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Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice

Reporter: Aviva Lev-Ari, PhD, RN


FDA 501(k) Approval Process

Posted by DCNGA » Wed Nov 03, 2010 4:24 pm

Medical Devices: Gaps, Tensions, and Conflicts in the FDA Approval Process: Medical Devices

Author: Richard A. Deyo, MD, MPH, Departments of Medicine and Health Services and the Center for Cost and Outcomes Research, University of Washington, Seattle

The FDA’s approach to approving medical devices differs substantially from the approach to drugs, being in some ways both more complex and less stringent.[13] The FDA’s authority over devices dates only to 1976. Device legislation was a response, in part, to public outcry over some well-publicized device failures. The most prominent was the Dalkon Shield—an intrauterine contraceptive device associated with serious infections.[14] In contrast, the FDA’s authority over drugs dates to 1938, although it existed in weaker form starting in 1906.[15]

With few exceptions, given the timing of the FDA’s authority, devices introduced before 1976 were never required to undergo rigorous evaluation of safety and efficacy. With the huge volume of “things” that suddenly fell under its purview, the FDA had to prioritize its resources and efforts.

One way of prioritizing was to focus first on safety. Evaluation of effectiveness, in many cases, was reduced to engineering performance: does the device hold up under its intended uses, does it deliver an electric current as advertised? The potential benefits for relieving pain, improving function, or ameliorating disease did not generally have to be demonstrated.

Another way of prioritizing was to assign categories of risk associated with the devices. Rubber gloves seemed less risky than cardiac pacemakers, for example. So the agency assigned devices to 1 of 3 levels of scrutiny. Class I devices have low risk; oversight, performed mainly by industry itself, is to maintain high manufacturing quality standards, assure proper labeling, and prevent adulteration. Latex gloves are an example.

At the other extreme, class III devices are the highest risk. These include many implantable devices, things that are life-supporting, and diagnostic and treatment devices that pose substantial risk. Artificial heart valves and electrical catheters for ablating arrhythmogenic foci in the heart are examples. This class also includes any new technology that the FDA does not recognize or understand. New components or materials, for example, may suggest to FDA that it should perform a more formal evaluation. In general, these devices require a “premarket approval,” including data on performance in people (not just animals), extensive safety information, and extensive data on effectiveness. This evaluation comes closest to that required of drugs. In fact, Dr. Kessler says, these applications “look a lot like a drug applications: big stacks of paper. They almost always require clinical data—almost always. And they often require randomized trials. Not always, but often” (L. Kessler, personal communication). These devices are often expensive and sometimes controversial because of their costs.

Class II devices are perhaps the most interesting. They comprise an intermediate group, generally requiring only performance standards. Examples would be biopsy forceps, surgical lasers, and some hip prostheses. The performance standards focus on the engineering characteristics of the device: does it deliver an electrical stimulus if it claims to, and is it in a safe range? Is it made of noncorrosive materials? Most of these devices get approved by the “510(k)” mechanism. The 510(k) approval requires demonstrating “substantial equivalence” to a device marketed before 1976. “And,” says Kessler, “the products that have been pushed through 510(k) are astonishing” (L. Kessler, personal communication).

Kessler points out, “For the first 5 to 10 years after 1976, this approach made sense. But in 2001, 25 years after the Medical Device Amendment, does it make sense? There was a lot of stuff on the market that wasn’t necessarily great in 1975—why would you put it back on the market now?” (L. Kessler, personal communication). The new device need not prove superiority to the older product—just functional equivalence. If a company wants to tout a new device as a breakthrough, why would it claim substantial equivalence to something 25 years old?

The reason is that the 510(k) process is easier and cheaper than seeking a premarket approval. The 510(k) process usually does not require clinical research. In the mid-1990s, a 510(k) application on average required 3 months for approval, and about $13 million. A premarket approval required, on average, about a year and $36 million. Both are modest compared with new drug approvals. The process by which the agency decides if something is “equivalent enough” to be approved by the 501(k) mechanism is subjective.

