Be Aware – or Beware Global Clinical Trial Regulations

Be Aware – or Beware
Global Clinical Trial Regulations
UT Southwestern Grand Rounds
Rick Robinson & Marti Cherry
November 7, 2012
Dallas, Texas
Introduction – Pfizer Troval Study,
Nigeria, 19961
Abdullahi v. Pfizer, 562 F.3d 163 (2d Cir. 2009), cert. denied, 130 S.Ct. 3541 (2010).
• Epidemic of bacterial meningitis
– Pfizer seeks approval for new antibiotic Trovafloxacin
Mesylate (“Trovan”) on children. Pfizer sponsored joint
American-Nigerian physician team to administer
Trovan to Nigerian children in April 1996 at a hospital.
– 200 children recruited as test subjects and received
Trovan; 11 died and others suffered symptoms such as
blindness, lameness, deafness, seizures, and
• Regulations to protect subjects include:
– Ethics Committee:2 Regulations require that an ethics
committee or Institutional Review Board (IRB) approve
the trial
– Informed Consent:3 Regulations require that the IRB
document that each child assent, and parents grant
permission for the child to be a test subject.
– Risk Justified:4 Risk must be justified by the
anticipated benefit to the subjects
See 21 C.F.R. § 50.52; 21 C.F.R. § 312.120
See 21 C.F.R. §50.55.
See 21 C.F.R. §50.52.
• Alleged failures to follow protocol that compromised care
of subjects:5
– Ethics Committee:
• IRB or ethics committee never actually approved the trial
• an investigator forged letter (in return for $20,000 from Pfizer) to the
FDA stating trial had been pre-approved by an ethics committee,
backdating the letter to a week before the experiment commenced.
JOURNAL OF RESEARCH ADMINISTRATION, April 1, 2012; Postal, Steven W., et al., After Guatemala and Nigeria: The Future of
International Clinical Research Regulation, American Bar Ass’n Health Law Section, 24 THE HEALTH LAWYER 1, October 2011; see also
Cameron, Nelson R., In Remembrance There is Prevention: A Brief Review of Four Historical Failures to Protect Human Subjects..
• Alleged failures to follow protocol that compromised care
of subjects (continued):
– Informed Consent:
• Patients allegedly did not know they were participating in an experiment
• Pfizer did not inform children or guardians and did not document risks or
viable alternatives (free, conventional & effective treatment provided in
same hospital)
• Information was not provided in a language that is understandable to the
subject or representative.
– Risk un-justified because
• a) little was known about Trovan;
• b) significant side effects in animal testing, including liver damage,
degenerative bone condition and other damage; and
• c) first time administered to children in oral form
Other allegedly unacceptable practices:
– Research protocol outlining trial to be completed in 6 weeks compared to
usual 1 year or more
– No preliminary tests conducted to determine
• children actually had meningitis
• the strain of meningitis affecting Nigeria was responsive to Trovan
– No screening to exclude children with liver and joint problems in
recognition of animal study results
– No blood tests or spinal taps required in the protocol to assets safety and
efficacy of Trovan
– No follow up care after the two-week trial when researchers departed
– Researchers did not present available alternative approaches to the
subjects, i.e. patients in control group given 1/3 of the recommended dose
of another antibiotic to exaggerate the comparative effectiveness of
• Fraud allegations
– Pfizer said it obtained proper approval of the local
government and ethics committee (experiment was
alleged a violation of Nigerian law and Nigeria’s FDAequivalent agency did not know about the trial)
– Pfizer represented that principal investigator was
Nigerian physician – whereas the Nigerian physician
admitted he was unaware of experiment’s data or
• U.S. Litigation Ensued
– Parents sued Pfizer in the U.S. under the Alien Tort
Statute in 2006
• This law allows foreigners to bring a cause of action in the
U.S. for a violation of customary international law
• Parents allege Pfizer conducted the trial without informed
consent and engaged in cruel, inhuman, and degrading
• U.S. Litigation Ensued (continued)
– 2nd Cir. Held:
• Nonconsensual medical research is of mutual concern among
• Parents establishes subject matter jurisdiction under the Alien
Tort Statute as a violation of a customary international law.
