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The FDA Watchdog Without a Bite(and With No
Incentive to Bark)

• Joe Lex, MD, FAAEM
• Temple University School of Medicine
• Philadelphia, PA
• Joseph.Lex_at_TUHS.Temple.edu

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Objectives

• History origins to present
• Position in government
• Limitations of powers
• Relations with Pharma / PDUFA
• Politicalization
• How bad decisions happen
• The IOM Report the future

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FDA Mission Statement

• The FDA is responsible for protecting the public
  health by assuring the safety, efficacy, and
  security of human and veterinary drugs,
  biological products, medical devices, our
  nations food supply, cosmetics, and products
  that emit radiation.

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FDA Mission Statement

• also responsible for advancing the public health
  by helping to speed innovations that make
  medicines and foods more effective, safer, and
  more affordable and helping the public get the
  accurate, science-based information they need to
  improve their health.

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Did You Know???

• Properly prescribed drugs cause gt100,000 deaths
  annually in US
• Vioxx probably caused gt100,000 deaths in its 6
  years
• Prescription drugs among top ten causes of death
  in US

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Generation Rx

• Average number yearly prescriptions per US
  citizen
• 1993 7
• 2000 11
• 2004 12

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Generation Rx

• In 2004
• 50 of Americans took one prescription drug
  daily
• 15 took three or more daily
• 3,000,000,000 prescriptions
• 180,000,000,000 worth of pills

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History of the FDA

• Responsible for safeguarding 25 of all products
  services consumed in US, valued at 1.5 trillion

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Buffering Force

• FDA regulates new drugs
• Congress funds the FDA
• White House appoints officials to oversee process
• All are politically motivated
• All blunted by pharmaceutical company political
  activity
• 6 pharma lobbyists per Senator

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• If men were angels, no government would be
  necessary. If angels were to govern men, neither
  external nor internal controls on government
  would be necessary. In framing a government
  which is to be administered by men over men, the
  great difficulty lies in this you must first
  enable the government to control the governed
  and in the next place oblige it to control
  itself.

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• A dependence on the people is, no doubt, the
  primary control on the government but experience
  has taught mankind the necessity of auxiliary
  precautions.
• The Federalist No. 51
• February 6, 1788
• James Madison

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History of the FDA
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History of the FDA

• Started as one chemist in U.S. Department of
  Agriculture in 1862, quickly grew

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History of the FDA

• Early 20th century no national rules, laws, or
  regulations to set standards of hygiene, purity,
  or honesty in food or drug labeling
• Many infants died from patent medicines
  containing opium and cocaine

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History of the FDA

• FDA founder Harvey Wiley Tens of thousands of
  people die yearly from patent medicines and
  adulterated food

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Morphine
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History of the FDA

• Widespread public outrage
• Petition to Congress demanding action
• Upton Sinclair The Jungle

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History of the FDA

• 1906 Food and Drug Act signed into law
• Nation's first regulatory agency
• Represented change in policy
• Government now protected citizens from commerce
  rather than just protecting commerce

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History of the FDA

• Acknowledged for first time circumstances where
  government must protect citizens against business
• Began U.S. federal bureaucracy and started public
  administration

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History of the FDA

• 1927 Congress authorized formation of Food,
  Drug, and Insecticide Administration
• But anyone could sell medicine, as long as it
  didnt contain narcotics or a listed poison

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History of the FDA

• If drug found harmful or fatal, maker not
  required to take it off market
• If FDA contested, maker could change name and
  start over
• 1930 name shortened to FDA

Then in 1937
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• six human beings, all of them my patients, one
  of them my best friend, are dead because they
  took medicine that I prescribed for themmedicine
  which I had used for yearssuddenly had become a
  deadly poison in its newest and most modern form,
  as recommended by a great and reputable
  pharmaceutical firm in Tennessee
• Letter from Dr. Archie Calhoun, October 22, 1937

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Massengill Massacre
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Massengill Massacre

