The Other Drug War

Richard Epstein*

Richard Epstein

Richard Epstein

Earlier this month, the Food and Drug Administration rejected the application of Biomarin Pharmaceutical to market its drug KyndrisaTM (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 beenestimated 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.

*Considered one of the most influential thinkers in legal academia, Richard Epstein is known for his research and writings on a broad range of constitutional, economic, historical, and philosophical subjects.

FDA Suspension of Ponatinib: Serious Problem, Wrong Solution

Richard Epstein

Bad News On December 14, 2012, the US Food and Drug Administration granted an accelerated approval to the drug Ponatinib, which is used to treat patients with serious and life threatening forms of leukemia.  Unfortunately, the risks associated with the use of the drug have proved to be far greater than anticipated.  Thus on October 31, 2013, the FDA switched course and asked the manufacturer of ponatinib, Ariad Pharmaceuticals of Cambridge Massachusetts, to suspend marketing and sales of the drug pending the FDA’s further evaluation of the potential costs and benefits of ponatinib’s use.  The FDA wants to conduct that study so that it can better determine which patients are the ideal targets for the drug, and which patients are most likely to succumb to its grave negative side effects, “the risk of life-threatening blood clots and severe narrowing of blood vessels.”

Accordingly, the ever-prudent FDA immediately recommends the adoption of a three part program.  First, no new patients should begin treatment with the drug. Second, those who are using the drug who are not responding to it should immediately cease use. And third, those patients who are responding favorably to the drug should be allowed to continue its use if their health care professionals believe that the potential benefits from the drug use justifies their filing for a “a single-patient Investigational New Drug (IND) application or expanded access registry program while FDA’s safety investigation continues.”  Not surprisingly a recent New York Times Editorial takes the view that the FDA has set up the right process for dealing with this problem by allowing physicians and other health care professionals to go through a “streamlined” process to continue drug use where they think that the anticipated benefits exceed the anticipated costs.

Whose Cost Benefit Analysis?  Both the FDA and the Times have done the wrong cost benefit analysis.  For starters, all the information about the adverse effects of ponatinib are in the public domain, available to all professionals who prescribe the drug.  If the FDA had done nothing other than republish the conclusion of the recent studies, we can be confident that the serious risks associated with its use would quickly work themselves through the system.  The amount of the drug prescribed for established and new patients would drop, given the increased revelation of the risk.  Higher cost means lower use.

The question therefore is what approach will accomplish two ends.  The first of these is to decide which patients should continue or initiate a course of treatment with ponatinib.  The second is what is the quickest way to target those subpopulations that are most likely to get a positive experience from use of the drug.  The correct answer to both questions is to leave the drug on the market.  The first point here is that any limited IND program takes time and costs money.  There will therefore be some cases in which doctors will be reluctant to go through the proceedings, at which point their best clinical judgment will be derailed by an unneeded administrative process. That is a serious risk because in all cases where the variance in response is critical, the downstream information about individual patients is likely to be far more reliable that the generalized upstream information that is all that is available to regulators.  There is no reason to displace an efficient decentralized sorting mechanism with an ineffective centralized sorting mechanism that is necessarily one step further removed from the patient.

Next, if we know that some patients have had positive experiences with a potentially deadly drug, there is every reason to believe that at least some new patients would be suitable candidates for use. The FDA, by preempting the process, blocks individual physicians from making those determinations.  The doctors in question need not rely only on their own prescribing experience, but can marshal data collected from all sorts of public sources to increase the confidence of their judgment.  The likelihood here is that there are higher levels of social utility with informed downstream judgment than with the FDA request for a blanket cessation.  Once again the structural mistake of the FDA is to assume that only its devices for drug safety matter in the world.  In fact cooperative actions by physicians and hospitals and HMO groups all contribute data that is of value in running the process, which is one reason why off-label use is so high with cancer drugs.