• The US Supreme Court denied cert. in June 2010
• 2nd Cir. Remanded the case to New York district court6
• Case settled in February 2011
6. See Abdullahi, et al v. Pfizer, Inc., No. 1:01-cv-8118-WHP, , Docket No. 105 (S.D.N.Y. Feb. 28, 2011).
• Nigerian Litigation Ensued
– State of Kano sued Pfizer alleging criminal and civil
violations in 20077
• Kano sought $2 billion in damages and restitution
• Pfizer allegedly settled out of court for about $75 million8
See Abdullahi v. Pfizer, 562 F.3d 163, 172 (2d Cir. 2009).
Armstrong, Walter, Did Pfizer Bribe Its Way Out of Criminal Charges In Nigeria?, THE ATLANTIC, December 2012; see also Secret Cable
Discusses Pfizer’s Actions in Nigeria Case, NEW YORK TIMES, December 10, 2010.
Overview of
Foreign Clinical Trials
Why Foreign Clinical Trials are Utilized
• Desire to study interaction of pharmaceutical in
ethnic population, population not getting other
• Costs associated with conducting clinical trial
• Less bureaucracy, countries want the US research,
companies doing business, access to meds
Growth of FTCs9
• More phase II and Phase III trial sites in rest of
world than in Europe
• More than 6,500 sites (4.3% of study sites) moved
outside the U.S. and Europe between 2008 and
• Major emerging regions: Eastern Europe, Asia,
Latin America
• Of 50,000 new study sites needed, 25% (or 12,500
sites per year) are located in emerging regions
Johan PE Karlberg, et al., Reviewing Clinical Trials: A Guide for the Ethics Committee, Ch. 2.8 Trial Phases, ASS’N FOR THE
Concerns with FCTs:
• Reliable Data: can you collect data reliably in very poor
countries, where people may not take pills, do what told,
get other infections and diseases?
• Economic Coercion: people desperate for medicines,
unwarranted faith in anyone with white coat
• Biological differences of ethnic areas may skew efficacy
of drug
• Post-Testing obligations: what obligations to subjects and
obligations to the country?
– continue to give effective drugs to poor subjects that cannot afford
– keep clinic running;
– continue supplying drug to the area
Conduct of Clinical Trials
• Situs
– Domestic sites conducted under Investigational New
Drug Application (“IND”)
– Foreign sites conducted under IND
– Foreign sites not conducted under IND
Conduct of Clinical Trials
• Players & Responsibilities
– Drug Regulatory Authority
– Sponsor
– Investigator
– Ethics Committee
– Trial Participant
– Clinical Trial Services Provider
– Site Supporting Organization
– Data Safety & Monitoring Committee
Conduct of Clinical Trials
• Efforts to Harmonize US & EU Regulations
– International Conference on Harmonization – Good
Clinical Practice (“ICH GCP”) Efficacy Guideline 6
– Published in 1996 to
• eliminate unnecessary delay in the global development and
availability of new medicines,
• while maintaining safeguards on quality, safety and efficacy,
and regulatory obligations to protect public health.
– ICH GCP E6 should be followed when generating
clinical trial data that are intended to be submitted to
regulatory authorities.
Conduct of Clinical Trials
• Efforts to Harmonize US & EU Regulations
– International Conference on Harmonization – Good
Clinical Practice E6
• describes the responsibilities and expectations of all
participants in the conduct of clinical trials
• GCPs cover aspects of monitoring, reporting and archiving of
clinical trials and incorporating addenda on the Essential
Documents and on the Investigator's Brochure which had been
agreed earlier through the ICH process.
– ICH GCP has had a significant impact on the
globalisation of industry-sponsored clinical research
• clinical trial data collected in one region in compliance with
ICH GCP can today be used to file new drug applications in
other regions.
U.S. Regulatory Framework
FDA Regulations
• Foreign Clinical Studies accepted by the FDA10
– Foreign Clinical Study Conducted under IND
• Regulation requires the greater protection of human subjects:
– U.S. regulations for IND (21 CFR Part 312) OR
– Local laws in country in which research was conducted
– Foreign Clinical Study Not Conducted under IND if:
• conducted in accordance with good clinical practice (GCP), including
review and approval by an independent ethics committee (IEC).11
• FDA is able to validate the date from the study through an onsite
inspection if necessary
10. FDA’s jurisdiction in human subjects is also subject to 21 C.F.R. § 50 (Protection of Human Subjects) and 21 C.F.R. § 56
(Institutional Review Boards
11. 21 CFR 312.120. See 73 Fed. Reg. 22800 (April 28, 2008) (final rule modifying 21 CFR 312.120 to accept non-IND foreign
clinical studies).
