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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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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)

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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