Drug Approvals and Deadly Delays

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Truth can be stranger than fiction, and bureaucracy can be stranger than metaphor.

In 1984 a man named John Nestor became notorious in Washington DC for his unusual driving habits on the Beltway.  Mr. Nestor had the unique habit of getting into the leftmost lane with his cruise control set at 55 mph, the posted speed limit.  He would drive at this speed regardless of what came up behind him.  Cars would zoom up close to his rear bumper; drivers would flash their lights and blast their horns, some swerving around him on the right while giving him the finger—none of this fazed Mr. Nestor in the least.  As he explained it, 55 mph was the law, and he had a right to drive in whichever lane he chose: “Why should I inconvenience myself for someone who wants to speed?”

John Nestor’s story stirred a huge amount of public reaction, some supportive, most of it as outraged as the drivers who encountered him on the road.  The term “nestoring” was coined to mean adhering to the precise details of the rules.  To me, John Nestor was a good metaphor for the U.S. Food and Drug Administration and its painstakingly slow approval process for drugs and devices.

But then it turned out that John Nestor wasn’t just a metaphor for FDA; he actually worked there.  In fact, in 1972 he had been transferred out of FDA’s cardio-renal-pulmonary unit because that division “had approved no new chemical entities … from 1968 to 1972, an experience that contrasted with the experience of every other medical modern nation and with the experience of other divisions of the FDA.”

But while John Nestor’s inactivity at FDA made him a villain to some, it made him a hero to others.  Ralph Nader’s Health Research Group argued that Nestor “had an unassailable record of protecting the public from harmful drugs” and helped Nestor eventually overturn his transfer.   When Nestor passed away in 1999, his Washington Post obituary fittingly read: “FDA Official Renowned for Strict Driving Habits.”

FDA is one of the most powerful federal agencies, regulating products that account for approximately one out of every four consumer dollars.  No new medical drug or device can be marketed until the agency has passed on its safety and effectiveness.

FDA’s approval process took its current form in the wake of the thalidomide tragedy.  In 1957, thalidomide was introduced in Germany as a sedative with remarkably few side effects.  It quickly became available in over 40 countries, and was especially popular among pregnant women for controlling morning sickness.  Its U.S. licensee filed for FDA approval here in 1960.  The application was handled by a Dr. Frances Kelsey, who withheld approval while she investigated possible peripheral nerve damage from the drug.  But during the course of her investigation, the drug became linked to severe fetal deformities, a discovery which soon resulted in its worldwide withdrawal.  Dr. Kelsey was hailed as a hero for preventing thalidomide’s widespread use in the U.S. and received the Presidential Gold Medal for Distinguished Service.  In September, 2010, she became the first recipient of a new FDA award named in her honor.

In retrospect, it’s unclear whether it was investigative skill or luck that led Dr. Kelsey to hold up the thalidomide application.  For one thing, she was investigating peripheral neuritis, not fetal deformities; her subsequent claim that the two were related is dubious.  Moreover, other countries with regulatory approval regimes, such as Sweden and Canada, had approved the drug.

The thalidomide episode spurred the congressional transformation of FDA into the agency it is today.  Before then, FDA’s basic responsibility was to certify the safety of new drugs prior to marketing.  But the 1962 Kefauver amendments added drug efficacy to FDA’s responsibilities, even though, ironically, the problem with thalidomide involved safety, not efficacy. 

But whether the issue is safety or efficacy, the thalidomide episode illustrated a basic precept—when it comes to approving new drugs, waiting may well be the best course of action.  As one commentary noted, the honors bestowed on Dr. Kelsey demonstrated to many others at FDA that “there is no credit to be gained for lives saved due to speed regulatory action …”

The power of that precept stems from the fact that, as a government agency, FDA is a political entity, subject to intense pressure from Congress and the media.  That precept, moreover, is strengthened by the huge difference between the two alternatives that face FDA when it comes to approving new therapies.  

If FDA approves a drug that later turns out to be disastrous, then people will clearly suffer.  On the other hand, if FDA delays or denies a truly needed drug, people will also suffer.  Medically, these two types of mistakes are both harmful.

But from a political standpoint, there is a huge difference between them.  Those injured by an incorrectly approved drug will often know that they are victims of FDA mistakes.  Their stories make riveting news, and their testimony, or that of their surviving families, is dynamite.  But for victims of incorrect FDA delays or denials, who are prevented from using drugs that could have helped them, the situation is far different.  All they know is that their doctors told them that nothing more could be done to help them.  Only a fraction of these people will understand the reason for this—namely, that a useful drug was bottled up at FDA.

And so, unlike in the first scenario, these people do not realize that they too are victims of FDA mistakes.  Their suffering or death is simply viewed, by them and by others, as reflecting the state of medicine rather than the status of an FDA drug application.