FDA Regulations
• Non-IND Studies accepted if they provide:12
– Oversight of Independent Ethics Committee 13
• IEC must
– consist of at last 5 members, one of whom is independent of the research institution
– members have qualifications and experience to review and evaluate the science,
medical aspects and ethics of the proposed trial
– members are diverse and reflect host community’s social and cultural diversity
– Members’ names and addresses available upon request; if impossible under foreign
law, must obtain waiver
• Approvals from IEC required before initiating study:
– Approval of the study protocol
– Prior approval of obtaining and documenting informed consent
• Continue to review on-going study
12. See FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND, Frequently Asked Questions (March 2012).
13. ICH GCP E6, Ch. 3.
FDA Regulations
• Non-IND Studies accepted if they provide: (continued)
– Trial Participants
• Patients must give informed consent
– Investigator
• Investigator must provide regular statements 14
– Sponsors 15
• must document compliance with Good Clinical Practice and
Independent Ethical Committee procedures
• submit required data, including description of investigator
qualifications, research facilities, drug product, study protocols
and results.
14. See ICH GCP E6, Chs. 4, 7
15. See ICH GCP E6, Ch. 5.
FDA Regulations
• Non-IND Studies accepted if they provide: (continued)
– Documents and Procedures 16
• Documents to submit
• Maintain records for 2 years after the FDA’s decision on an
application for marketing approval. If the marketing approval
is not requested, then for 2 years after the submission of the
16. See CH GCP E6, Ch. 8
Office of Human Resource Protection (OHRP)
Dep’t of HHS
• Office of Inspector General Report17
– The Food, Drug, and Cosmetic Act requires all new investigational
drugs and biologics to undergo clinical trials on human subjects to
demonstrate the safety and efficacy of these products prior to
approval for sale in the United States.
– Sponsors may submit data from foreign and domestic clinical trials
to support marketing applications.
– In FY 2008, sponsors relied heavily on data from foreign clinical
trials to support their marketing applications for drugs and
17. See Dep’t of Health & Human Servs., Office of Inspector General, Fiscal Year 2012, Online Performance Appendix, available at
Office of Human Resource Protection (OHRP)
Dep’t of HHS
• Office of Inspector General
– 80 % of approved marketing applications for drugs and biologics
contained data from foreign clinical trials. More than half of
clinical trial subjects and sites were located outside the U.S.
– The FDA inspected fewer than 1% of foreign clinical trial sites.
Challenges in conducting foreign inspections and data limitations
inhibit FDA’s ability to monitor foreign clinical trials
– Report includes 2012 International Compilation of Human
Research Protections.
• A compilation of laws, regulations, and guidelines that govern human subject
research in 103 countries.
Other Regulatory Concerns
• Alien Tort Statute – statute used by Nigerian
parents of children to assert claims against Pfizer
in the U.S.
• FCPA violations
– Hospitals and doctors employed by state-owned
facilities are “foreign officials” under the FCPA;
interactions related to clinical trials subject to FCPA
– Since 2002, 37 companies investigated for potential
corrupt payments outside the U.S. Law360
Foreign Regulatory Framework
EU Regulatory Framework
• Clinical Trials Directive 2001/20/EC
• Compliance with Local and Regional Regulations
On-Going Regulation of Global
Clinical Trials
2008 Changes to FDA Rules
• Good Clinical Practice – the new standard
• Review by IEC – mandates that foreign clinical trials be
reviewed and approved by IEC
• Informed Consent Requirements – document and disclose
to the FDA how informed consent is obtained unless “lifethreatening situations”
• Supporting information required, sound protocol, study
set-up and execution, study results, case records, additional
background data, how sponsor maintained consistency
with protocol
• Onsite Inspections: - FDA is allowed to conduct onsite
inspection to validate data from a study.
2009 FDA + Office of Human Research Protections
• Rules promulgated regarding registration requirements for
Investigative Review Board but foreign IRB registration
requirements remained voluntary
• Proposed FDA Rule requiring Sponsor to report
falsification or suspected falsification of data
• FDA expects timely review, evaluation, and
submission of relevant and useful data
• Proposed revision to the Department of Health & Human
Services (DHH) Common Rule governing human subject
protections and codified in 45 C.F.R. 46,18 including
– Expands jurisdiction of federal regulations from studies funded by
federal agencies that have adopted the Common Rule to all studies
where the sponsoring institution receives at least some funds from
a federal agency;
– Informed consent forms must be more concise
– Clarifies and restricts the studies that are exempt from the
18. See 76 Fed. Reg. 44,512 (July 26, 2011)