• Sulfanilamide used safely for some time as tablet
  or powder
• June 1937 salesman for S.E. Massengill Co., in
  Bristol, Tennessee, reported demand in the
  southern states for the drug in liquid form

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Massengill Massacre

• Companys chief chemist and pharmacist, Harold
  Cole Watkins, found sulfanilamide dissolved in
  diethylene glycol
• Also found flavor, appearance, and fragrance
  satisfactory
• Not tested for toxicity

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Massengill Massacre

• Diethylene glycol antifreeze
• September 633 shipments sent
• October 11 AMA received reports about several
  deaths
• AMA laboratory isolated toxic ingredient

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Massengill Massacre

• Issued warning through radio, newspapers
• 107 people died, many children
• Harold Watkins fired, later committed suicide

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Massengill Massacre

• Within six months, Congress passed Food, Drug,
  and Cosmetic Act of 1938
• Requires FDA to certify safety of new drugs
  before marketing
• No new funds allocated

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1938 New Authority

• Significant limitations remained
• Proof of efficacy not required
• Animal testing not standardized
• Human trials often poorly done
• FDA did not review application until drug
  manufacturer finished its own tests

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1938 New Authority

• Drugs studied in premarketing clinical trials
  exempted from review
• If FDA failed to consider new drug application
  within 60 days, drug automatically approved

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1962 Kefauver-Harris
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1962 Kefauver-Harris

• Drugs now required to be safe and effective
• Manufacturers required to prove premarket
  effectiveness
• No new funds allocated

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Approval Process

• Investigational New Drug (IND) application
• Phase I is it safe?
• Phase II does it work?
• Phase III is it better than standard treatment
  or placebo?
• New Drug Application (NDA)

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1983 Orphan Drug Act

• Promote development of drugs to treat illnesses
  afflicting less than 200,000 in US / year
• Manufacturer must show good ROI is remote
• Seven years market exclusivity plus tax breaks,
  administrative and financial aid from FDA

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1983 Orphan Drug Act

• Prevalence of disease may be greater in other
  countries, leading to profit
• Off-label use may lead to profit

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Thalidomide Story
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Thalidomide Story

• Sedative-hypnotic made in Europe, used in
  pregnancy
• FDA Pharmacologist Frances Oldham Kelsey didnt
  like safety profile, delayed US approval
• 1961 severe birth defects reported in Germany,
  others

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Thalidomide Story

• Kelsey declared hero
• FDA lionized
• Recently approved as orphan drug for leprosy

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1976 Medical Device Act

• Dalkon shield IUD killed, maimed 200,000 women
• FDA previously had no prior authority to either
  approve or force withdrawal from market

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Rough Times

• 1981 Reagan cut 1/10 of 7500 staff
• Several FDA initiatives giving consumers more
  information were stopped cold

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Rough Times

• Political pressure
• 1981 CDC reports strong link aspirin and Reyes
  syndrome
• Prevented by industry, White House from warning
  labels
• Public interest groups sued
• 1986 warning labels approved

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Rough Times
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Rough Times

• Approved dangerous products
• 1979 approved Bjork-Shiley heart valve
• Three manufacturer recalls for fractured struts
  
• Estimated 500 deaths
• 1986 Pfizer pulled from market

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Rough Times

• Not approving beneficial products
• 1987 refused to approve tPA
• Concerned about brain bleeds
• Approved after resubmitted at lower doses
• Many critics say delayed effective therapy by a
  year
• May have actually saved lives

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Rough Times

• Bribery
• After Hatch-Waxman, some generic manufacturers
  always got their product approved faster than
  others
• 1989 five FDA employees and 40 generic company
  employees convicted of felony bribery

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Rough Times
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Rough Times

• The AIDS dustup
• Activists said slow to research, develop, and
  approve drugs
• In reality, these were duties of NIH, CDC, drug
  industry
• FDA unjustly got most blame

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1984 Hatch-Waxman
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1984 Hatch-Waxman

• Drug Price Competition and Patent Term
  Restoration Act
• Generics get approved based on submission of
  Abbreviated New Drug Approval (ANDA)
• Dont replicate original studies
• 180 day exclusivity if first to file

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1984 Hatch-Waxman

• Title II (Public Law 98-417) extended patent life
  to compensate patent holders for marketing time
  lost while developing the product and awaiting
  government approval
• No new funds allocated

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1988 FDA Administration

• Senate to confirm commissioner (like FBI or
  Federal Reserve)
• Commissioner reports directly to Secretary of
  Health and Human Services
• Now just one level from cabinet
• No new funds allocated

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Where Does The FDA Fit?
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Where Does FDA Fit?

