New Drug Safety Initiatives & theDrug Safety Oversight Board

Drug Safety and Risk Management Advisory Committee,

Gaithersburg, MD

February 10th, 2006

Susan K. Cummins, MD, MPHExecutive Director, Drug Safety Oversight BoardCenter for Drug Evaluation and ResearchFood and Drug Administration

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Today’s Talk

Drug Safety landscape

New Drug Safety initiatives

Dr. Crawford’s November 2004 announcement

Secretary Leavitt’s February 2005 announcement

Drug Safety Oversight Board & New drug risk communication outlets

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Drug Safety Landscape

Drug Safety is a top priority for all of CDER at every stage of the product life cycle

Pre-NDA phase

New drugs

Manufacturing/regulation of drug quality

Generic drugs

Regulation of clinical trials and promotional activities

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32% Pre-Market Safety Work Effort

18% Post-Market Safety Work Effort

50% Non-SafetyWork Effort

Half of all CDER Work Effort is Devoted to Drug Safety

TM Mullin, PhD, Office of Planning, Office of CommissionerFDA Science Board Presentation April 15, 2005

2004 CDER Work Time Analysis

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Drug Safety Landscape

Laws: FD& C Act requires safety evaluation before approval “All tests reasonably applicable” to safety

FDA Drug Regulations: Information that “the product is safe…for recommended use.”

Guidances: FDA & International guidance documents spell out level of evidence needed for safety evaluation.

Bottom Line: Science plus judgment plus policy

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Drug Safety Landscape

Despite the rules, there is lots of room for honest disagreement

How safe is “safe”?

There is no single, simple risk/benefit equation

Tension between: Drive for innovation and new products VS.

Greater assurance of safety through larger and longer studies

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“The Drug Approval Pendulum” by Anne Applebaum

Washington Post Wednesday, April 13, 2005; Page A17

• "It just breaks my heart when I think of American citizens having to go to Switzerland or Mexico to get the drugs and devices they need to stay alive because the Washington bureaucracy won't approve them."

• Rep. Thomas Bliley (R-Virginia), 1995

• "When the FDA approves a drug, it should be a Good Housekeeping seal of approval. . . . Consumers shouldn't have to second-guess the safety of what's in their medicine cabinet."

• Sen. Chuck Grassley (R-Iowa), 2005

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November 2004: FDA Drug Safety Announcement

FDA Acting Commissioner Crawford announced a 5-Point Plan to improve management of drug safety concerns:

Sponsor an Institute of Medicine Study of the Drug Safety System UNDERWAY—Report due out July 2006

Implement a program for adjudicating differences of professional opinion

Individual level–-Resolution through Ombudsman

Organizational level—Drug Safety Oversight Board

Appoint a permanent Director, Office of Drug Safety

Gerald Dal Pan, MD, MHS appointed, October 2005

Conduct Drug Safety/Risk Management Consultations--UNDERWAY

Publish Risk Management Guidances—DONE

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2005 Published Risk Management Guidance for Industry

Pre-marketing Risk Assessment

Development and Use of Risk Minimization Action Plans

Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

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2005 Published FDA Reviewer Guidance

Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review

Component of good review practice guidance for NDAs and BLAs

Provides for standardization and consistency in format and content of safety reviews

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February 15th 2005HHS Secretary Mike LeavittAnnounces Drug Safety Reforms

"The public has spoken and they want more oversight and openness…We will address their concerns by cultivating openness and enhanced independence.“

"We will keep the promise of the FDA brand by putting in place more rigorous oversight and collecting and sharing important and emerging information about drug safety and effectiveness.“

HHS Secretary Mike Leavitt

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February 2005: HHS Secretary LeavittDrug Safety Announcement

Overall vision: Promote a culture of openness & Enhance oversight within the FDA

Specific areas of change:

More outside expert consultations

Improve drug safety management practices

Communicate emerging drug safety concerns early

Continue to improve scientific methods of adverse event signal detection

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Drug Safety Initiative

The initiative will:

Give patients, healthcare professionals & consumers quick & easy access to the most up-to-date and accurate information on medicines.

