Managing chronic pain is one of health care’s most enduring problems. Certain patient populations—for example, those with severe rheumatoid arthritis—wake up every morning to levels of pain equivalent to those caused by the blunt force trauma of a serious automobile crash. Without pharmaceutical help, it is impossible for such patients in some cases even to rise from their beds.

Though opiates remain the mainstay short-term pain reliever, to avoid drug dependency among patients with long-term or lifetime conditions, physicians usually turn to NSAIDs. The severity and pathogenesis of NSAID gastrointestinal side effects were not fully understood until the discovery of prostaglandins in the late 20th century. By 1998, one study could conclude NSAID-related GI events produced a higher death rate than cervical cancer, asthma or malignant melanoma.1

So pharmaceutical manufacturers began experimenting with NSAID derivatives that would produce fewer GI side effects. Against this clinical backdrop, the Vioxx scandal ran its course.

It is impossible to understand the FDA’s current efforts to improve its public image, change its internal workings and mend its relationship with industry without acknowledging the profound impact on the agency and society as a whole caused by the Vioxx scandal and the era it embodied: Within days of Merck’s September 30, 2004 withdrawal of the NSAID amid charges of its doubling the incidence of serious cardiovascular events, a public outcry erupted, led by surgeons and lawmakers. “I am concerned whether FDA has been sufficiently aggressive in monitoring drug safety,” said one Congressman at the time. On the New England Journal of Medicine website, a prominent cardiovascular surgeon wrote: “The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action and not recognizing that they are accountable to the public health.”

Critics put the death toll at a minimum of 55,000. Congress investigated, as the lay press offered up portrayals of a Food and Drug Administration in cahoots with the industry it regulates. Within a year, Merck’s CEO had stepped down, soon followed by the FDA commissioner, who departed under a cloud of additional accusations, including deliberate delay of the “morning after” pill. In 2006, he pled guilty to criminal charges stemming from financial holdings in companies under FDA purview during his reign. His replacement managed to last until the end of George W. Bush’s presidency, but not before enduring calls for his own resignation following the agency’s allegedly botched response to safety problems with the antibiotic Ketek (telithromycin), the blood thinner heparin, the cholesterol drug Vytorin (ezetimibe and simvastatin), the diabetes drug Avandia (rosiglitazone), and the spinach Salmonella outbreak of 2008.

Faced with an ongoing series of controversies, the FDA, perhaps understandably, closed ranks. An increased focus on safety at the expense of innovation marked the period of 2007 to 2011, according to agency critics. Approval times lengthened, red tape proliferated, FDA scientists grew remote and uncommunicative. Turnarounds that once took 30 days now took six months or a year. Review deadlines passed by unmet and without explanation. Meanwhile, healthcare innovations increasingly debuted in Europe rather than the United States. To this day, drug and device manufacturers continue to express frustration and bewilderment.

Though the agency disputes these gripes in their particulars, in public statements its leaders tacitly acknowledge the need for fence-mending. Speaking at an NEHI conference last year, FDA Commissioner Margaret A. Hamburg, a 2009 appointee, conceded, “For the people here from the medical product side—those who develop new devices, diagnostics, and drugs—these have not been easy times,” then added this olive branch: “The FDA must not be a roadblock. Just the opposite: Our job is to enable innovation.” Other high-ranking agency officials have voiced similar comments.2

Recognizing the discord, Congress passed laws last year aimed at streamlining and modernizing the FDA. Unfortunately, recent mandatory federal budget cuts triggered by the sequestration will almost certainly jeopardize these efforts (See Less Money, More Problems, page 85), yet another stumbling block confronting this institution’s anything-but-surefooted entry into the 21st century.

Current Incarnation

Vioxx is far from the first public disaster to drive government policy. On the contrary, the FDA owes its very existence to a litany of pandemic health debacles. Three stand-outs include: In the 1930s, the 73 deaths linked to “Dr. Massengill’s Elixir Sulfanilimide” persuaded Congress to grant the agency its fundamental function of evaluating the safety of new drugs before they go on the market, which it had not previously possessed. Before the widespread harm caused by birth-control intrauterine devices inspired the federal Device Amendments of 1976, the agency had little control over medical devices. Finally, the FDA’s current incarnation owes a great deal to the emergence 25 years ago of the AIDS virus.