• Not cabinet level, like Agriculture Department
  (USDA)
• Not independent agency, like Environmental
  Protective Agency (EPA)
• No direct mandate from voters

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2007 Budget

• USDA 96,440,000,000
• FDA 1,947,282,000

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What Does CDER Do?

• Consumer watchdog in healthcare system
• Best-known job evaluate new drugs before they
  can be sold
• Prevents quackery
• Provides doctors and patients with information
  they need to use medicines wisely

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Does CDER Test Drugs?

• FDA does not develop, test, or manufacture drugs
• Manufacturers submit full reports of studies to
  CDER
• Reviewers assess benefit-to-risk relationship to
  determine if drug will be approved

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CFR

• Code of Federal Regulations (CFR) codification
  of general and permanent rules published in
  Federal Register by Executive departments and
  Federal Government agencies
• Title 21 reserved for FDA

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Watchdogs Bite

• DTC advertising 791M in 1996 to 2.5B in 2000
• FDA staff assigned to review both DTC and
  advertising aimed at medical professionals went
  from 11 in 1996 to 14 in 2001

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Watchdogs Bite

• Presently can issue Notice of Violation or
  Warning Letter when company violates DTC laws or
  regulations
• Theoretically could seek criminal prosecution for
  repeated violations, but no known cases

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Whos in Charge Here?

• If the chicken is sick, USDA is in charge. If
  the chicken is not sick but lays infected eggs,
  the FDA is in charge.
• Caroline Smith DeWaal
• Director, Center for Science in the Public
  Interest food safety program

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Whos in Charge Here?

• Center for Food Safety and Applied nutrition at
  FDA regulates safety of all food
• except poultry and meat, which come under USDA
• unless its game meat (venison, quail) which is
  the FDA

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Whos in Charge Here?

• and bottled water, where EPA establishes the
  standards
• but FDA does the labeling
• and recreationally caught game fish, which is
  the EPA
• unless sold commercially, then its the FDA

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Whos in Charge Here?

• USDA is in charge of meat for human consumption
• but FDA regulates meat for animal consumption
  and the drugs given to animals
• except for biologics, which are under USDA

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Whos in Charge Here?

• USDA regulates field-testing of genetically
  modified plants
• unless the plants make their own pesticide,
  which comes under EPA
• but the FDA determines whether they are safe to
  eat

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Whos in Charge Here?

• Health claim on food box FDA
• Health claim on TV ad FCC
• Drug advertising in magazine combined FTC and FDA

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Whos in Charge Here?

• Drugs FDA
• Illegal drugs DEA
• Frozen cheese pizza FDA
• With pepperoni USDA

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Working with Pharma
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Patents

• Patents granted for the
• drug itself
• way the drug is made
• way the drug is to be used
• method of delivering / releasing the drug into
  the bloodstream

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1995 Uruguay Act

• Uruguay Rounds Agreements Act (Public Law
  103-465) changed US patent from 17 to 20-year
  patent life from date of first filing patent
  application filing
• Gives manufacturer of brand name drug sole market
  right while in effect

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Patents

• Usually, about 10 years elapse between the time a
  patent is obtained and the time the drug is
  approved, leaving the company only about half of
  the patent time to exclusively market a new drug.