Because pre-1976 devices were not subject to any rigorous tests of clinical effectiveness, a newly approved device may be equivalent to something that has little or no therapeutic value. Doctors, patients, and payers therefore often have little ability to judge the value of new devices. As an example, the FDA still receives 510(k) applications for intermittent positive pressure breathing machines.[12] Yet a thorough review by the federal Agency for Health Care Policy and Research found that these devices offer no important benefits.[16]

How much do manufacturers take advantage of the easier 510(k) approach? Since 1976, nearly 98% of new devices entering the market in class II or III have been approved through the 510(k) process.[13] In 2002, the FDA reported 41 premarket approvals and 3708 approvals through the 510(k) process.[17]

“It is a good thing to learn caution from the misfortunes of others.”

“If you wish to succeed in life, make perseverance your bosom friend, experience your wise counselor, caution your elder brother, and hope your guardian genius.”

Dr. Richard A. Deyo, has published an article on this topic in 2004. His observations and references are most valuable for our Blog.

For fulll article go to:

JABFP March–April 2004 Vol.17 No.2 http://www.science.smith.edu/departments/Biochem/Chm_357/Articles/Drug%20Approval.pdf



Author:  Richard A. Deyo, MD, MPH

Despite many successes, drug approval at the Food and Drug Administration (FDA) is subject to gaps, internal tensions, and conflicts of interest. Recalls of drugs and devices and studies demonstrating advantages of older drugs over newer ones highlight the importance of these limitations. The FDA does not compare competing drugs and rarely requires tests of clinical efficacy for new devices. It does not review advertisements before use, assess cost-effectiveness, or regulate surgery (except for devices). Many believe postmarketing surveillance of drugs and devices is inadequate. A source of tension within the agency is pressure for speedy approvals. This may have resulted in “burn-out” among medical officers and has prompted criticism that safety is ignored. Others argue, however, that the agency is unnecessarily slow and bureaucratic. Recent reports identify conflicts of interest (stock ownership, consulting fees, research grants) among some members of the FDA’s advisory committees. FDA review serves a critical function, but physicians should be aware that new drugs may not be as effective as old ones; that new drugs are likely to have undiscovered side effects at the time of marketing; that direct-to-consumer ads are sometimes misleading; that new devices generally have less rigorous evidence of efficacy than new drugs; and that value for money is not considered in approval. J Am Board Fam Pract 2004;17: 142–9.

The process of drug development and approval by the United States Food and Drug Administration (FDA) was recently reviewed by Lipsky and Sharp.1 Using clinical literature and web sites addressing FDA procedures, that review concisely described the FDA’s history, the official approval process, and recent developments in drug approval. However, it did not delve into common misconceptions about the FDA, tensions within the agency, or conflicts of interest in the drug approval process. The rapidly growing business of medical device development, distinct from the drug approval process, also was not addressed. Although most aspects of the FDA review process are highly successful, its limitations deserve careful consideration, because they may have important implications for choosing treatments in practice.

Recent recalls of drugs and devices call attention to limitations of the approval process.2–4 Recent news about complications of hormone replacement therapy5,6 and new data supporting the superiority of diuretic therapy over newer, more expensive alternatives for hypertension7 emphasize gaps in the process. Clinicians should be aware of regulatory limitations as they prescribe treatments and counsel patients, so they have realistic ideas about what FDA approval does and does not mean.

Because controversies relating to internal conflicts or political issues are infrequently reported in scientific journals, this discussion draws not only on scientific articles, but also internet resources, news accounts, and interviews.The goal was not to be exhaustive, but to provide examples of tensions, conflicts, and gaps in the FDA process. As Lipsky and Sharp noted, the FDA approves new drugs and devices (as well as assuring that foods and cosmetics are safe).It monitors over $1 trillion worth of products, which represents nearly a fourth of consumer spending.1 In the medical arena, the basic goal of the FDA is to prevent the marketing of treatments that are ineffective or harmful.

However, the agency faces limitations that result from many factors, including the agency’s legal mandate, pressures from industry, pressures from advocacy groups, funding constraints, and varied political pressures.

Pressures for Approval

Perhaps the biggest challenge and source of friction for the FDA is the speed of approvals for drugs and devices. Protecting the public from ineffective or harmful products would dictate a deliberate, cautious, thorough process. On the other hand, getting valuable new technology to the public—to save lives or improve quality of life—would argue for a speedy process. Some consumer protection groups claim the agency is far too hasty and lenient, bending to drug and device company pressure. On the other hand, manufacturers argue that the agency drags its feet and kills people waiting for new cures. Says Kessler: “That’s been the biggest fight between the industry, the Congress, and the FDA over the past decade: getting products out fast” (L. Kessler, personal communication).

