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What it Means to
Clinical Investigators & IRBs
The FDA’s Enforcement Agenda
HCCA Research Compliance Conference
April 21-24, 2010
Dallas, Texas
Rachel Nosowsky
Jeff Layne
Agenda
• FDA Enforcement in 2010– Recent regulatory and guidance activities
– Inspections in 2010
– Challenges for investigators and IRBs
– Risks of non-compliance
• Enforcement Options and Trends– Implications for grants and contracts
– Civil sanctions
– Criminal enforcement
• Risk Mitigation Strategies– Integrating cGCP in routine operations
– Preparation for and responding to inspections
– Developing and implementing corrective and preventive action plans
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Introduction
FDA Enforcement in 2010
Rachel Nosowsky
Principal Counsel
University of California
rachel.nosowsky@ucop.edu
Environmental Influences
• GAO 2009– Oversight of clinical investigators: disqualification and debarment
– Coast IRB “sting” operation
– High-risk series re: “compromise[d] ability to protect Americans from unsafe and ineffective products”
• Other recent headlines– Product recalls, internal whistleblowers
– Industry influence on advisory panels and otherwise in the development and approval process
– Preemption controversies
• Old news, still fresh– Gelsinger (Penn – gene therapy)
– Roche (Hopkins – asthma drug)
– Johnson (IUPUI – anti-depressive)
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5
Policy Developments
Inspections Then …
• (Largely) unchanged: predicate rules and interpretation– Clinical investigations require IRB approval and
continuing oversight
– Investigational drug trials require INDs unless exempt; investigational device trials require IDEs or (if NSR) are subject to abbreviated requirements
– Common Rule equivalents in 21 CFR parts 50, 56 apply to the conduct of FDA clinical trials
– ICH consolidated GCP guidance was issued in April 1996 … many “information sheets” date back to 1998
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The Role of Data Audits in Detecting Scientific Misconduct(M.F. Shapiro, R.C. Charrow – JAMA 1989;261:2505-2511)
• Recommendations– Certify clinical investigators (may help avoid honest error but not intentional
misconduct)– Competition for right to conduct studies (peer review)– Reduce over-commitment via regulation (limit per-site recruitment opportunities)– Penalize manufacturers– Pre-hearing suspensions
… and Inspections Now
• Changing (largely):
– Enforcement approach
• More, better trained, better prepared inspectors
• More careful (intrusive ?), targeted reviews
• 15-day response deadlines when 483s or WLs are
issued
– Inspection triggers
• Whistleblowers
• Follow-on inspections
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Frequent Citations (CI/SI)
• Failure to secure IRB approval, appropriate investigational permits
• Consent deficiencies (after screening, wrong version, inconsistent with protocol, opt-in missing for test performed, LEP)
• Protocol deviations; AE/UP reporting
• Missing fCOI disclosure statements; CVs
• Improper delegation, inadequate supervision, inadequate monitoring
• Drug/device accountability
• Documentation deficiencies (inconsistencies between medical and research records; failure to maintain appropriate research records)
• Failure to report (to IRB, sponsor, FDA)
• Fabrication, falsification
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Frequent Citations (IRB)
• Deficient SOPs or failure to follow SOPs
• Inadequate review of records (e.g., approval of problematic consent documents)
• Failure to achieve or maintain quorum for votes
• Documentation deficiencies (adequacy of minutes; retention)
• Inadequate oversight– Continuation review
– Response to red flags
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15 day response deadline
Reference to IRB Info. Sheets
No CAPA documentation
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Statistics(From http://www.fda.gov/ICECI/EnforcementActions/default.htm)
0
5
10
15
20
25
30
35
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
WL
NIDPOE
IRB (WL)
Challenges for IRBs and Investigators
• Resources
• Education and training of IRBs, investigators and research staff
• Identifying what studies are regulated
• Maintaining focus on basic GCP requirements (and avoiding getting lost in the weeds of esoteric questions)
• Assuring compliance with non-intuitive requirements
• Adequately staffing and responding to inspections
• Confusion re: accountability
• Resources
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Regulatory (and PR) Risks
of Noncompliance
• FDA-483
• Warning Letter
• NIDPOE
• Negotiated Restrictions
• Disqualification
• Debarment
• All but 483s are posted to the FDA website; all are FOIAble (together with associated EIRs and communications)
Looking Ahead
• 2/19/2010 Proposed Rule: “Reporting Information Regarding Falsification of Data” (revising 21 C.F.R. parts 312 and 812)– Requires sponsors to report potential falsification to FDA within
45 days of discovery
– Compare with ORI approach to fabrication, falsification and plagiarism
• Very process oriented– Complaint -> preliminary assessment -> inquiry -> investigation ->
institutional decision
– Emphasis on internal investigation and response
• Confidentiality is put at a premium given potential for reputation harm even of spurious allegations
– Both rules would apply in some cases, e.g., where NIH funds an investigator-initiated study and the investigator holds then IND
• Potentially influenced by Fals-Stewart case (researcher lied in investigation and almost got away with it)
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Introduction
ENFORCEMENT OPTIONS AND
TRENDS
Jeff Layne
Partner
Fulbright & Jaworski LLP
jlayne@fulbright.com
Background & Politics
• Obama Administration: Increased
emphasis on FDA enforcement and
visibility. Dr. Hamburg has publically
emphasized a more vigorous enforcement
role.