The benefits from allowing the drug to stay on the market are not only valuable in the short run, but also in the long run as well. Any effort to isolate good from bad cases will depend at least in part on a close examination of the patients who have used the drugs to figure out the markers that correspond to successful and unsuccessful treatment.  In general, the larger the population sample, and the longer the individual use, the more valuable this pool of information in helping with the assessment.  It should not be assumed therefore that the FDA or manufacturer studies will be as good without that new information as it is with it.  The point here is especially true with ponatinib, which is used to treat rare a rare form of leukemia, so that thus far only 2000 people have tried the drug in question.  Those numbers are already too small to get reliable information. There is no reason to shrink them further by government fiat.

Conclusion:  FDA Go Slow In making all these judgments, I of course have no knowledge of whether the additional work will salvage the market position of ponatinib as a viable drug.  The prospects do not look rosy.  But there is no reason to make the suspension of the drug the quid pro quo for the accelerated approval.  The basic truth remains is that the FDA treads on dangerous ground whenever it uses its gatekeeper power of new entry.  I think that so long as drugs are prescription only, those barriers should be torn down.  But if they are kept up, it does very little good to enforce the back end of the approval bargain if it makes all present and future sufferers of this leukemia worse off than they would otherwise be.  Collective ignorance is not a good reason for collective government action.  It is a good reason for the administrative state to hold its hand.

Government Overreach Threatens Lives

Richard Epstein 

Throughout its long history, the Federal Food and Drug Administration has insisted that its mission is “protecting and promoting your health.” Take that your seriously. In area after area, the record suggests that the paternalist FDA fails you in its announced purpose. Far from protecting “your health,” the FDA prevents you from making the informed decisions to preserve and promote your own health. All too often, the FDA lacks both the judgment and technical expertise to decide which treatments ordinary people may choose to undergo and which they must turn aside.

To take one example, the FDA’s critics have bemoaned its ignorance on such cutting-edge technologies as mobile health apps. Uncertain of its own footing, the FDA’s habitual regulatory caution drives away private investment from venture capital firms that know that millions of dollars in equity can disappear the instant the FDA issues a single adverse notice, which in practice can never be reversed by anyone else.

The FDA misfires at the outset by insisting that on matters of human health the correct approach is “better safe than sorry.” Like all rules of thumb, this one is at best a crude proxy for choosing your optimal risk bearing strategy. All too often, errors from delay can dwarf those from the hasty deployment of chancy technologies. Without any detailed knowledge of your relevant situation, the FDA has no idea whether you face a greater risk from going too fast or too slow.

Yet the FDA boldly exercises its premarket approval power early on in the risk cycle, when it typically acts in total ignorance of the individual elements of your cost-benefit decision. If it lets a risky product on the market, you need not deploy it if its risks are too high in your case. But if the FDA keeps a drug or device off the market, no matter how well informed or advised, you no longer have it within your power to make any downstream correction of the FDA’s initial error.

Stem-cell treatment.

In light of all these difficulties, it is absolutely critical that the FDA should not be allowed to extend its power over new drugs and devices to regulate the practice of medicine, where it is singularly ill-equipped to intervene. Unfortunately, the FDA has sought with some success to insert itself into the regulation of medical practice in the highly promising area of stem-cell technology.

In the 2012 watershed decision Regenerative Sciences LLC v. United States, Judge Rosemary Collyer sustained the FDA’s asserted control of this entire area. Now that her decision is on appeal, I have attacked her opinion at length in my essay for the Manhattan Institute, “The FDA’s Misguided Regulation of Stem-Cell Procedures: How Administrative Overreach Blocks Medical Innovation.”

It is widely recognized that stem-cell therapies hold the key to the next generation of medical advances in connection with such devastating conditions such as leukemia and Parkinson’s diseases. It is also common ground in the medical profession that so-called “allogenic” treatments, whereby stem-cells from one person are ultimately transferred into the body of another, run the risk of immunological rejection by the recipient. The preferred road to medical advance lies therefore through “autologous” transfers that remove your own cells, which are then manipulated under laboratory conditions to grow new tissue forms that can then be reinjected into your body to restore its lost function.

