission  Products are safe and effective  Honest, accurate, informative representation of products  Correction of noncompliance or removal of unsafe or unlawful products  Human subject protection is a goal shared with HHS’s OHRP
  3. 3. GCP -- Learning From FDA’s Warning Letters to Investigators --  No geographic concentration: they are issued from district offices all over the country  CDER, CBER and CDRH are all active  Reputation and compliance don’t always go together  The specificity of detailing violations: no compliance detail is too small
  4. 4. GCP -- Learning From FDA’s Warning Letters to Investigators …  Warning Letters can be issued much later than the 483 and adverse publicity  Lots of money is spent on legal fees during the enforcement process: avoidance is your best policy!  Foreign clinical site Warning Letters are very rare – in part, because the pure number of inspections is dramatically lower
  5. 5. Investigators – Inspections by The Numbers (closed since 1977)  U.S. – 7,920  Canada – 159  UK – 98  Germany – 67  France – 53  Russia – 50  Italy – 38  Poland – 38  Sweden – 38  South Africa – 30  Belgium – 28  Netherlands – 27  Argentina – 25  Brazil – 20  Mexico – 18  Spain – 18  Australia – 9  India – 8  China – 7  Japan – 3 Source: Clinical Investigator Inspection List For Investigational New Drug Studies –
  6. 6. So How Do You Learn How FDA Is Enforcing GCP Compliance Overseas  Very limited foreign examples – only two warning letters in last four years aimed at foreign clinical investigators.  But, if done under a U.S. IND, must meet all clinical study requirements  IND rules – Part 312  Informed Consent – Part 50  Financial Disclosure – Part 54  EC/IRB – Part 56  Thus, U.S. enforcement activity provides clear guidance
  7. 7. Moscow City Hospital WL -- 2006  You failed to maintain adequate and accurate case histories that record all observations and data pertinent to the investigation [21 CFR 312.62(b)] .  For Subject #_, the baseline ECG recording obtained on June 21, 2004, and the, Visit 4 ECG recording obtained on August 3, 2004, were identical except for the information hand-written on each ECG, including subject number and date of tracing.  For Subject #_, the baseline ECG recording obtained on June 21, 2004, and the Visit 4 ECG recording obtained on Aug 2, 2004, were identical except for the information hand-written on each ECG, including subject number and date of tracing.  Source records for Subjects #_ and #_, document that the same individual performed the baseline physical examinations on the same day (June 21, 2004) and at the same time (0900).
  8. 8. Moscow City Hospital WL – 2006 …  You failed to maintain adequate records of the disposition of the drug including dates, quantity and use by subjects [21 CPR 312.62(a)] .  Dispensing records show 5 mg. given out to Subject X, but 2.5 mg. tabs returned by same Subject  Length of inspection – 3 days
  9. 9. Children’s Hospital of E. Ontario WL -- 2003  You failed to protect the rights, safety, and welfare of subjects under your care and failed to ensure that the investigation was conducted according to the investigational plan. [21 CFR 5 312.60]  overdoses of the study drug interleukin-2 (IL-2) that were 22 to 25 times higher than the dose specified in the protocol  One death  Cause – incorrect dosing form used that did not jibe with the protocol
  10. 10. Children’s Hospital of E. Ontario WL …  You failed to ensure that the investigation was conducted according to the investigational plan. [21 CFR 312.60].  Subject hospitalized for three days, but not so documented.  Records did not say at all how long she was in hospital  CRFs submitted 4 months late; required under protocol to be filed in one week  No record of storage in refrigerated conditions as required by protocol  Length of inspection – 5 days per WL  Average length of U.S. inspections leading to WL’s – sampling of 10 from last two years, showed average number of days (measured start to finish) was 28 days
  11. 11. GCP Run Amuck? Johns Hopkins University: June 2001  FDA Inspection followed report of death of a healthy volunteer who had inhaled hexamethonium  FDA’s 483 to the IRB (September 2001) cites:  failure to obtain effective informed consents: failure to disclose that inhalation administration of the drug was experimental
  12. 12. GCP -- Johns Hopkins University …  Warning Letter Issued March 31, 2003 to Investigator  failure of clinical investigator to submit an IND prior to conducting the investigation (3 subjects)  changes to IRB approved protocol without notifying the IRB (and without IRB approval)  failure to report an unanticipated AE to the IRB  Note: time interval between incidents and Warning Letter – unusual, but not unprecedented.