• Congress agrees: House Commerce and
Energy Committee pushing for more
vigorous FDA enforcement; and Sen. Chuck
Grassley (R-Iowa) among others pushing for
greater transparency and accountability
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Background & Politics
• Oct. 2009: FDA releases “Guidance for Investigator Responsibilities- Protecting the Rights, Safety, and Welfare of Study Subjects.”– Response to FDA concerns that doctors undertaking clinical trials
were not properly trained in research protocols
• Nov. 2009: GAO releases report “Oversight of Clinical Investigators: Action Needed to Improve Timeliness & Enhance Scope of FDA’s Debarment & Disqualification Processes for Medical Product Investigators.”– Report focuses on how the FDA is slow to debar or disqualify
– Highlights problems of internal FDA control weakness, competing priorities, limited resources
– Report spurs political & public focus on greater FDA enforcement of clinical regulations in 2010
More Legislation & Guidance Expected
• HR 3932: Strengthening of FDA Integrity Act (Rep. Joe Barton (R-Texas)). Seeks to give FDA:– Authority to debar any company or individual
convicted of crimes relating to any drug or device;
– Authority to debar a medical device company (not just drug companies); and
– Authority to debar companies for any misconduct relating to the drug or device;
– Referred to House Energy & Commerce Committee
• Spring 2010: NIH Conflict of Interest Rule expected, outlining procedures for investigators who get research money.
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More Legislation & Guidance Expected
IRBs under pressure as well:
• GAO Report: Coast IRB– Sting operation
– Three private IRBs targeted; cherry-picked
– Asked to approve fake, potentially risky study
– Coast cited for taking the bait; implications for industry not clear.
– Not just Coast – Ketek/Copernicus also shed bad light on private IRBs
• House Energy and Commerce Hearing:
– Testimony from FDA about oversight of IRBs
Common Research & Investigator
Violations
• Bigger picture: FDA focus on:
– Conflicts of interest; payments that affect
clinical or educational judgment
– Fraud, and even plain old incompetence
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Common Research & Investigator
Violations
• Specific Investigator Violations:– Failure to follow guideline protocols
– Failure to obtain informed consent
– Failure to maintain ongoing review by IRB
– Fabrication of data or false statements
– Undisclosed conflicts of interest
• Specific IRB Violations:– Inadequate documentation
– Inadequate training and qualifications
– Inadequate due diligence and review
– Undisclosed conflicts of interest
Increased Risk of Detection
• Enforcement environment:
– FDA; DOJ; FBI
– Issues are on their radar screen
• The “W” word:
– Whistleblowers! There I said it.
– False Claims Act liability?
– Increasing number of complaints
• Study subjects, study sponsors, other insiders
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FDA Enforcement Case Study - IRB
• Coast IRB - 2008
– FDA investigation (DSI) preceded GAO sting
– Expedited reviews performed by inexperienced
IRB member
– Inadequate minutes and communication with
the rest of the IRB
– Coast advertised its fast turnarounds
FDA Enforcement Case Study - IRB
• Wellmont Holston Valley Med Center
IRB - 2008
– Failure to properly document IRB activities
and reviews
– Too few board members present for review
– Improper use of expedited procedures
– Failure to enforce COI policies
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FDA Enforcement Case Study - CI
• Dr. Brewer - 2009
– Physician at prestigious academic medical
center
– Failure to obtain informed consent
– Failure to maintain IRB oversight and
approval
– Failure to conduct study according to the
investigational plan
Criminal Cases
• What will raise the bar and turn an
administrative case into a criminal one?
– Look for fraud; purposeful misconduct;
repeated bad behavior; patients put at risk
• What criminal statutes apply to clinical
research?
– Potentially, lots
– FDA specific statutes, criminal fraud statutes,
wire fraud, mail fraud, conspiracy
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Criminal Case Study: Palazzo
• Specifics: New Orleans clinical investigator charged criminally for failure to adhere to the FDA’s recordkeeping & reporting requirements.– Hired to conduct clinical drug trial regarding safety & efficacy of
antidepressant Paxil in children.
– According to the indictment, petitioner violated the record-keeping requirements of 21 C.F.R. 312.62(b) by falsifying case histories and diagnoses of children who were not qualified to participate in the study because they did not in fact suffer from obsessive-compulsive disorder.
• Finding: §331(e) of F.D.C.A. allows imposition of criminal penalties on clinical investigators who fail to maintain records required by section 355(i).– The fact that Palazzo, as a clinical investigator, was not required to report
directly to the FDA was irrelevant; §331(e) applies to directly & indirectly submitted records.
– Also convicted of health care fraud, sentenced to 87 months in prison and $655,260 in restitution payments.
