Unanticipated Risk in Clinical Research

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Unanticipated Risk in Clinical Research

• Principles and Practice
• of Clinical Research
• November 18, 2003
• Stephen E. Straus, M.D.

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Clinical research involves risks and benefits
both for the participant and the
investigator Unanticipated injuries to research
subjects lead to progressive changes in research
regulation, oversight and conduct
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Benefits of Conducting Clinical Research

• Acquiring special expertise
• Improving patient outcome
• Humanitarian gesture
• Grant support
• Professional advancement

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Risks of Conducting Clinical Research

• Time consuming
• Studies may fail
• Lower income
• Intense regulatory and public scrutiny
• Personal and professional liability

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Benefits of Participating in Clinical Research

• Diagnosed by experts
• Personalized attention and education
• Access to novel therapies
• Committed follow-up
• Improved prognosis
• Humanitarian gesture
• Free care and other financial incentives

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Risks of Participating in Clinical Research

• More frequent and more invasive interventions
• Assignment to placebo or ineffective treatments
• Greater time investments
• Less privacy
• Known and unanticipated side effects

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An Unexpected Death in aGene Therapy Trial
Background

• Investigators at U of P and their partners in
  industry invent an adenovirus vector that
  expresses ornithine transcarbamylase
• Approval granted by IRB, IBC, RAC, FDA to conduct
  clinical trials in OTC-deficient patients
• Research patient Jessie Gelsinger dies

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An Unexpected Death in a Gene Therapy Trial
Reactions

• NIH, FDA, DHHS, Congressional investigations and
  hearings
• Prolific media coverage
• New mandates for DSMB, AER, clinical research
  training and conflict of interest reporting
• Creation of OHRP IRB closures
• Law suits

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Questions Asked on The Morning After

• Protocol Scientifically and ethically
  appropriate?
• Patient consent Fully informative?
• Investigator training Adequate?
• Financial conflicts None?
• Approvals All obtained and updated?
• Subject selection Appropriate?

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Questions Asked onThe Morning After

• Protocol adherence Consistent?
• SAEs Identified? Reported promptly?
• Documentation Complete?
• Study monitoring Independent?
• Data entry Accurate?
• Statistical analysis Valid?
• Reports Objective?

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Chronology of FIAU Studies
1970s Synthesis of fluoropyrimidine
analogues FIAC and FIAU Both inhibit
herpesvirus replication
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Chronology of FIAU Studies
1983-6 Phase I-II studies of IV and oral
FIAC 30-1000 mg/m2 for 5-10
days in cancer and AIDS patients with
HSV, VZV, or CMV infections suggest antiviral
activity, but with nausea, ALT rises, and bone
marrow suppression
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Chronology of FIAU Studies
1984 FIAC and FIAU inhibit HBV DNA
polymerase activity
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Chronology of FIAU Studies
1990 ACTG 122A Oral FIAC 0.6-5.0
mg/kg/d x 14d in CMV-infected AIDS pts.
Nausea, fatigue, and CPK elevations limit
the dose to 1.0 mg/kg/d, without anti-CMV
effects. FIAC studies cease. FIAU
is safe for 28d in animals.
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Chronology of FIAU Studies
1990-1 ACTG 122B Oral FIAU in 10 HIV-
infected pts at 1 mg/kg x 14d.
Nausea and fatigue at 1.7 mg/kg/d are
dose-limiting. 6 HBV/HIV- infected pts
treated at NIH. Marked suppression of
HBV levels, with acceptable side
effects.
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Chronology of FIAU Studies
1991-2 Dose de-escalation studies in 43 pts
with HBV/HIV confirm short-term
tolerance and antiviral activity down
to 0.1 mg/kg/d.
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Chronology of FIAU Studies
1991 Protocol modified to allow
retreatment of earlier study subjects. 3/4
NIH pts die 2-5 months after ending
retreatment pancreatitis on ddI 2 with
liver failure. Autopsies - no
microvesicular fat.
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Chronology of FIAU Studies
1992 NIH trial in 24 HIV-negative HBV pts
FIAU 0.05-0.5 mg/kg/d x 28d. Dose-
related inhibition of HBV DNA. ALT
flares. Complications peripheral
neuropathy and cholecystitis 4 mo after
FIAU neuropathy and hepatic failure 3
mo after treatment - dies 2 mo later.
Autopsy - microvesicular fat!
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Chronology of FIAU Studies
1992 Eli Lilly assumes FIAU
development. More animal studies. March, Lilly
multi-center trial of 0.1 vs 0.25 1993
mg/kg/d x 90d. NIH 180d trial 15 pts
enrolled all get baseline nerve
conduction studies.
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Chronology of FIAU Studies
May- Dose reduced or stopped for GI June
upset in 3 pts and tingling in one. 1993
One pt admitted for fatigue and
nausea. June 26, Pt presents with lactic
acidosis. 1993 Trial is stopped. NIH, FDA, HHS,
and Lilly are notified. All pts are
admitted.
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Chronology of FIAU Studies
July- Despite termination of FIAU, 5 pts
August die of progressive liver failure, lactic
1993 acidosis, pancreatitis, myopathy
and neuropathy.Two survive with
emergency liver transplantation. Five
suffer reversible effects. Three
remained well. The investigations begin
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FIAU in the Media