By the 1980s, a new drug application took an average of two and a half years to be acted upon, and some took as long as seven or eight. “Drug lag,” a catchphrase of the era, resulted in 70 percent of new therapies first gaining approval overseas, and 60 percent available elsewhere for more than a year before being approved in the United States.3

When the AIDS epidemic occurred, the wasting, swiftly moving, infectious disease put enormous pressure on the agency to speed up its drug-approval process.4 Lawmakers, industry and patient activists all came together to figure out a way to finance the streamlining of clinical trials. What they came up with was the Prescription Drug User Fee Act (PDUFA) of 1992. This law paid for additional FDA drug review staffers by charging pharmaceutical companies a fee for every new drug application. In exchange for this extra financial support, the FDA committed for the first time to adhere to review deadlines. In 1994, for example, PDUFA required the FDA to review and act upon 55 percent of new drug applications within 12 months. Designed to be evaluated and renewed every five years, PDUFA is now in its fifth iteration.

Despite sporadic criticism that industry’s funding of FDA constituted a conflict of interest, PDUFA has been considered a success. By all accounts, application times shrunk significantly in the 15 years following its passage. Encouraged by PDUFA, the medical device industry and Congress agreed to a similar law called the Medical Device User Fee and Modernization Act (MDUFMA) of 2002, which also established user fees and agency deadlines.

Matters proceeded harmoniously until the renewal of PDUFA IV and MDUFMA II in 2007, which, following Vioxx and other problems, granted the FDA broad new powers. For example, PDUFA IV imposed more stringent conflict-of-interest rules on physician advisory committees. But, since most physician experts in any given field often have ties to the field’s drug manufacturers, even assembling a committee now requires an excessive amount of time, industry argues. Additionally, something called Risk Evaluation and Mitigation Strategies (REMS), a PDUFA IV tool designed to codify manufacturers’ post-approval safety evaluations and thus shift burden and risk away from the pre-approval process, has been widely labeled a failure. According to one industry white paper, REMS have had the opposite of their intended effect: “Negotiating with the Agency on REMS requirements has stretched review times and lengthened FDA’s review processes.”5

Much as when in 1992 industry and the FDA came together to negotiate the terms of PDUFA, the two did so again last year to hash out PDUFA V, MDUFMA III, and a companion law called the FDA Safety and Innovation Act (FDASIA) of 2012.

Provisions of the new laws include:

• Accelerated review times. Experimental drugs aimed at treating serious or life-threatening diseases can gain “breakthrough therapy” status, and thereby earn the right to be judged by surrogate endpoints that could bring it to market faster. For the device industry, the FDA committed to the goal of issuing decisions on 91 percent of 510(k) submissions within 90 days.

• Enhanced communication and transparency. A plan for better relations between the FDA and biopharmaceutical companies calls for “additional review clock time for the agency to meet with applicants during the review as well as to address activities that occur late in the review cycle for these highly complex applications,” according to an FDA commitment letter.

• New risk calculator. To replace the agency’s traditional ad hoc decision making process, the FDA agreed to develop a codified framework for weighing risks against benefits during human drug and biologic reviews. The law calls for the framework to be consistent and systematic, and give greater consideration to the perspectives of patients who are to receive the drug. In February the FDA unveiled a draft document for its proposed risk calculating framework. Following industry input, a final draft is expected next year.

• Patient-focused drug development. The agency agreed to a program that would gather patient perspectives on the severity of their condition, their unmet medical needs and their willingness to bear the risk of potential side effects. The law calls for 20 nationwide, patient-focused meetings to occur over the next five years. The first meeting, held in April, canvassed the concerns of patients with chronic fatigue syndrome and myalgic encephalomyelitis. Other topics for meetings scheduled for this year include HIV, lung cancer and narcolepsy.

• Higher User Fees. With each PDUFA and MDUFMA renewal, user fees have risen, and this round proved no exception. Last year drug companies paid an estimated $1 billion in fees, and device companies paid about $90 million (if you count the Mammography Quality Standards Act), or about 25 percent of the agency’s total spending. Factoring in fees collected from tobacco companies, food manufactures, etc., user fees account for about 40 percent of FDA revenue.