In short, victims of incorrect FDA approvals are highly visible, while victims of incorrect FDA delays or denials are practically invisible.

For example, consider FDA’s incredibly long delay in approving beta-blockers to reduce the risk of second heart attacks.  By the mid-1970s this had been documented in clinical trials and a number of beta-blockers were approved for this use in Europe.  But in the U.S., FDA imposed a moratorium on beta-blocker approvals due to their possible carcinogenicity in animals.  (Among the staffers involved in this delay was that fastidious driver, John Nestor. )  In effect, FDA was denying needed cardiac drugs to people at high risk of heart attacks because of the unproven possibility that those drugs might cause cancer years in the future. 

Finally, in 1981 FDA approved the first such drug, boasting that it might save up to 17,000 lives per year.  That meant, of course, that as many as 100,000 people may have died waiting for FDA to act —an explosive point, but one that very few journalists pursued.  For all practical purposes, these people were invisible in a very literal sense– we’ve all seen photos of thalidomide victims, but I suspect that not one of us has ever seen a photo of someone who suffered or died due to FDA’s beta-blocker moratorium.

Similarly, in the early 1990s it took FDA over three years to approve interleukin-2 as the first therapy for advanced kidney cancer.  By the time FDA acted, the drug was available in nine European countries.  In clinical trials, the drug had produced remissions of six months or longer in 15-20% of patients.  Then why did FDA delay so long?  Because the drug was relatively toxic and resulted in the deaths of approximately five percent of those who took it.  It was this latter issue that occupied FDA’s attention, obscuring the fact that metastatic kidney cancer has the even worse side effect of killing 100% of its victims.  If we roughly estimate that the drug might have helped 10% of those who otherwise die of kidney cancer, then FDA’s delay might have contributed to the deaths of over 3,000 people.   Have we seen any photos of them?

These episodes clearly illustrate the political and journalistic differences between the opposing goals of avoiding both incorrect approvals and incorrect delays and denials.  Medically, both types of agency action are harmful, but politically there is no comparison between them.  One has impact, the other doesn’t.  In the words of FDA Commissioner Alexander M. Schmidt,

“In all of FDA’s history, I am unable to find a single instance where a Congressional committee investigated the failure of FDA to approve a new drug.  But, the times when hearings have been held to criticize our approval of nf new drugs have been so frequent that we aren’t able to count them …. The message to FDA staff could not be clearer.”

He went on to note that

“Congressional pressure for our negative action on new drug applications is, therefore, intense.  And it seems to be increasing, as everyone is become as self-acclaimed expert on carcinogenesis and drug testing.”

Dr. Schmidt made that statement in 1974.  Fifteen years ago it seemed that the tide had turned, as FDA’s handling of drug and device applications improved somewhat with staff increases and with a growing recognition of the need to streamline approvals, reflected in the 1997 FDA Modernization Act.  But in recent years that trend has been reversed.  FDA has come under increasing assault by outside groups, from the press, and from the Democrat-controlled Congress.  Those same groups have enabled dissenters within FDA to gain more clout as well, resulting in

“a culture … at FDA … in which agency employees who dislike a regulatory decision are able to keep raising the issue and, if they don’t like the results, to go outside established agency procedures …to enlist support from members of Congress and their enabling lapdogs in the media.”

In the view of these critics, every unanticipated side effect from a new drug demonstrates that FDA has become too cozy with industry and too sloppy in reviewing new applications.  As Dr. Sidney M. Wolfe, longtime head of the Health Research Group, puts it, FDA is controlled by “spineless and gutless” officials infected with a “please the industry” attitude and interested only in getting drug applications out the door.   Dr. Wolfe is highly dubious about most new pharmaceuticals; most of the drugs recommended in his book, Worst Pills, Best Pills , are older drugs. 

If Dr. Wolfe were practicing medicine, he would be free to apply these views in treating his patients; advocating them as national policy, however, is an entirely different matter.  This is the same distinction that exists between FDA approvals and FDA denials.  When the agency approves a drug, no one is forced to use it; when it disapproves a drug, no one is able to use it.  These are not two sides of the same coin; to the contrary, there is a huge ethical difference between them. 

What critics such as Dr. Wolfe are demanding is pharmaceutical omniscience in advance of widespread use.  But testing new drugs on hundreds or thousands of people will only rarely reveal all the side effects that might occur when those drugs are subsequently used by millions of people.  The only way to guarantee zero unexpected side effects is to have zero new drugs, period.  That, however, would result in a public health disaster dwarfing all side effects combined.