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Patent Protection

• Once patent expires, 80 of brand name sales can
  vanish in a year as generics reach market
• Typically last average 11 years market life from
  20 year patent
• 1991 average FDA review time more than 30 months

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Patent Protection

• Drug companies file patent after patent to try to
  extend drug life
• When generic drug challenged in court, FDA forced
  by law to freeze approval for 30 months unless
  case settled before that

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Patent Protection

• FDA has no authority to litigate patent
  infringement law
• Members of Congress tag patent extension onto
  bills, favoring companies which have contributed
  to their campaigns

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Show Me the Money
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PDUFA

• 1992 Congress passed Prescription Drug User Fee
  Act
• 1997, 2002 reauthorized
• Coming up again this year
• Before PDUFA, taxpayers alone paid for product
  reviews through budgets provided by Congress

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PDUFA

• Application fee with NDA
• Product fee paid annually for previously
  approved entities
• Establishment fee assessed annually on approved
  manufacturing facility

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PDUFA
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PDUFA

• PDUFA III FY 2007 fee revenue
• Application 86,434,000
• Product 86,433,000
• Establishment 86,433,000
• Before adjustments 259,300,000

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PDUFA

• PDUFA allows one-trial for new drug
• It provides more than half of money spent on NDA
• Crucial source of funds
• Congress less likely to fund FDA

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PDUFA

• Has it accomplished its goal of shorter times to
  approval?

Yes
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Months to approval NDA
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PDUFA

• 1980s 2 3 of new drugs in world were first
  introduced in US
• 1998 60 of new drugs first introduced in US
• 1986-1992 163 drugs approved
• 1993-1999 232 drugs approved (42 increase)

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PDUFA

• Proportion of drugs reviewed ultimately approved
  increased from 60 at beginning of 1990s to 80
  by end of decade

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PDUFA

• 2000 Los Angeles Times investigative report
  revealed that FDA leadership believed that what
  they were really being asked for was not simply
  timely review decisions, but more speedy drug
  approvals

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PDUFA

• Survey of FDA employees
• we are told that approvability is our goal
  with problems to be addressed in labeling.
• we are shifting the burden of proof of safety
  on ourselvesIf we cannot show the drug is
  dangerous, it is assumed safe.

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PDUFA

• There is still critical under-funding of
  activities not defined as part of drug approval
  process, such as monitoring of adverse events and
  oversight of post-launch advertising campaigns
  (Phase IV studies)

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What Can Go Wrong?
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FDA Approval Errors
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Type I Errors

• Post-PDUFA drugs withdrawn due to safety concerns
  include Raxar, Baycol, Raplon, Duract, Redux,
  Lotronex, Propulsid, Rezulin, Posicor,
  RotaShield, Vioxx
• Five drugs approved from 1985 through 1992 were
  withdrawn

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Type I Errors

• Raplon, Raxar, Duract, Posicor, Redux and Vioxx
  approved despite known safety problems and
  availability of multiple treatment options in
  other, older, and safer drugs approved for same
  uses

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Rezulin

• Redundant drug given rapid review and approved
  despite known safety problems
• LA Times pressure from Warner-Lambert led FDA to
  reassign John Gueriguian, first Medical Officer
  to review drug, who said do not approve

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Rezulin

• Gueriguians review purged from FDA files,
  withheld from advisory committee
• Liver toxicity not discussed at FDAs December
  1996 advisory committee meeting
• Drug unanimously approved

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Rezulin

• 1997 approved for type-2 diabetes
• Many other drugs on market
• 43 deaths in Japan and America due to liver
  failure
• 60 patients with liver damage
• 1999 removed from market

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Relenza

• Flu drug shown not effective in US studies
• FDA received reports linking it to respiratory
  distress and at least 22 deaths
• 13 to 4 vote against approval by FDAs Antiviral
  Drugs Advisory Committee

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Relenza

• Approved despite problems

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Sue the FDA?

• Regulatory Compliance Defense Liability of the
  United States, Under Federal Tort Claims Act (28
  U.S.C.A. 1346, 2680) For Damages Caused by
  Ingestion or Administration of Government-Approved
  Drugs, Vaccines, and Medications, 173 A.L.R. FED
  431(2001)

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FDA as a Political Tool
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WSJ 20 Apr 1999

• The FDA is caught in pincers between two
  intense political pressures demands from the
  drug industry and the political right to move
  faster and faster in approving new drugs, and
  rising insistence from consumer groups and the
  left to show more caution.