Strained Relationship

In the run-up to the most recent federal legislation, the health-care manufacturing industry and its lobbyists unleashed an onslaught of position papers laying out their argument against the FDA. One of the most comprehensive and eloquent emerged from the California Healthcare Institute, a biomedical industry organization. A sample from its introduction by CHI President David Gollaher, PhD, encapsulates industry’s universal theme: “The Agency-industry partnership is strained by unexplained regulatory delays, by a lack of clear standards for what clinical data are necessary for product approval, and by a bureaucracy whose communications are neither consistent nor predictable.”5

Since 2007, agency performance has slipped, according to some calculations. Drug and biological review times have increased 28 percent, device 510(k) clearances have slowed by 43 percent and pre-market device reviews (i.e., for those not deemed substantially equivalent to existing products) are taking 75 percent longer. 5

Additionally, the United States now faces increased regulatory competition from overseas, particularly the European Union, whose 27 member states now form the world’s largest health-care market. For complex medical devices evaluated by the FDA’s pre-market approval process, the EU has consistently offered a faster route to market. But in recent years the delay has grown longer still, with products being approved in Europe nearly four years ahead of the United States, up from just over a year ahead in 2004 (See Figure 1).

Between 2007 and 2011, the number of drugs approved in the EU first has risen significantly, as well, pharmaceutical firms contend. “Recent years show some evidence of a new ‘drug lag’ with products approved on average two and half months earlier in the EU than in the United States.”5 (See Figure 2.) The resulting loss of business harms more than just U.S. employment and corporate profits. “There is no substitute for tinkering with an invention in the real world,” observes the CHI paper. “Over time, this process builds the chain of experience essential to technological innovation. Thus an American company’s decision to launch a novel device in Germany because the regulatory pathway there is faster and more predictable, results in German surgeons and technicians learning the fine points of applying the technology first. And, of course, it also means that German patients benefit from U.S. innovation before Americans do.”5

Although industry trade organizations signed off on the various provisions of the new laws last year, whatever positive effect they may have will take time to be realized. Large swaths of the legislation—the new risk calculator stipulation, for example—remain works-in-progress not yet implemented.

When not tight-lipped, the rank and file admit to limited expectations. “I don’t know whether things are changing,” says Eric Buckland, PhD, CEO of Bioptigen, manufacturer of specialized OCT scanners. “I know that Jeff Shuren [director of CDRH] has said he is turning over a new leaf. He has said publicly and privately that the FDA is going to be faster and more responsive. But what we don’t know is the impact of the budget sequester. Will they have the time to make these things happen? Will they have the staff?”

A Lightning Rod

While industry makesa compelling argument, it is by no means the only point of view. The FDA has long been “a lightning rod for strong criticism from across the political and ideological spectrum,” according to a JAMA editorial.6 Like a lenticular print, the agency’s appearance changes depending upon the angle from which it is viewed. To offer just one example, many blame the review deadlines imposed during the PDUFA era for higher rates of post-market safety problems.

A study published last year in the American Journal of Political Science examined a dataset of FDA drug approvals for decision timing and quality. It found that limiting review times induced “a piling of decisions before deadlines, and these ‘just-before deadline’ approvals are linked with higher rates of post-market safety problems (market withdraws, severe safety warnings, safety alerts).”7

On the device side, a 2011 report issued by the Institute of Medicine, an independent non-profit organization, concluded that the 510(k) process, used to evaluate devices that are substantially equivalent to those already functioning in the marketplace, should be scrapped and replaced. “Rather than continuing to modify the 35-year-old 510(k) process,” the paper states, “the FDA’s finite resources would be better invested in developing an integrated premarket and post-market regulatory framework that provides a reasonable assurance of safety and effectiveness throughout the device life cycle.”8

Industry itself has expressed frustration with the 510(k) process, saying it has become too burdensome and time-consuming. Some companies have suggested the United States follow the lead of the European Medicines Agency, the regulatory body of the EU market, which differentiates its moderate-risk devices into two tiers, higher risk and lower risk. Such a system might forestall the kind of incongruities often found in the United States, where relatively non-invasive products like OCT scanners are grouped in the same category as hip replacement joints.

Science or Theater?

FDA reviewers and advisory committees have always taken into consideration the views of patient populations and the severity of the conditions to which a drug or device is targeted. For instance, it can be widely agreed upon that pregnant women experiencing nausea and patients with a particularly deadly form of cancer will have wildly divergent tolerances for potential treatment risks, and regulators might act accordingly. What the agency has lacked until now is a systematic, ongoing program for gathering and assessing such patient perspectives, especially for conditions where conclusions might be less prima facie obvious.

Thus the model legislated by PDUFA’s Patient Focused Drug Development provision offers a fresh paradigm for public health and is receiving a great deal of attention from patient advocacy groups, industry and the agency itself. According to draft documents, it will serve as an important information source for whatever new risk calculation framework the FDA eventually develops: “FDA recognizes that patients have a unique and valuable perspective on these considerations [benefit-risk assessment] and believes that drug development and FDA’s review process could benefit from a more systematic and expansive approach to obtaining the patient perspective.”

