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Improving FDA’s approach to new drug approval and post-marketing surveillance Jerry Avorn, M.D. Professor of Medicine, Harvard Medical School Chief, Division of Pharmacoepidemiology and Pharmacoeconomics Brigham and Women’s Hospital

Improving FDA’s approach to new drug approval and post-marketing surveillance

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Improving FDA’s approach to new drug approval and post-marketing surveillance. Jerry Avorn, M.D. Professor of Medicine, Harvard Medical School Chief, Division of Pharmacoepidemiology and Pharmacoeconomics Brigham and Women’s Hospital. Conflicts of interest. - PowerPoint PPT Presentation

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Page 1: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Improving FDA’s approach to new drug approval and post-marketing

surveillanceJerry Avorn, M.D.

Professor of Medicine, Harvard Medical SchoolChief, Division of Pharmacoepidemiology

and PharmacoeconomicsBrigham and Women’s Hospital

Page 2: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Conflicts of interest• Neither I nor anyone in my division

accepts personal compensation of any kind from any pharmaceutical manufacturers.

• Our unit does receive research support from several drug companies through unrestricted grants to the Brigham and Women’s Hospital.

Page 3: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Three clinical vignettes• an otherwise healthy 60 year old man with

mild arthritis unexpectedly has a heart attack and dies.

• an unmarried 16 year old girl has unprotected sex, can’t get emergency contraception, seeks an abortion, and has serious medical and psychological complications.

• after a storm, a family of four is trapped by rising flood waters in their home four feet below sea level in a major American city; all drown.

Page 4: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

What do these events have in common?

• a failure of science-based infrastructure.

• In each case:– We had clear evidence pointing to the

need for specific governmental action.– Better federal decisionmaking could have

averted tragedy.– The right decisions were not made.– The resulting human and economic costs

were enormous, far greater than doing it right the first time.

Page 5: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

The “telephone” problem• First-rate bench-level clin pharm research• Rigorous but sometimes irrelevant review• Non-scientific factors influence approval• Inadequate post-marketing safety

surveillance• Distorted communication of benefits, risks

– to prescribers and to patients• Flawed reimbursement policies encourage

suboptimal use

Page 6: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

From a good beginning……

Siebert K, Zhang Y, Leahy K, et al. “Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.” – -- Proc Natl Acad Sci, 1994

Page 7: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

..…to a bad end.

Martinez B, Mathews AW, Lublin JS, and Winslow R.

“Merck pulls Vioxx from market after link to heart problems.”– --Wall Street Journal, 2004

Page 8: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Benefits, risks, and cost-effectiveness

do not reside exclusively within the drug molecule.

They are also determined in large part by how prescribers and patients use a product.

Page 9: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Limits of clinical trial data• small N’s• volunteer patients• short duration• under-representation of important groups • atypical clinicians, settings• protocolized care: compliance, monitoring• surrogate endpoints• comparator is often placebo

Page 10: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Some notable withdrawals• Duract: hepatotoxicity• Posicor: hypotension, bradycardia• Fen-phen: pulmonary htn, valvulopathy• Rezulin: hepatotoxicity• Baycol: rhabdomyolysis• PPA: intracerebral hemorrhage• Vioxx: MI, stroke• Bextra: SJS, MI• [Avandia: CHF, ?MI?]

Page 11: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Financial and practical issues• cost of capital (a function of time)

looms large in drug development expenses

• incentive for smaller, quicker trials• motivation to avoid “messy” patients• PDUFA:

– faster approvals– problems later

Page 12: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Efficacy and safety:a policy dilemma?

• To make drugs available quickly, trials must:– be brief and have modest N– include easy-to-study patients

• To define all adverse events, trials would:– last longer– be larger– include more vulnerable, complex patients

• But beware the Heisenberg fallacy!

Page 13: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Needed changes in approval

• Inclusion of more representative patients

• Longer duration– a two-stage process?

• Better flagging of signals in need of followup

• More critical thinking about surrogate outcomes

Page 14: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Origins of FDA’s problems• Anti-regulatory trends:

– “Government is not the solution to our problem; government is the problem.” – President Ronald Reagan, 1st Inaugural

Address– growing reliance on the marketplace to

solve most social issues– the power of lobbying and $$ to shape

policy• Adverse effects of PDUFA

Page 15: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Post-marketing safety surveillance

Page 16: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Two views of an adverse drug event report:

– Physician: “This drug could be a real threat to the life of my patient!”

– Manufacturer:“This patient could be real threat to the life of my drug!”

Page 17: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Two industry perspectives• ostrich view:

– liability fears– marketing concerns

• enlightened view:– What we don’t know can hurt us– information could save drug

Page 18: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

FDA problems• Inadequate clout over

manufacturers after approval– most “mandated” PMS

“commitments” are never even begun• Inadequate funds to do or

commission studies• Low staffing, expertise, morale

among PMS staff

Page 19: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Fixing the three M’s• Money

• Mandate

• Methodology

Page 20: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Money • FDARA ???

– not adequate• CMS realizes that it has become the

nation’s biggest drug purchaser– prudent use of its own $– more comparative trials

• Where are the other payors??– Medicaid, private insurers, VA

Page 21: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Mandate • FDARA

– one small step…• FDA needs more power to compel

studies to protect public health• The marketplace

– Will the sleeping giant ever awaken?

Page 22: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Methodology • Pre-approval studies

– innovative designs– more research on surrogate outcomes

• Post-marketing surveillance– less reliance on spontaneous reports– more ubiquitous databases– evolution of pharmaco-epi methods

• Large pragmatic post-approval trials

Page 23: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Head-to-head risk-benefit comparisons

• continuing coxib-NSAID confusion– about efficacy– about side effects

• a dozen other clinical areas– CHF, HTN, diabetes, depression,

insomnia, Parkinson’s Disease, etc., etc.

• no-one’s in charge at present

Page 24: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

“How can we ever afford this?!”• The U.S. already spends more per

capita on drugs than any other nation.• Much of that is wasted.

– Government (federal, state, VA) is footing a big part of the bill.•e.g., Medicaid spent $1 billion a year on

Vioxx• Publicly funded comparative drug

trials and better PMS would pay for themselves quickly.

Page 25: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

The future

Page 26: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Drivers of change• Growing need to use powerful new

medications appropriately• Aging of the population• Escalating drug costs• Greater sophistication in data

accessibility, informatics• Changing political climate

– the public / the Congress / 2008

Page 27: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

“The lion shall lie down with the lamb…

…but the lamb won’t get much sleep.

– Woody Allen

Page 28: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

Katrina, 2 years later• Ample data exist documenting the problem.• Solutions are obvious, do-able, and relatively

inexpensive, compared to inaction.• What has thwarted intelligent policy?

– governmental inertia and ineptitude – misguided ideology – interest-group politics

• We need to overcome all three.

Page 29: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

A pharmacological New Orleans• Every drug and every patient who takes it

are potentially four feet below sea level.• Category 3 to 5 medication disasters will

occur inevitably, though we can’t predict each one in advance.

• Science-based public policies on drug evaluation and regulation are the levees that keep us all from drowning.

• The bad news: The levees are leaking.• The good news: It won’t take that much to

fix them.

Page 30: Improving FDA’s approach  to new drug approval  and post-marketing surveillance

For more information….“Powerful Medicines: the Benefits,

Risks, and Costs of Prescription Drugs”(Knopf 2004, Vintage 2005):

www.PowerfulMedicines.org

The BWH Division of Pharmaco-epi and Pharmaco-eco (“DOPE”): www.DrugEpi.org