  13. 13. GCP -- Warning letters: Informed Consent Failure to obtain informed consent in accordance with the provisions of 21 CFR Part 50. [21 CFR Part 312.60] There are no consent forms for two subjects, three consent forms were signed after the test article was administered, and one subject signed the wrong consent form as follows: • no informed consent forms for certain patients • Signed the wrong consent form (different study) • Signed the informed consent form over four months after the test article was administered
  14. 14. Warning Letters – Lessons …  If protocol requires patient to complete a diary card during 5 days from pre-screening and screening visits, they CANNOT be pre- screened and screened on the SAME day  “Your (investigator’s) response indicates that you were not aware of the deviations in study drug dosage and administration due to the blinded nature of the study randomizations. Nevertheless, as the clinical investigator, you are ultimately responsible for the pharmacy staff.”  Investigator submitted incorrect data to sponsor
  15. 15. GCP: SOP Auditing  To measure compliance with GCP, FDA audits sponsors’ SOPs  informed consent  protocol preparation  adverse experience reporting  data entry and compilation  recordkeeping
  16. 16. GCPs – What FDA Reviews In Inspecting a Clinical Site  How (e.g., telephone, memo, etc.) the monitor explained to the clinical investigator the status of the test article, nature of the protocol, and the obligations of a clinical investigator  Whether authority for the conduct of the various aspects of the study was delegated properly so that the investigator retained control and knowledge of the study
  17. 17. GCPs – What FDA Reviews In Inspecting a Clinical Site  If and why the investigator discontinued the study before completion  If laboratory tests are performed in the investigator’s own facility, whether that facility is equipped/staffed to perform each test specified (example: CLIA high complexity certification)  Protocol and all EC/IRB approvals and modifications
  18. 18. GCP -- Protocol Amendments – Must Be Up to Date  Subject selection (i.e., inclusion and exclusion criteria)  Number of subjects  Frequency of subject observations  Dosage, frequency
  19. 19. GCP -- Protocol Amendments – Must Be Up to Date  All changes to protocol must be:  documented by an approved amendment (and may need FDA pre- clearance under IND rules)  dated  maintained with the protocol  approved by the EC/IRB and reported to the sponsor before implementation, except where necessary to eliminate apparent immediate hazard to human subjects
  20. 20. GCP: Clinical Site Source Documents  FDA’s right to inspect must be in informed consent  Organization, condition, completeness, and legibility of source documents  Adequate documentation to assure all audited subjects did exist and were alive and available for the duration of their stated participation in the study  Comparison of source documents in the clinical investigator’s records with CRFs completed for the sponsor (don’t use CRFs as source docs)  Presence of completed clinical laboratory testing (including EKGs, X- rays, eye exams, etc.)  Whether all AEs were reported in the CRFs
  21. 21. GCP: Completeness of Patient Records Each patient record must contain:  Observations, information, and data on the condition of the subject at time subject entered clinical study AND records of exposure of subject to the test article  Observations and data on condition of subject throughout investigation, including results of lab tests, development of unrelated illnesses, and other factors that might alter effects of the test article; and  Signature log: identity of all persons and locations obtaining raw data or involved in the collection or analysis of such data
  22. 22. GCP: EC/IRB Matters  Investigator must maintains copies of all reports submitted to the EC/IRB and reports of all actions by the EC/IRB  Nature and frequency of periodic reports submitted to the EC/IRB  Investigator must submit a report to the EC/IRB of all deaths, adverse experiences and unanticipated problems involving risk to human subjects
  23. 23. GCP: Patient/Subject Recruitment  Use of media advertising  any promotional material or representation that the test article is safe and effective for the purpose for which it is under investigation is violative  all promotional materials must be submitted to the EC/IRB for review and approval before use  Payment of enrollment bonus to coordinator
  24. 24. GCP: Test Article Accountability  What is the date the last subject completed the study?  Were test articles returned when either:  The investigator discontinued or completed his/her participation;  The sponsor discontinued or terminated the investigation; or  The FDA terminated the investigation.  Unqualified or unauthorized persons may not administer or dispense the test article
  25. 25. GCP: Records Retention  Identification of custodian of required records and means for prompt access  Period of Retention  Two years following the date on which the test article is approved by FDA for marketing for the purposes which were the subject of the clinical investigation; or  Two years following the date on which the entire clinical investigation (not just the investigator’s part in it) is terminated or discontinued by the sponsor
  26. 26. Financial Certification/ Disclosure By Sponsors and Clinical Investigators  “No conflict, no interest” - University researcher  While some institutions flat out prohibit financial conflicts of interest, others permit their “management” - stock in escrow, disclosure to patients and in publications  Trend – rapidly moving away from allowing