But here too, when looked at from a different angle, questions emerge. Are patients really the best judges of what therapies they should receive, or even what risks they are willing to bear? The most fiercely dedicated patient advocates sometimes change their minds when serious side effects materialize. One AIDS advocate, looking back on PDUFA’s drug approval acceleration, lamented: “We have arrived in hell … AIDS activists and government regulators have worked together, with the best intentions, over the years to speed access to drugs. What we have done, however, is to unleash drugs with well-documented toxicities onto the market, without obtaining rigorous data on their clinical efficacy.”7

There is also the question of whether the Patient Focused Drug Development program in its current state represents the most scientific means of collecting data. “I find the outreach effort rather poorly thought through,” remarks Daniel Carpenter, PhD, a professor of government at Harvard University who has studied the FDA and other regulatory bodies. “It risks substituting theater for science. A more scientific approach would be to commission anthropologists, psychologists and sociologists to conduct surveys, experiments and ethnographies to get a better sense of patient risk and benefit perception. Instead, the FDA is inviting people to come to meetings, ensuring that the population will not be a representative one. The public meeting strategy will select for a population that is likely to tell the FDA a message that is different from that of the average patient. The power of placebo effects alone could tilt the subsample of participants toward those with a favorable benefit-risk profile for new treatments.”

An added concern is that the meetings invite the participation of drug companies, Dr. Carpenter adds. “This is a red flag. One might ask why treatment specialists, i.e., doctors, are not included,” he says. “If the FDA’s concern is that patients would be afraid to speak truthfully with doctors in the room, do they honestly believe that having drug company representatives in the room is not going to shape what patients tell them?”

Quantitative vs. Qualitative

Another new mandate closely watched by the health-care world will be the development of a benefit-risk template for agency decision-making. In the draft document outlining its proposed framework, the FDA acknowledged that in the two years of negotiations leading up to PDUFA V, industry made it clear it would have preferred a more quantitative model, such as the “semi-quantitative” framework developed by PhRMA’s Benefit-Risk Assessment Team, which has been used by the private sector for several years. However, such an approach, the FDA argued, would “require assigning numerical weights to benefit and risk considerations in a process involving numerous judgments that are at best debatable and at worst arbitrary.”

The FDA document continues: “The subjective judgments and assumptions that would inevitably be embodied in such a quantitative decision modeling would be much less transparent, if not obscured, to those who wish to understand a regulator’s thinking.”

Describing its own proposed framework as a more “qualitative descriptive approach,” the FDA did still acknowledge that many components of any scientific risk-benefit assessment would, by necessity, be quantitative.

The FDA’s proposal consists of a simple spreadsheet with five key decision factors running down the left side:

1. Analysis of Condition—describes the severity of the disease.
2. Current Treatment Options—describes what treatments exist.
3. Benefit—results of the clinical trial and the implications of the primary and secondary endpoints.
4. Risk—the adequacy of the safety database, clinical pharmacology, etc.
5. Risk Management—what can be done to mitigate safety concerns.

These five decision factors are judged by two subjective criteria, listed along the top row of the chart:

1. Evidence and Uncertainties—unknowns and how they could affect risk and benefits.
2. Conclusions and Reasons—describes the implications of the facts, as the reviewers see them.

Finally, in the bottom row of the framework, the reviewers include their Benefit-Risk Summary Assessment, a succinct, well-reasoned summary that clearly explains the rationale for whatever regulatory action is taken.

In May, PhRMA issued a written response to this model. Among its main concerns appears to be the question of how much input and access the reviewed drug’s sponsor would have to the chart during its assembly: “While PhRMA understands that one of the primary uses of the framework will be to facilitate internal decision-making within the agency, PhRMA encourages the FDA to consider what information sponsors can provide to support FDA’s assessment of benefit-risk, either in marketing applications, during review, or in post-marketing safety reports.” The letter then adds: “PhRMA would like to understand if sponsors will have the opportunity to review the FDA’s benefit-risk framework for their products before the assessment is posted.”

Vioxx Revisited

At their core, the FDA’s responsibilities entail weighing potential risks against potential benefits of new drugs and devices. A look at the past quarter century reveals the essential dilemma confronting the agency to be a Janus-faced one, perhaps insolubly so: If the FDA focuses on protecting against risk and review times slow down, it finds itself criticized for jeopardizing the public’s health. If it errs of the side of benefits and review times accelerate, it finds itself accused of the very same thing.