• Newspapers, magazines, radio, and TV report
  patient deaths
• Patient and family anger is highlighted
• Trial design and consent forms criticized
• Investigators accused of negligence for ignoring
  clues to FIAUs dangers

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FIAU in the Media

• Investigator charged with retribution against an
  angry patient
• Video broadcast on ABCs Prime Time Live
• Speculation on the mechanism of FIAU toxicity and
  implications for antiviral drug development
• Summary reports on the sequential investigations

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Congressional Inquiries
Sept, 1993 House Committee on Government
Operations requests all documents, including
patient records. Oct,1993 Committee raises
serious questions of possible misconduct.
Requests an impartial DHHS review of the
study.
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Congressional Inquiries
Nov, The Senate Committee on Labor 1993
and Human Relations inquires. June, The House
Committee calls the NIH 1994 Directors
investigation a whitewash. Demands
an independent review by the IOM. 1995
Congressional interest wanes.
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FDA Investigations
Aug, FDA investigators inspect all study
1993 sites and records Sept, FDA
Antiviral Drugs Advisory 1993 Committee
discusses mechanisms and implications of
FIAU toxicity Nov, FDA issues inspection
reports, citing 1993 lack of prompt
notification of deaths
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FDA Investigations
Nov, Task Force reports that investigators
1993 misinterpreted the ALT
flares May, FDA Warning Letters late
death 1994 reports inadequate consent
forms, and poor clinical judgment Oct,
FDA proposes new regulations for 1994
documenting and reporting SAEs
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NIH Responses
June 26, Study terminated Pts, Clinical 1993
Directors, IRBs, FDA, and drug sponsors
notified July Formal study summaries
sent to Institute Directors and
DHHS Sept NIH Office of Human Subjects
Research reports to OPRR that the protocols
complied fully with NIHs Multiple Project
Assurance
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NIH Responses
Nov NIH Clinical Center Quality
Assurance Service reports that the patient
charts are exemplary Dec NIH Director
convenes an ad hoc 1993 Advisory Committee
to review the studies. All investigators
and patients interviewed, and all records
examined.
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NIH Responses
June, NIH Directors Advisory Committee
1994 concludes that the studies were
appropriate, conducted according to the
best of current clinical practice, and
that the FIAU toxicity
is a novel
type of reaction that was
unexpected.
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Institute of Medicine Review
June, Independent review commissioned by
1994 the Secretary, DHHS. All records
reviewed again, and all investigators,
patients, sponsors, and FDA Medical
Officers are interviewed. March, The
IOM concludes that the studies were 1995
justified, properly designed, and well
conducted.There was no evidence of
negligence. The proposed FDA reporting
guidelines are considered to be excessive.
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Legal Issues
Aug, Private and NIH legal counsel sought by
1993 the investigators Nov , First
lawsuit filed. Referred to the 1993
Department of Justice for defense under the
Federal Tort Claims Act 1994 Additional
suits filed Dec, All lawsuits are settled
out of court 1995
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The Scientific Community Responds

• Meetings on treatment and mechanisms
• Public interest groups decry lack of clinical
  research safeguards
• Industry points out inherent risks of clinical
  research
• Ethicists debate informed consent and the
  competing loyalties of clinical investigators
• Hepatitis drug development ceasesfor 2 years

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Mechanisms of FIAU Toxicity

• Utilized by gamma polymerase and incorporated
  into nuclear and mitochondrial DNA
• Loss of oxidative enzymes
• Depletion of glycogen stores
• Microvesicular fat accumulation
• Lactic acidosis
• Cellular apoptosis
• Liver failure, pancreatitis, myopathy, neuropathy

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Recommendations

• Preclinical studies Analyses in relevant
  species, but may not predict all events in
  humans.
• Training For all PIs and associate
  investigators
• Review Separate scientific and ethical reviews
  with relevant expertise. Support IRBs and train
  their members.

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Recommendations

• Consent forms Uniform consent text Simplify and
  shorten emphasize dialogue update document
  electronically
• Follow up Adequate for the nature and known
  risks of trial materials
• Data entry Create one set of electronic records
  for all study patients. Support data management

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Recommendations

• Reporting harmonize all reporting forms and
  requirements.
• Monitoring Formalize and support DSMBs. Provide
  on-line access to study records.
• Incentives Reward clinical research conduct and
  participation. Cover study-related injuries.

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Conclusion

• There is no way to avoid all risk while
  participating in, or conducting, clinical
  research.

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National Institute of Allergy and Infectious
Diseases National Institutes of Health U.S.
Department of Health and Human Services