To speed up the review process, Congress passed a law in 1992 that allowed the FDA to collect “user fees” from drug companies. This was in part a response to AIDS advocates, who demanded quick approval of experimental drugs that might offer even a ray of hope.These fees, over $300,000 for each new drug application, now account for about half the FDA’s budget for drug evaluation, and 12% of the agency’s overall $1.3 billion budget.18 The extra funds have indeed accelerated the approval process.By 1999, average approval time had dropped by about 20 months, to an average of a year.In 1988, only 4% of new drugs introduced worldwide were approved first by the FDA.By 1998, FDA was first in approving two thirds of new drugs introduced worldwide.The percentage of applications ultimately approved had also increased substantially.18 Nonetheless, industry complained that approval times slipped to about 14 months in 2001.19

In 2002, device makers announced an agreement with the FDA for similar user fees to expedite approval of new devices, and Congressional approval followed with the Medical Device User Fee and Modernization Act.20 Critics, such as 2 former editors of the New England Journal of Medicine, argue that the user fees create an obvious conflict of interest. So much of the FDA budget now comes from the industry it regulates that the agency must be careful not to alienate its corporate “sponsors.”21

FDA officials believe they remain careful but concede that user fees have imposed pressures that make review more difficult, according to The Wall Street Journal .22 An internal FDA report in 2002 indicated that a third of FDA employees felt uncomfortable expressing “contrary scientific opinions” to the conclusions reached in drug trials.Another third felt that negative actions against applications were “stigmatized.”

The report also said some drug reviewers stated “that decisions should be based more on science and less on corporate wishes.”22  The Los Angeles Times reported that agency drug reviewers felt if drugs were not approved, drug companies would complain to Congress, which might retaliate by failing to renew the users’ fees 18 (although they were just re-approved in summer, 2002).This in turn would hamstring FDA operations and probably cost jobs.

Another criticism is that the approval process has allowed many dangerous drugs to reach the market. A recent analysis showed that of all new drugs approved from 1975 to 1999, almost 3% were subsequently withdrawn for safety reasons, and 8% acquired “black box warnings” of potentially serious side effects. Projections based on the pace of these events suggested that 1 in 5 approved drugs would eventually receive a black box warning or be withdrawn. The authors of the analysis, from Harvard Medical School and Public Citizen Health Research Group, suggested that the FDA should raise the bar for new drug approval when safe and effective treatments are already available or when the drug is for a non–life-threatening condition.2

According to The Los Angeles Times, 7 drugs withdrawn between 1993 and 2000 had been approved while the FDA disregarded “danger signs or blunt warnings from its own specialists. Then, after receiving reports of significant harm to patients, the agency was slow to seek withdrawals.” These drugs were suspected in 1002 deaths reported to FDA. None were life-saving drugs.They included, for example, one for heartburn (cisapride), a diet pill (dexfenfluramine), and a painkiller (bromfenac). The Times reported that the 7 drugs had US sales of $5 billion before they were recalled.18

After analysis, FDA officials concluded that the accelerated drug approval process is unrelated to the drug withdrawals. They pointed out that the number of drugs on the market has risen dramatically, the number of applications has increased, and the population is using more medications.3  More withdrawals are not surprising, in their view. Dr. Janet Woodcock, director of the FDA’s drug review center and one of the analysts, argued that “All drugs have risks; most of them have serious risks.”

She believes the withdrawn drugs were valuable and that their removal from the market was a loss, even if the removal was necessary, according to The Los Angeles Times.18 Nonetheless, many believe the pressures for approval are so strong that they contribute to employee burnout at FDA.In August 2002, The Wall Street Journal reported that 15% of the agency’s medical officer jobs were unfilled.22 Their attrition rate is higher than for medical officers at the National Institutes of Health or the Centers for Disease Control and Prevention. The Journal reported that the reasons, among others, included pressure to increase the pace of drug approvals and an atmosphere that discourages negative actions on drug applications.