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Mark McClellan, 2002-2004

• Brother of ex-White House Press Secretary Scott
  McClellan
• Son of Texas comptroller Carole Keeton Strayhorn

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Mark McClellan, 2002-2004

• Harvard MD
• MIT PhD
• Stanford professor in both
• Worked Treasury under Clinton
• Thought politically independent

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Mark McClellan, 2002-2004

• FDA changed from tough independent regulatory
  body to partner in nurturing promotion of
  pharmaceutical industry
• Spoke out against drug imports as dangerous

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Mark McClellan, 2002-2004

• On cover of Medical Marketing and Media We
  wont bite.
• Went on pharma speakers circuit
• Spoke at marketing meetings which promised how
  to push the promotional envelope

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Mark McClellan, 2002-2004

• Employees found advocating regulation at FDA was
  career-killing move
• Number of warning letters to advertisers plummeted

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Mark McClellan, 2002-2004

• March 2004 took job as head of Medicare /
  Medicaid
• Considered promotion
• Immediately reversed his opinion on drug imports

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Andrew von Eschenbach

• Sworn in 13 December 2006 as FDA head
• Former Director of National Cancer Institute
• Another Bush family friend

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FDA Mission Statement

• also responsible for advancing the public health
  by helping to speed innovations that make
  medicines and foods more effective, safer, and
  more affordable and helping the public get the
  accurate, science-based information they need to
  improve their health.

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As Moral Arbiter

• President Bush appointed Dr. W. David Hager as
  Chair of Reproductive Health Drugs Committee
• Author of book advocating Bible reading, prayer
  for headache, premenstrual syndrome

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As Moral Arbiter

• Hager OTC Morning After pill encourage(s) teen
  sex
• Also said individuals who did not want to take
  responsibility for their actions and wanted a
  medication to relieve those consequences.

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As Moral Arbiter

• FDA says it makes decisions based on science
• First consideration always safety and efficacy
• Does NOT make decisions on cost, ethics, or
  political trends
• These are sociological, political arguments

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As Moral Arbiter

• 2004 panels recommended approval by 23 4 vote
• FDA declined to approve
• Announcement made same day as annual National Day
  of Prayer at White House
• 2004 also an election year

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As Moral Arbiter

• 37 congress members sent letter to FDA condemning
  move as clearly based on right-wing ideology
  rather than sound science.
• Eventually approved

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UCS Survey

• Union of Concerned Scientists (UCS) surveyed FDA
  scientists
• 18.4 said they have been asked for
  non-scientific reasons to inappropriately
  exclude, or alter technical information or their
  conclusions in FDA scientific documents

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UCS Survey

• Echoes previous complaints by FDA scientists who
  said that their findings on painkiller Vioxx were
  dismissed
• Merck pulled Vioxx from market when study linked
  doubling of heart risk to use of drug

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UCS Survey

• 17 had been asked by FDA officials to provide
  incomplete, inaccurate or misleading information
  to the public, regulated industry, media, or
  government officials
• 40 fear retaliation from voicing safety concerns
  in public

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UCS Survey

• 47 think that the FDA routinely provides
  complete and accurate information to the public
• 61 knew of cases where Department of HHS or FDA
  appointees inappropriately injected themselves
  into FDA determinations of actions

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UCS Survey

• 81 agreed that the public would be better served
  if the independence and authority of FDA
  post-market safety systems were strengthened

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IOM On Safety
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Institute of Medicine

• Nonprofit organization
• Created by Congress to advise federal government
  on health issues
• Issued report on Drug Safety in September 2006

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Institute of Medicine

• The mission of the Institute of Medicine is to
  advance scientific knowledge and the health and
  well-being of all people of this nation and the
  world, consistent with the role conferred by its
  congressional authority.

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Institute of Medicine

• It accomplishes this mission by providing
  objective, timely and authoritative information
  to government, the professions and the public
  through its elected membership and access to the
  best expertise.

