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Earlier this month, the Food and Drug Administration rejected the application of Biomarin Pharmaceutical to market its drug Kyndrisa™ (drisapersen) for use in the treatment of Duchenne muscular dystrophy. The FDA, as is often the case when it rejects a drug application, listed all sorts of technical reasons why the data presented was not sufficient to establish by respectable scientific means that the drug in question was safe and effective in its intended use. Without question, much evidence from the clinical trials revealed serious complications from the drug’s use, including blood-platelet shortages that were potentially fatal, kidney damage, and severe injection-site reactions. But the no-treatment alternative could prove far worse.
Duchenne is a rare but fatal genetic disorder that attacks only young boys, roughly 1 in 3,500 to 5,000. Typically, it first manifests itself between two and five years of age. With time, it relentlessly weakens the skeletal muscles that control movement in the arms, legs, and trunk. Most of its victims are wheelchair-bound between the ages of seven and 13. By 20, many have died.
The source of the problem is the absence from the cell of the key chemical dystrophin, which is needed to control muscular movement. The proposed treatment is known as “exon-skipping,” which allows the body to produce the needed quantities of dystrophin. At present no drugs are on the market to fix the genetic defect. But other drugs are also under investigation. If the door is closed for drisapersen, it remains ajar for an unnamed drug produced by Sarepta Therapeutics, which will be reviewed by the FDA shortly. But, based on early rumblings from the FDA, it is likely that this drug too will be kept from the marketplace.
As might be expected, the decision by the FDA has left parent groups and their physicians tied up in knots. You can get a sense of their frustration by looking at the desperate petition of a mother whose son has the disease. Tonya Carlone wrote a public letter to the FDA pleading for the drug to be allowed on the market: “This medication has allowed my son, Gavin, to be able to ride a 2 wheel bike, to play on a soccer team, to run and play with his healthy 10 year old peers. Dr. Craig McDonald of UC Davis Medical Center and a Duchenne expert of over 30 years, has stated that he has never seen a boy with Duchenne at the age of 10 have as much function as Gavin.”
All irrelevant, says the FDA. But it’s critical to understand why parents like Ms. Carlone and physicians like Dr. McDonald are right and why the FDA is dead wrong. The FDA thinks the problem lies in the merits of a particular drug when it really lies in its deeply flawed approval process. That process got started in the early 1960s after Thalidomide was taken off the market for causing serious birth defects and deaths among children.
In its rush to judgment after the incident, Congress passed the 1962 Kefauver Harris Amendments, which initiated the modern system of drug review that featured two major reforms. The first changed an FDA rule that was on the books since 1938 that allowed drugs to reach the market if the FDA did not ask to review them within 60 days after they were ready for market. The second required the FDA to review these new drug applications prior to approval not only for safety, but also for effectiveness. Now for a drug to reach market it must be supported by “substantial evidence” which is “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved.” As the Supreme Court observed in 1973, the FDA’s “strict and demanding standards, barring anecdotal evidence indicating that doctors ‘believe’ in the efficacy of a drug, are amply justified by the legislative history.”
The FDA still treats the 1962 law as a triumphant moment that “revolutionized drug development” because its scientific safeguards ensure “that consumers will not be the victims of unsafe and ineffective medications.” And therein lies the problem. The FDA celebrates the supposed advantages of Kefauver-Harris, but it ignores the major monkey wrench that it has introduced into drug development. Its proclamation looks at only the benefits of the drug-approval process, but wholly ignores its attendant costs by tacitly assuming that the only drugs that the FDA keeps off the market are unsafe and ineffective.
Regrettably, in this, as in all other regulatory endeavors, there are two kinds of error. The FDA is keen to note the bad drugs that are kept off the market. But it downplays the good drugs caught inside its web that are kept off the market. In some cases, there are deadly delays in getting good drugs onto the market. As the period for drug review becomes longer, the cost of getting a drug onto the market rises. Taking into account both the time value of money and out-of-pocket expenditures, that cost has been estimated to be $2.6 billion. That figure, of course, does not include the social losses from drugs that never get through to clinical trials because of the heavy obstacles that the FDA places in the path of their development—nor does it include the number of lives lost or compromised as a result of the FDA’s regulatory hurdles.
To make matters worse, the clinical trial format, which often works well for mainline drugs, like those used to control cholesterol and high-blood pressure, is less effective for drugs aimed to treat certain rare diseases, where too many potential drugs are chasing too few patients. Thus in the Sarepta study, both the treatment and the placebo group each enrolled only 12 patients, which enabled the FDA to challenge the comparability of the two groups, and for both parties to dispute individual patient responses. It doesn’t help that the FDA insists that individual patient and doctor reports do not count as scientific evidence because of their anecdotal nature.
