Monitoring the Safety of FDAApproved Drugs: A Legislative Review

1
Monitoring the Safety of FDA-Approved Drugs A
Legislative Review

• Nicole Davarpanah, M.D.
• Preceptor Dr. Eileen Moore
• February 22, 2007

2
The Future of Drug Safety Promoting and
Protecting the Health of the Public Institute of
Medicine Report, 2006

• It is impossible to have complete information
  about drug safety at the time of approval
• Drugs mechanism of action are complex
• Pre-approval clinical testing is generally
  conducted in controlled settings in defined,
  carefully-selected populations
• Insufficient sample size to detect serious but
  rare adverse effects

3
Institute of Medicine Recommendation

• Lifecycle approach to drug risk and benefit
• For the FDA, this will require a continuous
  availability of new data and ongoing, active
  reassessment of risk benefit both before and
  after approval
• For physicians, this will require following FDA
  communication about drug safety matter and
  exercising appropriate caution in drug-related
  decision making in recognition of limited
  information available at the time of drug
  approval.

4
Georgetown Center for Education and Research in
Therapeutics

• Four Projects spanning four years
• New epidemiological tools to assess drug safety
• Use of existing adverse drug event databases for
  post-market drug surveillance
• Legal analysis to explore optimal ways to
  incorporate scientific information on adverse
  drug effects into the FDA regulatory process
• Development of education interventions for
  physicians

5
Legal Analysis of Existing FDA Regulatory Process

• Intense review of existing FDA regulatory process
  and the IOM recommendations
• Legal analysis of litigation and judicial
  proceedings taken in response to adverse drug
  effects discovered post-FDA approval
• Primary goal collaborate with the FDA to help
  implement post-approval drug safety monitoring
• Final goal presentation of research findings and
  recommendations before Congressional hearing

6
FDA Drug Approval Process

• Phase 1 healthy volunteers or patients 20 to 80
  subjects
• Look at the metabolism, structure-reactivity
  relationships, mechanism of action, and side
  effects of the drug in humans. If possible, phase
  1 studies are used to determine how effective the
  drug is.
• Phase 2 several hundred patients
• used to determine the efficacy of a drug to treat
  patients with a specific disease or condition, as
  well as learn about common short-term side
  effects or risks.
• Phase 3 several hundred to several thousand
  subjects
• provide more information about the effects and
  safety of the drug and they allow scientists to
  extrapolate the results of clinical studies to
  the general population.

7
The New Drug Development Process Steps from Test
Tube to New Drug Application Review

• FDA estimates 8 year time-span for entire
  process
• Pharmaceutical industry claims 802 million
  spent for each new drug brought to market
• www.fda.gov/cder/handbook/develop.htm, 2007.

8
The Vioxx RecallAn example to critically analyze
the FDA drug approval policy

• In 2000, Merck Co. released its powerhouse
  COX-2 inhibitor Vioxx on the market.
• Merck invested 500 million in consumer and
  professional advertising
• 20 million American users
• Merck profit 50 million/month
• On September 30, 2004, Merck announced an
  immediate withdrawal of Vioxx following a
  clinical study indicating it more than doubled
  the risk of heart attack and stroke
• An FDA study published post-recall estimated that
  Vioxx caused as many as 140,000 heart-related
  injuries 56,000 deaths in five years
• By March 2005, Merck was facing 1357 injury
  claims against its defective drug

9
FDA Withdrawal of Drugs

• 20 drugs withdrawn since inception of FDA in 1936
• Omniflox antibiotic that causes hemolytic
  anemia
• Rezulin diabetes drug that causes acute liver
  failure
• Fen-Phen and Redux weight loss drugs that cause
  heart valve injury
• PPA (Phenylpropanolamine) OTC decongestant and
  weight loss drug that caused hemorrhagic stroke
  in women
• Rovan antibiotic that cause acute liver failure
• Lotronex drug for IBS that caused ischemic
  colitis
• Baycol cholesterol-lowering drug that caused
  severe muscle injury, kidney failure, and death
• Seldane antihistamine that caused heart
  arrhythmias and death
• Propulsid drug for nighttime heartburn that
  caused heart arrhthythmias and death

10
A Brief History of Drug Safety Disasters in the
U.S.
Testimony of Dr. David J. Graham, Associate
Director of FDA Office of Drug Safety, before
Congress 11/18/2004.
11
Vioxx Timeline