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2006 IOM Report
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2006 IOM Report

• FDA and pharmaceutical industry do not
  consistently demonstrate accountability and
  transparency to the public by communicating
  safety concerns in a timely and effective fashion

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2006 IOM Report

• Drug safety system impaired by serious resource
  constraints that weaken the quality and quantity
  of the science brought to bear on drug safety

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2006 IOM Report

• Organizational culture in Center for Drug
  Evaluation and Research is not optimally
  functional
• Regulatory authority is unclear and insufficient,
  particularly with respect to enforcement

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Recommendation 3.1

• Appoint FDA Commissioner for 6-year term
• Should have expertise to head science-based
  agency
• Should have commitment to public health,
  scientific integrity, transparency, communication

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Recommendation 3.2

• Guidance from HHS to help
• Improve morale
• Retain professional staff
• Strengthen transparency
• Restore credibility
• Create a culture of safety

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Recommendation 3.5

• Restore balance between dual goals of speeding
  access to innovative drugs and ensuring drug
  safety
• Introduce specific safety-related performance
  goals in PDUFA IV in 2007

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Recommendation 4.10

• Require that a substantial majority of the
  members of each advisory committee be free of
  significant financial involvement with companies
  whose interests may be affected by the
  committees deliberations

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Recommendation 4.11

• Post (at a minimum) all Phase 2 through Phase 4
  clinical trials at www.clinicaltrials.gov
• Post structured field summary of efficacy and
  safety results of all studies

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Recommendation 5.2

• Enact legislation to ensure that FDA has
  increased enforcement authority and better
  enforcement tools directed at drug sponsors,
  including fines, injunctions, and withdrawal of
  drug approval

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Recommendation 5.3

• For first two years of new drug
• Place special symbol on product label, such as
  black triangle used in the UK
• Restrict DTC advertising
• FDA may shorten or extend time on case-to-case
  basis

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Recommendation 5.4

• Evaluate all emerging data on new molecular
  entities no later than 5 years after approval
• Sponsors submit report of accumulated data
  relevant to drug safety and efficacy, including
  additional data from peer reviewed journals

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Recommendation 7.1

• To support improvements in drug safety and
  efficacy activitiesthe Administration should
  request and Congress should approve substantially
  increased resources in both funds and personnel
  for the FDA.

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Some Other Ideas
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Some Other Ideas

• Problem no long-term safety data
• Solution give extended period of exclusivity for
  drugs with data that show long-term safety

Wood AJJ. N Engl J Med 20063556, 618-623
145
Some Other Ideas

• Problem no head-to-head comparisons
• Solution give extended period of exclusivity for
  drugs with data that show improvement over same
  class of drugs on market

Wood AJJ. N Engl J Med 20063556, 618-623
146
Some Other Ideas

• Problem Phase 4 commitments are not fulfilled
• Solution give extended period of exclusivity
  when phase 4 commitments are met

Wood AJJ. N Engl J Med 20063556, 618-623
147
Some Other Ideas

• Problem must boost incentive to develop drugs
  with high commercial risk
• Solution grant extended period of exclusivity
  for predefined high-need, high-risk drugs which
  are first in class, rather than me too

Wood AJJ. N Engl J Med 20063556, 618-623
148
Some Other Ideas

• Problem surrogate endpoints dont necessarily
  mean clinically meaningful endpoints
• Solution
• Give limited exclusivity if approval based on
  surrogate endpoints
• Give extended exclusivity only with clinically
  meaningful endpoint

Wood AJJ. N Engl J Med 20063556, 618-623
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Some Other Ideas

• Limit accelerated approval to life-saving drugs
  only
• Penalize drug companies for attempting to
  influence FDA
• Reward FDA employees for reporting attempts
• Encourage patients to report adverse events

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Conclusions

• FDA walks a tightrope between too fast and too
  slow
• Remove politics
• Strengthen authority
• Remove those being regulated from process
• Give them money to do right job

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Joseph.Lex _at_TUHS.Temple.edu