Attrition caused by employee “burnout” is now judged to threaten the speed of the approval process. In 2000, even Dr. Woodcock acknowledged a “sweatshop environment that’s causing high staffing turnover.”18 FDA medical and statistical staff have echoed the need for speed and described insufficient time to master details.18,19  An opposing view of FDA function is articulated in an editorial from The Wall Street Journal, by Robert Goldberg of the Manhattan Institute. He wrote that the agency “protects people from the drugs that can save their lives” and needs to shift its role to “speedily put into the market place… new miracle drugs and technologies…. ” He argues that increasing approval times for new treatments are a result of “careless scientific reasoning” and “bureaucratic incompetence,” and that the FDA should monitor the impact of new treatments after marketing rather than wait for “needless clinical trials” that delay approvals.23

Thus, the FDA faces a constant “damned if it does, damned if it doesn’t” environment. No one has undertaken a comprehensive study of the speed of drug or device approval to determine the appropriate metrics for this process, much less the optimal speed. It remains unclear how best to balance the benefits of making new products rapidly available with the risks of unanticipated complications and recalls.

Postmarketing Surveillance of New Products

Although user fees have facilitated pre-approval evaluation of new drugs, the money cannot be used to evaluate the safety of drugs after they are marketed. Experts point out that approximately half of approved drugs have serious side effects not known before approval, and only post-marketing surveillance can detect them. But in the opinion of some, FDA lacks the mandate, the money, and the staff to provide effective and efficient surveillance of over 5000 drugs already in the marketplace. 24 Although reporting of adverse effects by manufacturers is mandatory, late or non reporting of cases by drug companies are major problems. Some companies have been prosecuted for failure to report, and the

FDA has issued several warning letters as a result of late reporting. Spontaneous reporting by practitioners is estimated to capture only 1% to 13% of serious adverse events. 25  Widespread promotion of new drugs—before some of the serious effects are known—increases exposure of patients to the unknown risks. It is estimated that nearly 20 million patients (almost 10% of the US population) were exposed to the 5 drugs that were recalled in 1997 and 1998 alone.26 The new law allowing user fees for device manufacturers does not have the same restriction on post-marketing surveillance that has hampered drug surveillance.

Conflicts of Interest in the Approval Process

Another problem that has recently come to light in the FDA approval process is conflict of interest on the part of some members of the agency’s 18 drug advisory committees. These committees include about 300 members, and are influential in recommending whether drugs should be approved, whether they should remain on the market, how drug studies should be designed, and what warning labels should say. The decisions of these committees have enormous financial implications for drug makers.

A report by USA Today indicated that roughly half the experts on these panels had a direct financial interest in the drug or topic they were asked to evaluate. The conflicts of interest included stock ownership, consulting fees, and research grants from the companies whose products they were evaluating. In some cases, committee members had helped to develop the drugs they were evaluating. Although federal law tries to restrict the use of experts with conflicts of interest, USA Today reported that FDA had waived the rule more than 800 times between 1998 and 2000.

FDA does not reveal the magnitude of any financial interest or the drug companies involved.27 Nonetheless, USA Today reported that in considering 159 Advisory Committee meetings from 1998 through the first half of 2000, at least one member had a financial conflict of interest 92% of the time. Half or more of the members had conflicts at more than half the meetings. At 102 meetings that dealt specifically with drug approval, 33% of committee members had conflicts.27 The Los Angeles Times reported that such conflicts were present at committee reviews of some recently withdrawn drugs.18

The FDA official responsible for waiving the conflict-of-interest rules pointed out that the same experts who consult with industry are often the best for consulting with the FDA, because of their knowledge of certain drugs and diseases. But according to a summary of the USA Today survey reported in the electronic American Health Line, “even consumer and patient representatives on the committees often receive drug company money.”28  In 2001, Congressional staff from the House Government Reform Committee began examining the FDA advisory committees, to determine whether conflicts of interest were affecting the approval process.29


Despite derogatory comments from some politicians and some in the industries it regulates, the FDA does a credible job of trying to protect the public and to quickly review new drugs and devices. However, pressures for speed, conflicts of interest in decision-making, constrained legislative mandates, inadequate budgets, and often limited surveillance after products enter the market mean that scientific considerations are only part of the regulatory equation. These limitations can lead to misleading advertising of new drugs; promotion of less effective over more effective treatments; delays in identifying treatment risks; and perhaps unnecessary exposure of patients to treatments whose risks outweigh their benefits.