Criminal Case Study: Reuben
• Specifics: Anesthesiologist admitted he “totally fabricated results” of research on pain management purportedly performed for Pfizer, Inc., then sent results for publication to the journal Anesthesia & Analgesia. Agreed to conduct study on Celebrex, never enrolled patients.– “knowingly & willingly executed a scheme and artifice to
defraud Pfizer in connection with delivery of and payment for health care benefits, items, and services.” 18 U.S.C. § 1347
• Penalties: Pled guilty in fed. ct. to 1 count health care fraud.– Jail: Up to 10 years in prison, 3 years supervised release
– Money: $5,000 fine; $361,932 restitution to pharmaceutical companies; $50,000 forfeiture
– Practice: Stripped of right to perform research & education
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Criminal Case Study: Synthes
• Specifics: June 2009 medical device maker and four executives indicted for conducting unauthorized clinical trials of medical device bone cements for off-label use. – Performed surgeries despite warning on FDA-approved label against
this specific use & despite serious concerns about device safety. 3 operating table deaths.
– “Consciously & deliberately chose the illegal solution,” then trained surgeons in improper use (DOJ).
– Promoted device through “test markets” in effort to save time and money by cutting out FDA oversight of clinical trials.
– Company denies allegations and intends to defend vigorously.
• Penalties: Corporations face fines of $26 million and $8.8 million respectively; maximum 5 years probation; full restitution & forfeiture of $469,800.– Individual defendants face maximum 1 year prison sentence, $100,000
fine, full restitution, 1 year supervised release.
Criminal Case Study: Campbell
• Specifics: In September 2008, the FDA “permanently” debarred a physician investigator from providing services to any person who has an approved or pending drug product application.– Convicted of mail fraud for submitting false
information to the sponsors of a drug trial.
– Submitted false data to Aventis & PPD in connection with clinical study for FDA approval of antibiotic for respiratory tract infections.
• Penalties: Debarred; 57 months in federal prison; restitution to Aventis for $925,774; fined $557,251 for mail fraud.
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Penalties and Trends: Debarment
• Mandatory Debarment:– Occurs when FDA finds an individual has been
convicted of federal felony offense related to the development or approval of a medical product.
– But, can apply for termination of debarment.
– Medical device investigator debarments only apply to the specific product that led to proceeding, so can be debarred but still participate in clinical trials.
• Permissive Debarment:– If investigator convicted of state felony conviction for
which FDA deems debarment appropriate.
• Penalties Extend Further:– Anyone who knowingly uses a debarred investigator’s
services is subject to civil money penalties.
Penalties and Trends : Disqualification
• Disqualification: FDA may disqualify any
investigator who has repeatedly or
deliberately submitted false information to
the Agency or study sponsor in a required
report.
– The FDA will not accept or review any
abbreviated new drug application submitted
by or with the assistance of an investigator
during debarment period.
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Penalties and Trends: Pay Up
• Civil Money Penalties: Recent fines
range from potential of $26 million
(Norian) to $5,000 (Reuben)
• Forfeiture: Recent range of
$655,260.97 (Palazzo) to $50,000
(Reuben)
• Restitution: To pharmaceutical
companies, federal health care
programs
Penalties and Trends : Jail or Probation
• Palazzo- Sentenced to 87
months in prison.
• Norian & Synthes Execs- Face
a maximum 1 year sentence &
1 year supervised release.
• Reuben- Faces a maximum 10
years in prison & 3 years
supervised release.
• Campbell- Sentenced to 57
months in federal prison.
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Penalties and Trends : Funding
Implications
• Currently: no federal
oversight of research that
does not receive funding
from HHS and is not
testing a product that
needs FDA approval to
be sold on the U.S.
market.
• Soon: FDA will likely try
to directly regulate
commercial IRBs.
Statutory Basis for Enforcement
Lingering ambiguities about the scope or limits of the FDA’s authority over clinical investigators. But….
• 21 U.S.C. §335(a)- Authorizes debarment or disqualification.
• 21 U.S.C. §355(i)- Under Palazzo, when §355(i) is read in conjunction with F.D.C.A. provisions §331(e) and §333(a)(1), clinical investigators can be subject to criminal liability for violations of record-keeping requirements.– §355(i) does not provide for criminal sanctions on its face. Instead,
violations of §355(i) are prohibited by §331(e), and criminal penalties for violating §331(e) are found in §333(a).
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Violation Implications Summary
• Both individuals & corporations face criminal, civil, and monetary penalties
– Jail or probation
– Permissive or mandatory debarment or disqualification
– Fines, restitution, forfeiture
• Administrative consequences
– Funding withdrawal
– Inability to gain approval for later products or studies related to debarred investigator
Takeaway Messages
• More FDA scrutiny – investigations,
warning letters, other regulatory
actions.
• Debarments and disqualifications likely
to increase and speed up.
• No one is immune; IRBs, sponsors,
clinical investigators all under the
microscope.
• Stress: competency, training, resources,
robust policies and procedures, and
appropriate checks and balances.
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What Now?
• Risk Mitigation Strategies
– Integrating cGCP in routine operations
– Preparation for and responding to inspections
– Developing and implementing corrective and
preventive action plans
– Robust compliance program
– Devoting appropriate resources (time, money,
staff, training) to research endeavors
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