  27. 27. Financial Disclosure By Sponsors and Clinical Investigators  21 C.F.R. Part 54 (applicable since 1999)  sponsors of a marketing application must submit information concerning certain compensation to, and certain financial interests of, any clinical investigators or subinvestigators (including spouses and dependent children) conducting certain clinical studies to support the application  March 20, 2001 Guidance Document from FDA clarifies disclosable financial interests, covered clinical studies, use of Forms 3454/3455
  28. 28. Financial Disclosure -- To Whom Does The Rule Apply?  Investigators and subinvestigators and their family members (aggregated interests)  March 2001 Guidance specifically exempts “nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make direct and significant contribution to the data”
  29. 29. Financial Integrity – via Disclosure??  Five types of compensation and rights (collectively “Interests”) are the primary focus of the regulation  Direct payments of more than $25,000.  excludes the costs for the conduct of clinical studies  includes honoraria, grants to fund ongoing research, compensation for or in the form of equipment or services, or retainers for ongoing consultation  disclosure (for all interests) must be made during the “covered” clinical trial and for one year following completion of the trial  “SPOOS” = Significant Payments of Other Sorts
  30. 30. Financial Disclosure…  Equity interest of more than $50,000 in a publicly traded company  Ownership interest, stock, stock option or other financial interest, no matter how small, the value of which cannot be readily determined through reference to public prices, (e.g., any privately held company or unlisted equity interests)
  31. 31. Financial Disclosure…  Proprietary interest in the investigational product  including, but not limited to, patents, copyrights, trade secrets, and licenses  Financial arrangements under which the compensation (e.g., money, equity interest, royalty interest) could be higher for a favorable trial outcome than for an unfavorable trial outcome
  32. 32. Financial Disclosure…  Interests are evaluated for disclosure on a “per investigator” basis  Interests of an investigator include the Interests held or received by an investigator and his/her spouse and dependent children, and are aggregated
  33. 33. Financial Disclosure…  “covered study” is a trial that FDA or the sponsor relies on to establish that the tested product is effective OR  a study in which a single investigator makes a significant contribution to the demonstration of safety  FDA is particularly concerned with Phase II and III trials (efficacy) and bioequivalence studies where results obtained by a single investigator can have a profound statistical effect on trial outcome
  34. 34. Financial Disclosure…  In general, large open-label studies conducted at multiple sites, treatment protocols, Phase I tolerance studies, pharmacokinetic studies, and most clinical pharmacology studies are not “covered” studies
  35. 35. Financial Disclosure By Sponsors and Clinical Investigators  Compliance with financial disclosure/ certification should be part of the clinical investigator selection process and be documented in compliance with regulations  Clinical study agreements should contain provisions requiring disclosure of Interests or a certification that there is nothing to disclose  CRO agreements should obligate the CRO to obtain disclosure/ certification  All clinical study agreements should include the right to obtain a one-year post study update regarding interests – and define, up front, when study ends!!
  36. 36. Financial Disclosure…  Licensing agreements with clinical investigators on a new investigational product should now contain a clause that requires them to comply with disclosure/certification requirements if their clinical data will be pivotal or relied upon in any subsequent marketing application  Establish and maintain a company-wide tracking system for investigators to enable the company to verify and substantiate its disclosures  Establish and implement procedures for the types of Interests held by investigators and how such Interests will be managed
  37. 37. Closing Sermon  Please -- Procedures  Teach – Training  Risk – Records  Avoidance – Audits  Vigorously – Validate And  Comprehensively – Corporate Culture of Compliance
  38. 38. Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President The Weinberg Group Inc. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.454.2979 Cell 760.815.4762 Questions?
  39. 39. About Your Speaker Michael A. Swit, Esq., is a Vice President at The Weinberg Group, where he develops and ensures the execution of a broad array of regulatory and other services to clients, both directly and through outside counsel. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His vast and multi-faceted experience includes serving for three and a half years, from 1990 to late 1993, as general counsel of Par Pharmaceutical, a prominent, publicly-traded, generic drug company. Mr. Swit then served for over four years as CEO of Washington Business Information, Inc. (now known as FDANews), a premier publisher of FDA regulatory newsletters and other specialty information products. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Groups in the San Diego office of Heller Ehrman White & McAuliffe and at McKenna & Cuneo, both in the firm's Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities. A former member of the Food & Drug Law Journal Editorial Board, Mr. Swit also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA. He earned his A.B., magna cum laude, with high honors in history, from Bowdoin College, and his law degree at Emory University School of Law. Mr. Swit is admitted to the D.C., Virginia and California bars. 38