Regulatory approval provides many critical functions. However, it does not in itself help clinicians to identify the best treatment strategies. Physicians should be aware that new drugs may not be as effective as old ones; that new drugs are likely to have undiscovered side effects at the time they are marketed; that direct-to-consumer ads are sometimes misleading; that new devices generally have less rigorous evidence of efficacy than new drugs; and that value for money is not considered in the approval process. If clinicians are to practice evidence-based and cost-effective medicine, they must use additional skills and resources to evaluate new treatments. Depending exclusively on the regulatory process may lead to suboptimal care.


1.Lipsky MS, Sharp LK. From idea to market: the drug approval process.J Am Board Fam Pract 2001; 14:362–7.

2.Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH.Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;287:2215–20.

3.Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ.The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA 1999;281:1728 –34.

4.Maisel WH, Sweeney MO, Stevenson WG, Ellison KE, Epstein LM.Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator devices. JAMA 2001;286:793–9.

5.Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33.

6.Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 68 years of hormone therapy: Heart and Estrogen/progestin Replacement Study Follow-up (HERS II). JAMA 2002;288:49–57.

7.ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97.

8.Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo.The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8.

9.Moore TJ. Deadly medicine: why tens of thousands of heart patients died in America’s worst drug disaster. New York: Simon and Schuster; 1995.

10.Petersen M. Diuretics’ value drowned out by trumpeting of newer drugs. The New York Times 2002 Dec 18;Sect A:32.

11.Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003;289: 2947–57.

12.Gahart MT, Duhamel LM, Dievler A, Price R. Examining the FDA’s oversight of direct-to-consumer advertising. Health Aff (Millwood) 2003 Suppl W3– 120–3.

13.Ramsey SD, Luce BR, Deyo R, Franklin G. The 148 JABFP March–April 2004 Vol.17 No.2  limited state of technology assessment for medical devices: facing the issues. Am J Manag Care 1998;4 Spec No:SP188–99.

14.Merrill RA. Modernizing the FDA: an incremental revolution. Health Aff (Millwood) 1999;18:96–111.

15.Milestones in US food and drug law history. United States Food and Drug Administration. http://www. fda.gov/opacom/backgrounders/miles.html, accessed 8/19/02.

16.Handelsman H. Intermittent positive pressure breathing (IPPB) therapy. Health Technol Assess Rep 1991;(1):1 9.

17.FDA Center for Devices and Radiological Health. Office of Device Evaluation annual report 2002. Available at: URL:http://www.fda.gov/cdrh/annual/ fy2002/ode/index.html.

18.Willman D. How a new policy led to seven deadly drugs. The Los Angeles Times 2000 Dec 20;Sect. A:1.

19.Adams C, Hensley S. Health and Technology: drug makers want FDA to move quicker. Wall Street Journal 2002 Jan 29; Sect.B:12.

20.Adams C. FDA may start assessing fees on makers of medical devices. The Wall Street Journal 2002 May 21;Sect.D:6.

21. Angell M, Relman AS.Prescription for profit. The Washington Post 2001 Jun 20; Sect.A:27.

22.Adams C. FDA searches for an elixir for agency’s attrition rate. The Wall Street Journal 2002 Aug 19;Sect.A:4.

23. Goldberg R.FDA needs a dose of reform.The Wall Street Journal 2002 Sep 30;Sect.A:16.Available at: URL: http://www.aei.brookings.org/policy/page. php?id113

24.Moore TJ, Psaty BM, Furberg CD. Time to act on drug safety. JAMA 1998;279:1571–3.

25.Ahmad SR. Adverse drug event monitoring at the Food and Drug Administration: your report can make a difference. J Gen Intern Med 2003;18:57–60.

26.Wood AJJ. The safety of new medicines: the importance of asking the right questions. JAMA 1999;281:


27. Cauchon D.FDA advisers tied to industry.USA Today 2000 Sep 25; Sect.A:1.

28.Cauchon, D. Number of drug experts available is limited. Many waivers granted for those who have conflicts of interest. USA Today 2000 Sep 25;Sect. A:10.

29.Gribbin A. House investigates panels involved with drug safety. Mismanagement claims spur action. The Washington Times 2001 Jun 18;Sect.A:1.




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