FDA - Watchdog without a Bite

FDA - Watchdog without a Bite - The FDA: The Watchdog...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: The FDA: The Watchdog Without a Bite Watchdog (and With No Incentive to Bark) Joe Lex, MD, FAAEM Joe Temple University School of Medicine Philadelphia, PA [email protected] Objectives 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 FDA Mission Statement FDA 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 nation’s food supply, cosmetics, and products that emit radiation. FDA Mission Statement FDA …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, sciencebased information they need … to improve their health. Did You Know??? Did • Properly prescribed drugs cause >100,000 deaths annually in US • Vioxx® probably caused >100,000 deaths in its 6 years • Prescription drugs among top ten causes of death in US Generation Rx Generation • Average number yearly prescriptions per US citizen: 1993: 7 2000: 11 2004: 12 Generation Rx Generation 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 History of the FDA History • Responsible for safeguarding 25% of all products & services consumed in US, valued at $1.5 trillion Buffering Force Buffering • • • 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 “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.” “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 History of History the FDA the History of the FDA History • Started as one chemist in U.S. Department of Agriculture in 1862, quickly grew History of the FDA History • 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 History of the FDA History • FDA founder Harvey Wiley: “Tens of thousands of people die yearly from patent medicines and adulterated food” Morphine History of the FDA History • • Widespread public outrage Petition to Congress demanding action • Upton Sinclair: The Jungle History of the FDA History • 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 History of the FDA History • Acknowledged for first time circumstances where government must protect citizens against business • Began U.S. federal bureaucracy and started public administration History of the FDA History • 1927: Congress authorized formation of Food, Drug, and Insecticide Administration • But anyone could sell medicine, as long as it didn’t contain narcotics or a listed poison History of the FDA History • 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… “…six human beings, all of them my “… patients, one of them my best friend, are dead because they took medicine that I prescribed for them…medicine which I had used for years…suddenly 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 Massengill Massacre Massengill Massengill Massacre Massengill • 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 Massengill Massacre Massengill • Company’s chief chemist and pharmacist, Harold Cole Watkins, found sulfanilamide dissolved in diethylene glycol • Also found flavor, appearance, and fragrance satisfactory • Not tested for toxicity Massengill Massacre Massengill • • • Diethylene glycol: antifreeze September: 633 shipments sent October 11: AMA received reports about several deaths • AMA laboratory isolated toxic ingredient Massengill Massacre Massengill • Issued warning through radio, newspapers • 107 people died, many children • Harold Watkins fired, later committed suicide Massengill Massacre Massengill • 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 1938: New Authority 1938: 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 1938: New Authority 1938: • Drugs studied in premarketing clinical trials exempted from review • If FDA failed to consider new drug application within 60 days, drug automatically approved 1962: Kefauver-Harris 1962: 1962: Kefauver-Harris 1962: • Drugs now required to be safe and effective • Manufacturers required to prove premarket effectiveness • No new funds allocated Approval Process Approval • 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) 1983: Orphan Drug Act 1983: • 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 1983: Orphan Drug Act 1983: • Prevalence of disease may be greater in other countries, leading to profit • Off-label use may lead to profit Thalidomide Story Thalidomide Thalidomide Story Thalidomide • Sedative-hypnotic made in Europe, used in pregnancy • FDA Pharmacologist Frances Oldham Kelsey didn’t like safety profile, delayed US approval • 1961: severe birth defects reported in Germany, others Thalidomide Story Thalidomide • Kelsey declared hero • FDA lionized • Recently approved as orphan drug for leprosy 1976: Medical Device Act 1976: • Dalkon shield IUD killed, maimed 200,000 women • FDA previously had no prior authority to either approve or force withdrawal from market Rough Times Rough • 1981: Reagan cut 1/10 of 7500 staff • Several FDA initiatives giving consumers more information were stopped cold Rough Times Rough 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 Rough Times Rough Rough Times Rough Approved dangerous products • 1979: approved Bjork-Shiley heart valve • Three manufacturer recalls for “fractured struts” • Estimated 500 deaths • 1986: Pfizer pulled