• May 1999 FDA approves Vioxx.
• March 2000 Merck reveals that a new study found
  Vioxx patients had double the rate of serious
  cardiovascular problems than those on naproxen,
  an older nonsteroidal anti-inflammatory drug, or
  NSAID.
• November 2000 The New England Journal of
  Medicine publishes the VIGOR study
• 5-fold increase in heart attack risk
• the company said the drug was safe naproxen was
  cardio-protective
• February 2001 An advisory panel recommends the
  FDA require a label warning of the possible link
  to cardiovascular problems
• Merck did not place this in the Warnings
  section but in the Precautions section
  ultimately had no effect on how often high-dose
  Vioxx was prescribed.
• September 2001 The FDA warns Merck to stop
  misleading doctors about Vioxx's effect on the
  cardiovascular system.

Rubin, Rita How did Vioxx Debacle Happen? USA
Today, Oct. 2004.
12
Vioxx Timeline

• April 2002 The FDA tells Merck to add
  information about cardiovascular risk to Vioxx's
  label.
• Aug. 25, 2004 An FDA researcher presents results
  of a database analysis of 1.4 million patients
  it concludes that Vioxx users are 3.7 times more
  likely to suffer a heart attack or sudden cardiac
  death than those taking Celebrex or an older
  NSAID.
• Sept. 23, 2004 Merck says it learned this day
  that patients taking Vioxx in a study were twice
  as likely to suffer a heart attack or stroke as
  those on placebo
• Mercks decision was based on a study initiated
  by Merck in 2000 and concluded in 2004 called
  Adenomatous Polyp Prevention of Vioxx (APPROVe)
  to study the protective effects of the drug in
  preventing colon polyps
• the study unexpectedly indicated that patients
  had an increased risk of developoing heart
  attacks or strokes after taking Vioxx for more
  than 18 months.

• Sept. 30, 2004 Merck withdraws Vioxx from the
  U.S. and the more than 80 other countries in
  which it was marketed.

Rubin, Rita How did Vioxx Debacle Happen? USA
Today, Oct. 2004.
13
The Judicial Response

• May 3, 2005 Texas Ernst v. Merck
• Ms. Ernst claimed that her husband, a 59-year-old
  triathlete died in 2001 after taking Vioxx for
  his OA for 7 months
• Texas jury found Merck liable and awarded 253.5
  million
• 24.5 million mental anguish economic losses
• 229 million punitive damages (later limited to
  1.6 million Texas cap)
• Decision based on finding that Merck acted
  recklessly by its aggressive marketing and
  failure to appropriately warn doctors

• Fall 2005 New Jersey Humeston v. Merck
• Humeston 60 year-old postal worker had
  cardiac risk factors (obesity, lipids) was not
  an athlete took Vioxx for only two months before
  his heart attack, which he survived.
• Merck won decisively (81 jury vote) because
  it could not be proven that Vioxx was the
  causative agent of the heart attack.

14
Post Approval Studies by the Drug Industry

• Pending The study has not been initiated, but
  does not meet the criterion for delayed
• Ongoing The study is proceeding according to or
  ahead of the original schedule
• Delayed The study is behind the original
  schedule
• Terminated The study was ended before
  completion, but a final study report has not been
  submitted to FDA or
• Submitted The study has been completed or
  terminated, and a final study report has been
  submitted to FDA.
• Clearly, if 65 of these studies haven't even
  started and only 14 have been completed and
  submitted, the FDA does need more authority to
  enforce these commitments by the industry.

15
Steps to Save the FDA Drug Approval Process

• The Drug Safety Oversight Board
• Created in February 2005
• 15-member advisory board comprised of NIH, V.A.,
  FDA, medical expert members to monitor
  prescription drug safety
• 1) Create a drug watch website
• 2) Resolve disagreements between organization
  over approaches to drug safety
• 3) Education physicians and the public about
  safety developments for newly approved drugs
• Does not have authority to remove a drug from the
  market or make changes to a drug sales practice

16
Optimal ways to incorporate scientific
information on adverse drug effects into the FDA
regulatory process

• Change the scientific standard used by the FDA
  Office of New Drugs to classify a post-marketing
  drug as unsafe.1
• Under current paradigm, an approved drug is safe
  until you can show with 95 certainty that it is
  not safe.
• Make Phase IV post approval drug testing a
  federal requirement for all new drugs.
• Create a national registry at the FDA for the
  voluntary reporting of adverse drug effects by
  physicians and federally mandate their review as
  part of the post approval process.

1 Testimony of Dr. David J. Graham, Associate
Director of FDA Office of Drug Safety, before
Congress 11/18/2004.