In response to these critics, FDA itself has imposed new regulatory burdens, ranging from Risk Evaluation and Management Strategies (REMS), which severely restrict the use of certain drugs after they are approved, to a severe tightening of its medical device approval procedures, to high-profile reconsiderations of certain previous approvals.  And in one sign of the times, last year Dr. Wolfe joined FDA’s Drug Safety and Risk Management Committee.

Most physicians’ views of FDA are significantly different from those of Dr. Wolfe.  Over the last 15 years, the Competitive Enterprise Institute has conducted six surveys of physicians on their views of FDA.  In each survey, an overwhelming majority of respondents viewed FDA as being too slow in approving new drugs and devices. 

Each survey involved a different medical specialty, ranging from oncologists to cardiologists to emergency room physicians and, most recently, orthopedic surgeons.  On the basic question of FDA approval speed, those viewing FDA as too slow ranged from 61% to 77%.  In our most recent survey, of orthopedic surgeons in 2007, 76% took this view, and 78% believed that FDA has hurt their ability to give patients the best possible care.   (Eighty percent, by the way, would like to Vioxx available again.)

But when it comes to influencing FDA, the views of practicing physicians carry far less weight than those of “public interest” advocates and politicians.  Given the skewed incentives to which it is subject, is there any hope of FDA reform? 

The short answer is yes.  For one thing, with the rise of the internet information about new pharmaceutical developments is becoming far more widespread; the same is true about information concerning where such new drugs can be obtained.  When it comes to important but unapproved therapies, it may be much harder in the future for people to be kept complacently in the dark.

One simple but seemingly radical approach would be to leave the agency’s safety and effectiveness standards in place, while simply removing its veto power.  In effect, FDA would become a certifying agency.  Rather than being banned outright, as they are now, uncertified therapies would be available under medical supervision, with informed consent documentation of their uncertified status.

For those doctors and patients who trust FDA, nothing would change; they would simply continue to use FDA-approved therapies.  But patients who, in consultation with their doctors, have to go beyond such therapies would now have new options.

As for FDA itself, it would no longer be the only game in town.  Instead of enjoying its monopoly status, it would now come under competitive pressure to issue timely and credible evaluations, knowing that failure to do so would make it irrelevant to many physicians.

And while this approach may sound radical, it isn’t.  Most of the physicians in each of our surveys indicated that they would favor it.  As for where they would go for information about such unapproved therapies, their answers were to be expected: medical journals, approval status in other medically advanced countries, and the views of their colleagues.

But if doctors have this view of FDA, why don’t their patients?

Whenever FDA announces its approval of a major new drug or device, there is a basic question that needs to be asked:  If this drug will start saving lives tomorrow, then how many people died yesterday waiting for the agency to act?  As our surveys indicate, many doctors already have this question on their minds.  Getting the word out to patients, and to the public at large, may well be the key to truly reforming FDA.

John Nestor:  Strife in the Fast Lane, Washington Post, Nov. 21, 1984.

Ross W.S., The Life/Death Ratio 1977, 195.

Kazman S., Saying Yes to Drugs, J. Regulation and Social Costs, 2: June 1992, 33, 34.

John Kelly’s Washington, Washington Post, Oct. 24, 2008, http://www.washingtonpost.com/wp-dyn/content/discussion/2008/10/21/DI2008102100590.html, accessed Nov. 8, 2010.

Ross, supra at 38-39.

Urquhart J. and Heilmann K., Risk Watch—The Odds of Life 1984, 118.

The analysis which follows is based on Grabowski H.G. and Vernon J.M., The Regulation of Pharmaceuticals 1983, 9-13.

Ross W.S., supra at 195.

Urquhart and Heilmann, supra at 118.

Kazman S., supra at 39.

As quoted in Grabowski and Vernon, supra at 5.

Commentary–End the War, BioCentury, Mar. 8, 2010: 1.

PBS Frontline, Interview with Sidney Wolfe, Nov. 13, 2003,         http://www.pbs.org/wgbh/pages/frontline/shows/prescription/interviews/wolfe.html, accessed Nov. 8, 2010.

Pocket, 2005.

Sidney Wolfe:  Outsider Becomes FDA Insider, WSJ Health Blog, Jan. 9, 2009
http://blogs.wsj.com/health/2009/01/09/sidney-wolfe-outsider-becomes-fda-insider/, accessed Nov. 8, 2010.

Competitive Enterprise Institute, A National Survey of Orthopedic Surgeons Regarding FDA and the Availability of New Therapies, 2007, http://cei.org/studies-issue-analysis/national-survey-orthopedic-surgeons-regarding-food-and-drug-administration-an, accessed Nov. 8, 2010.  (This document summarizes the previous CEI survey results as well.)

Krauss M., Loosening the FDA’s Drug Certification Monopoly—Implications for Tort, George Mason Law Rev. 1996: 458-483.

CEI Survey, supra, at 17.