from market Rough Times Rough 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 Rough Times Rough 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 Rough Times Rough Rough Times Rough 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 1984: Hatch-Waxman 1984: 1984: Hatch-Waxman 1984: • Drug Price Competition and Patent Term Restoration Act • Generics get approved based on submission of Abbreviated New Drug Approval (ANDA) • Don’t replicate original studies • 180 day exclusivity if first to file 1984: Hatch-Waxman 1984: • 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 1988: FDA Administration 1988: • 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 Where Does Where The FDA Fit? The Where Does FDA Fit? Where • Not cabinet level, like Agriculture Department (USDA) • Not independent agency, like Environmental Protective Agency (EPA) • No direct mandate from voters 2007 Budget 2007 USDA: $96,440,000,000 FDA: $1,947,282,000 What Does CDER Do? What • “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 Does CDER Test Drugs? Does • 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 CFR 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 Watchdog’s Bite Watchdog’s • 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 Watchdog’s Bite Watchdog’s • 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 Who’s in Charge Here? Who’s “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 Who’s in Charge Here? Who’s Center for Food Safety and Applied nutrition at FDA regulates safety of all food… …except poultry and meat, which come under USDA… …unless it’s game meat (venison, quail) which is the FDA Who’s in Charge Here? Who’s …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 it’s the FDA Who’s in Charge Here? Who’s 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 Who’s in Charge Here? Who’s 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 Who’s in Charge Here? Who’s • • Health claim on food box: FDA Health claim on TV ad: FCC • Drug advertising in magazine: combined FTC and FDA Who’s in Charge Here? Who’s • • Drugs: FDA Illegal drugs: DEA • Frozen cheese pizza: FDA • With pepperoni: USDA Working Working with Pharma with Patents 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 1995: Uruguay Act 1995: • 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 Patents 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. Patent Protection Patent • 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 Patent Protection Patent • 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 Patent Protection Patent • 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 Show Me Show the Money the PDUFA 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 PDUFA PDUFA • • Application fee: with NDA Product fee: paid annually for previously approved entities • Establishment fee: assessed annually on approved manufacturing facility PDUFA PDUFA 1993 Application fee Product fee Establishment fee To Sep Annual % 30, 2007 increase $100,000 $896,200 $6,000 17% $49,750 17% $313,100 13% PDUFA PDUFA • • • • • PDUFA III: FY 2007 fee revenue Application: $86,434,000 Product: $86,433,000 Establishment: $86,433,000 Before adjustments: $259,300,000 PDUFA 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 PDUFA PDUFA • Has it accomplished its goal of shorter times to approval? 33.6 35 28.2 30 25 20.4 18.6 20 16.1 15 10 5 0 19792002 19791986 P 1987- D 19931992 U 1997 F A 19982002 PDUFA 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) PDUFA PDUFA • Proportion of drugs reviewed ultimately approved increased from 60% at beginning of 1990s to 80% by end of decade PDUFA 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 PDUFA PDUFA Survey of FDA employees • “[w]e are told that approvability is our goal with ‘problems’ to be addressed in labeling.” • “[w]e are shifting the burden of proof of safety on ourselves…If we cannot show the drug is dangerous, it is assumed safe.” PDUFA PDUFA • There is still critical underfunding 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) What Can What Go Wrong? Go FDA Approval Errors FDA Drug is beneficial FDA allows Correct drug decision FDA does not allow drug Type 2 error: Type victims not identifiable identifiable Drug is harmful Type 1 error: Type victims identifiable identifiable Correct decision Type I Errors Type • 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 Type I Errors Type • 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 Rezulin 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” Rezulin Rezulin • Gueriguian’s review purged from FDA files, withheld from advisory committee • Liver toxicity not discussed at FDA’s December 1996 advisory committee meeting • Drug unanimously approved Rezulin 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 Relenza 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 FDA’s Antiviral Drugs Advisory Committee Relenza Relenza • Approved despite problems Sue the FDA? Sue 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 GovernmentApproved Drugs, Vaccines, and Medications, 173 A.L.R. FED 431(2001) FDA as a FDA Political Tool Political WSJ: 20 Apr 1999 WSJ: “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.” Mark McClellan, 2002-2004 Mark Brother of exBrother White House Press Secretary Scott McClellan Son of Texas comptroller Carole Keeton Strayhorn Mark McClellan, 2002-2004 Mark • • • • • Harvard MD MIT PhD Stanford professor in both Worked Treasury under Clinton Thought politically independent Mark McClellan, 2002-2004 Mark • FDA changed from tough independent regulatory body to partner in nurturing promotion of pharmaceutical industry • Spoke out against drug imports as “dangerous” Mark McClellan, 2002-2004 Mark • On cover of Medical Marketing and Media: “We won’t bite.” • Went on pharma speakers’ circuit • Spoke at marketing meetings which promised “how to push the promotional envelope” Mark McClellan, 2002-2004 Mark • Employees found advocating regulation at FDA was careerkilling move • Number of warning letters to advertisers plummeted Mark McClellan, 2002-2004 Mark • March 2004: took job as head of Medicare / Medicaid • Considered “promotion” • Immediately reversed his opinion on drug imports Andrew von Eschenbach Andrew • Sworn in 13 December 2006 as FDA head • Former Director of National Cancer Institute • Another Bush family friend FDA Mission Statement FDA …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, sciencebased information they need …to improve their health. As Moral Arbiter As • 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 As Moral Arbiter As • 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.” As Moral Arbiter As • 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 As Moral Arbiter As • 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 As Moral Arbiter As • 37 congress members sent letter to FDA condemning move as “clearly based on right-wing ideology rather than sound science.” • Eventually approved UCS Survey UCS • 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” UCS Survey UCS • 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 UCS Survey UCS • 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 UCS Survey UCS • 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 UCS Survey UCS • 81% agreed that the public would be better served if the independence and authority of FDA post-market safety systems were strengthened IOM On IOM Safety Safety Institute of Medicine Institute • • Nonprofit organization Created by Congress to advise federal government on health issues • Issued report on Drug Safety in September 2006 Institute of Medicine Institute “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.” Institute of Medicine Institute “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.” 2006: IOM Report 2006: 2006: IOM Report 2006: • FDA and pharmaceutical industry do not consistently demonstrate accountability and transparency to the public by communicating safety concerns in a timely and effective fashion 2006: IOM Report 2006: • Drug safety system impaired by serious resource constraints that weaken the quality and quantity of the science brought to bear on drug safety 2006: IOM Report 2006: • Organizational culture in Center for Drug Evaluation and Research is not optimally functional • Regulatory authority is unclear and insufficient, particularly with respect to enforcement Recommendation 3.1 Recommendation • 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 Recommendation 3.2 Recommendation Guidance from HHS to help: • Improve morale • Retain professional staff • Strengthen transparency • Restore credibility • Create a culture of safety Recommendation 3.5 Recommendation • 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 Recommendation 4.10 Recommendation • 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 committee’s deliberations Recommendation 4.11 Recommendation • 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 Recommendation 5.2 Recommendation • 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 Recommendation 5.3 Recommendation 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 Recommendation 5.4 Recommendation • 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 Recommendation 7.1 Recommendation • To support improvements in drug safety and efficacy activities…the Administration should request and Congress should approve substantially increased resources in both funds and personnel for the FDA. Some Other Some Ideas Ideas Some Other Ideas Some • 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 2006:355;6, 618-623 Some Other Ideas Some • 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 2006:355;6, 618-623 Some Other Ideas Some • 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 2006:355;6, 618-623 Some Other Ideas Some • 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 2006:355;6, 618-623 Some Other Ideas Some • Problem: surrogate endpoints don’t 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 2006:355;6, 618-623 Some Other Ideas Some • 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 Conclusions 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 ...
View Full Document

This note was uploaded on 01/11/2012 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

Ask a homework question - tutors are online