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

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. 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. 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. 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. 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 – http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Closing Sermon
 Please -- Procedures
 Teach – Training
 Risk – Records
 Avoidance – Audits
 Vigorously – Validate
And
 Comprehensively – Corporate Culture of
Compliance

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
michael.swit@weinberggroup.com
www.weinberggroup.com
Questions?

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.
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