Its mission would be difficult enough if it only required predicting the future. But the agency cannot even benefit from an agreed-upon, retrospective assessment of its past. As a case in point, a second look at the Vioxx recall proves instructive. Does Vioxx really deserve to be called, in the words of one Congressional testimony, the “single greatest drug safety catastrophe in the history of this country or the history of the world”?

For starters, studies published after public attention moved on raise significant questions about the 55,000-deaths estimate. Although Vioxx and other COX-2 inhibitors (like Bextra, which was pulled from the market in 2005) present some increased risk of cardiovascular events, it has been found to be no higher than that posed by other NSAIDs.9 Furthermore, the one factor distinguishing COX-2 inhibitors from other NSAIDs, their GI protective qualities, has been greatly missed by practitioners. Rates of GI events serious enough to require hospitalization rose 21 percent among NSAID users in the years following the recalls, according to a study presented at the 2007 annual meeting of the American College of Rheumatology.10 Many physicians question whether the cardiovascular health gains achieved by removing Vioxx and Bextra from the market have now been outweighed by a surge in serious gastrointestinal events.

While Merck certainly tried to minimize the drug’s negative side effects, it did nothing more untoward than any other drug firm does when marketing a product, according to Ted Frank, an attorney and adjunct fellow at the Manhattan Institute’s Center for Legal Policy, who followed and wrote weblog posts about the Vioxx litigation, which eventually resulted in a $4.85 billion settlement in 2007. “There were Merck executives who were taking Vioxx,” he notes. “Merck’s corporate officers were not hovering over this drug cackling and tensing their fingers. This is a drug they thought worked and they thought was safe.”It also bears mention that, despite extensive investigation, criminal charges were never filed against Merck or any of its employees.

None of this is meant as an apologia for Merck, nor any corporate malfeasance it may have committed, nor the FDA’s role in any wrongdoing, but merely to illustrate that if the Vioxx imbroglio itself, the locus of so much angst and turmoil in health care and society at large, cannot be clearly characterized, even at a decade’s remove, we can better appreciate the difficulties that lie ahead for the FDA.

In the final analysis, the questions presented by FDA’s reform efforts are the same ones that arise whenever health care and limited public resources overlap: How much funding should the safeguarding of public health receive? How much say should patients have in the treatments they undergo? At what point do the needs of the many supersede the needs of the few, and vice versa?

Every society must answer such questions for itself, sometimes more than once a generation. If the FDA’s current reformation throws light on their resolution or brings more transparency and visual acuity to the terms of their public debate, then at least a portion of its genuine but uncertain promise might be fulfilled.  REVIEW


Mr. Celia is a freelance health-care writer based in the Philadelphia area.



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2. Shuren J. Cover letter to proposed reforms: A Letter from the Center Director. FDA CDRH. Jan. 19, 2011. (Dr. Shuren referred to the 510(k) approval process for medical devices as “unpredictable, inconsistent, and opaque.”)
3. U.S. Food and Drug Administration. Third Annual Performance Report: Prescription Drug User Fee Act of 1992.
4. FDA Pressed to Approve More AIDS Drugs, by Warren E. Leary. New York Times, Oct. 11, 1988.
5. Competitiveness and Regulation: The FDA and the Future of America’s Biomedical Industry. Published by the California Healthcare Institute (CHI), February 2011. Available at advanmed.org.
6. Steinbrook R, Sharfstein J. The FDA Safety and Innovation Act. JAMA, Oct. 10, 2012; 308(14):1437-1438.
7. Carpenter D, et al. The complications of controlling agency time discretion: FDA review deadlines and postmarket drug safety. American Journal of Political Science;56(1):98-114.
8. Institute of Medicine. Medical devices and public’s health: The FDA 510(k) Clearance process at 35 years. Washington DC: National Academies Press;2011. Available at www.iom.edu.
9. Warner TD, Mitchell JA. COX-2 selectively alone does not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugs. Lancet; Jan. 2008;371:270-273.
10. Vioxx Ban Tied to Rise in Serious GI Trouble, by E.J. Mundell. HeathDay magazine, Nov. 8, 2007. Available at: http://consumer.healthday.com/bone-and-joint-information-4/arthritis-drug-news-39/vioxx-ban-tied-to-rise-in-serious-gi-trouble-609867.html. Accessed Sept. 5, 2013.