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Drug Safety Initiative

New drug safety information outlets

Patient Information Sheets Healthcare Professional Sheets Proposed Drug Watch Program

Drug Safety Oversight Board

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Definition: Important Drug Safety Issue

A Drug Safety issue with the potential to:

Significantly alter the risk-benefit analysis of a drug

Affect physician’s decision to prescribe

Affect patient’s decision to use

Includes and is broader than regulatory definition of “serious and/or life-threatening” adverse event

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Drug Safety Oversight BoardCharge

Provide independent oversight and advice to Center Director on:

Management of Important Drug Safety Issues

Adjudication of organizational disputes

Policies about management of drug safety issues

Risk communication about important emerging drug safety concerns

Development of HCP & patient information sheets

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Drug Safety Oversight BoardCharge

“Ensure that CDER decisions about a drug’s safety benefit from the input and perspective of experts within and outside FDA who have not conducted the primary review or served as a deciding official in the ongoing pre-market evaluation or post-market surveillance activities with respect to that drug.”

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Drug Safety Oversight Board Organizational Principles

Voting members independent of primary decision-making for a drug with an important safety issue

Federal employees

Equal number of representatives from Offices of Drug Safety & New Drugs

25% of membership external to CDER Other FDA Centers with related activities NIH & Veterans Administration

Expert, Consumer or Patient Consultants as needed

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Drug Safety Oversight BoardOrganizational Principles

Fosters effective CDER management of important emerging drug safety concerns

DOES NOT replace Public Advisory Committees

DOES NOT replace current internal responsibility for Regulatory Decision-making

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Drug Safety Oversight Board Membership

CDER Offices: Drug Safety (3) New Drugs (3) Counter-terrorism &

Pediatrics Compliance Pharmaceutical Science Clinical Pharmacology &

Biopharmaceutics Biostatistics Medical Policy (non-voting)

External to CDER: Center for Biologic

Evaluation & Research Center for Radiological

Health Department of Veterans

Affairs National Institute of Health

(National Cancer Institute)

Chair—Deputy Director, CDER (non-voting) Executive Secretary—Director, DSB (non-voting)

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Proposed Drug Watch: Definition, Goal and Status

Definition: Web page on CDER Internet site about emerging important safety issues undergoing investigation

Goal: Communicate emerging risk information to the public so that it can inform treatment decisions

Status: Draft Guidance undergoing review and revision in response to public comment submitted during 2005 comment period

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When does FDA communicate about emerging risk?

Factors that favor early communication:

Risk is a “important drug safety concern”

Affect prescribing or monitoring

Whether measures can be taken in response to the information to prevent harm

If unapproved (off-label) use poses a significant and/or yet undescribed risk

If a specific and/or vulnerable subpopulation may be affected (children or the elderly)

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Drug Safety HC Professional & Patient Information Sheets

At least 44 drugs with safety postings through December 31, 2005

6 Product class issues

3 Market suspensions Palladone (hydromorphone hydrochloride extended release) Tysabri (natalizumab) Neutrospec [Technetium (99m Tc) fanolesomab]

2 Product withdrawals Bextra (valdecoxib) Cylert (pemoline)

37 with added warnings to product label

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Drug Class Risks Described in HC Professional & Patient Information Sheets

Antidepressants—suicidality in adults & children

Atypical antipsychotics—increased risk of death in dementia (unapproved use)

Non-steroidal anti-inflammatory drugs—increased cardiovascular risk

Erectile dysfunction drugs—non-arteritic anterior ischemic optic neuropathy

Topical Immunosuppressant calcineurin inhibitors—potential cancer risk

Long-acting beta agonists—increased risk of severe asthma episodes that may lead to death

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Drug Safety HC Professional & Patient Information Sheets

At least 44 drugs with safety postings through December 31, 2005

Examples: Accutane (isotretinoin)—new restricted access program to

prevent pregnancy in treated women Paxil (paroxetine)—Pregnancy Category changed from C to D Strattera (atomoxetine)—increased pediatric suicidality risk Palladone (hydromorphone)— Withdrawn due to dose

dumping with concomitant alcohol exposure Campath (alemtuzumab)—idiopathic thrombocytopenic purpura

in patients with multiple sclerosis (unlabeled use) Neutrospec (99mTechnetium fanolesomab)—serious and life

threatening cardiopulmonary events shortly after administration

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Summary Drug Safety Oversight Board established to:

Improve public knowledge of emerging important drug safety concerns

Strengthen internal drug safety management

Foster practical policy development to improve consistency and timely resolution of important drug safety concerns

Provide a standing venue for resolution of CDER organizational disputes

Central component of CDER’s initiative to improve management of drug safety & inform the public about emerging medication risks