Here too, the FDA errs. Individual variation in drug response is a common feature, and individual patients like Gavin Carlone are well advised to continue using the drug, no matter what the FDA’s overall evaluation of the drug’s features. The two forms of information should always be used in tandem. To be sure, the risk of adverse side effects can never be ignored, but neither can the deadly effects of Duchenne, for which there is no recourse. The FDA’s major blunder in this area is to rely exclusively on the statistical significance of various treatment options, ignoring all evidence from other sources.
Doing so became a true disaster. Under the 1962 law, drug after drug was removed from the market after years of successful use because the FDA decided that well-controlled clinical trials, for all their cost and limitation, were better than the long-term success of various drugs in the marketplace. It is for good reason that children, parents, and physicians are asking a different question from that which the FDA puts to itself: are they better off with the drug than without it? And when there is no alternative remedy, the answer is that they are better off with it.
At this point, the first question has nothing to do with abstract standards of scientific evidence. It has to do with the simple issue of who gets to decide what type of evidence, systematic or anecdotal, is most valid. American law today wrongly vests that power in the FDA on the ground that its expertise is needed on matters of public health. But Duchenne and similar genetic diseases are not communicable, as most public health concerns are. They are individual, not interconnected, tragedies.
It is simply mindboggling that the FDA should extol its naked paternalism in keeping patients from becoming “victims of unsafe and ineffective drugs,” when it is cutting them off from their only chance of salvation. The usual judicial conceit is that FDA regulation just deals with economic matters, as if a child’s fight against a deadly disease is to be treated in the same fashion as a minimum wage or maximum hour law. Both types of regulation are unwise—but, that said, no one should ignore their differential impact, as rich and poor alike are throttled by the FDA.
Fortunately, there are two developments that can help reduce the FDA’s deadly grip on pharmaceutical progress. The first is that it cannot prevent off-label uses of permitted drugs. Under current law, once a drug is approved for any purpose, physicians can prescribe it for any other purpose they please. The FDA is not allowed to regulate the practice of medicine, and thus physicians can put these drugs to use without approval.
Needless to say, by every estimate, off-label uses are common, especially in cancer cases. These uses are not unstructured, as there are many voluntary institutions, such as the National Comprehensive Cancer Network, that collate the clinical experiences that the FDA ignores and make recommendations on which drugs should be used in what sequence and in what combinations to treat various kinds of conditions. The off-label uses commonly set the standard for medical malpractice for physicians in ways that bypass the FDA approval process altogether.
Yet the inability to get that first approval forces desperate people to beg the FDA and drug companies for a compassionate license for experimental use, which often comes too late, even for cancer drugs like Erbitux, which later makes it on the market. Indeed, this off-label process was especially important for thalidomide, for once it was allowed on the market under the brand-name Thalomid to treat leprosy, its effectiveness as a miracle drug for cancer became apparent from its off-label use. Dr. Frances Kelsey of the FDA, who discovered the drug’s harmful side effects on children, should have issued stern warnings on its use in pregnancy. But, in retrospect, the FDA was wrong to ban the drug from the market.
The second major development deals with the ability of drug companies to present truthful information about off-label uses to physicians and patients. The FDA has long vigorously asserted that it is a criminal offense for a drug company to make any statements or distribute any information that tends to promote the use of an approved drug for an off-label use. Its view was that these statements made false representations that the drug had been approved for that purpose. The FDA could not prevent the identical statements from being made in medical journals or by individual physicians, but its ban on truthful company promotion obviously slowed down the adoption of off-label uses. Two recent cases have broken the FDA’s stranglehold on information on off-label uses: one in 2012, dealing with drug promotion by individual sales representatives, and a second in 2015, dealing with a company’s publication of the full record of its futile negotiations with the FDA to get formal approval for a new permitted use for a drug already on the market.
The FDA’s richly deserved defeat on this front is consistent with the general libertarian view that government agencies have ample power to prevent fraud and misbranding, but none to prevent speech that is neither false nor misleading. The current First Amendment law thus breaks down the FDA’s monopoly over information. But it does nothing to break down the FDA’s monopoly over the licensing of new drugs, which are all too often kept in limbo with endless haggling over clinical trials. That situation has to change now.
Congress should strip the FDA of its power to keep individuals from receiving drugs for experimental purposes before they receive FDA approval. If not, the courts should do it on constitutional grounds, holding that the current legal regime is an intolerable interference of personal autonomy. No one would ever let the FDA use its now formidable police powers to force people to take medicines that it thinks appropriate. That same logic should not prevent informed patients, with the aid of their own physicians, from taking medicines that they think offer the best opportunity for their restored health and survival.