Regenerative Sciences uses its “Cultured Regenexx Procedure” for treating patients suffering from certain musculoskeletal damage, including those arising from athletic injuries, like those suffered by professional athletes, who have every incentive to select the right treatment. Like all stem-cell treatments, the Regenerative Science protocol required the standard autologous treatment that requires your cells to be grown and concentrated before being reinjected into the body at the site of damaged joints.

Regenerative Sciences’ track record of successes led large numbers of patients to beat a path to its door. But that same success also attracted FDA attention in 2008 when Mary A. Malarkey, director of the Office of Compliance and Biologics Quality at the Center for Biologics Evaluation and Research at the FDA, delivered a a letter to the firm, which shut its activities down:

Please be advised that in order to introduce or deliver for introduction a drug that is also a biological product into interstate commerce, a valid biologics license must be in effect. Such licenses are issued only after a showing of safety and efficacy for the product’s intended use. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application in effect as specified by FDA regulations.

A small medical practice like Regenerative Science cannot hope to recover through its medical practice the huge-front end costs that often prove too much to bear from large well-capitalized pharmaceutical companies. But rather than fold its tent, Regenerative Sciences challenged the FDA in court in ways that put the agency’s powers and wisdom in the spotlight. Let us take these matters up in order.

The FDA’s Power

Ms. Malarkey’s letter bases the FDA’s power on the fact that the new technology affects “interstate commerce.” As a matter of plain English, her approach is surely wrong-headed because every stage of Regenerative Sciences treatment took place within the state of Colorado.

Judge Collyer’s answer to that interpretive issue lies in the modern jurisprudence of Article I the Commerce Clause—“Congress shall have the power to regulate commerce with foreign nations, among the several states and with the Indian tribes.” That Clause received an indefensibly broad reading in the key New Deal decision Wickard v. Filburn, where the Supreme Court allowed Congress to regulate purely local activities within a given state that, when aggregated, influenced the total level of national economic activity—which is surely the case with respect to stem-cell research.

Yet by running first to the Constitution, Judge Collyer never addressed the key statutory provisions, which tell a different tale. Under the Federal Food Drug and Cosmetic Act, “The term ‘interstate commerce’ means (1) commerce between any State or Territory and any place outside therefore, and (2) commerce within the District of Columbia or within any other Territory not organized with a legislative body.” Similarly, the Public Health Service Act authorizes the FDA to make rules and regulations “to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession.”

These key definitions of commerce and communicable diseases were not chosen at random. Historically, they reflect the pre-New Deal vision that the FDA’s jurisdiction only reaches those drugs that actually move in interstate commerce, where they present a risk of communicable diseases. The statutory language consciously reflects the 1903 Supreme Court decision in Champion v. Ames, where the Supreme Court by a five-to-four vote found that Congress had—under the Commerce Clause—the power to prohibit the movement of lottery tickets in interstate commerce.

The decision was notable for two reasons. First, it was consistent with the then well-established rule that Congress could not regulate the manufacture of lottery tickets or indeed anything else. Second, it was a limited power insofar as it left it unclear whether Congress could prohibit the sale of any good in interstate commerce, a position that was widely rejected prior to the Civil War.

Champion exerted a powerful influence over the shape of the 1906 Pure Food and Drug Act, which gave Congress the power to regulate the manufacture of drugs within the territories while denying it the power to regulate the manufacture of drugs within the states. At the same time, it seized on Champion to allow Congress to prohibit, if need be, the shipment of drugs in interstate commerce.

Those limitations were carried forward into the 1938 Food Drug and Cosmetic Act, where they functioned just as they did in the earlier statute. It takes therefore an extraordinary level of judicial imagination to take a statute intended to prevent the shipment of some dangerous substances in interstate commerce and use it to regulate the growth of new substances that pose no threat of a communicable disease within the state.

Under the statute, however, it is not enough that some product used in the course of this stem cell procedure had moved in interstate commerce, even if it did pose any threat of a communicable disease. To be sure, these products could, if improperly prepared, result in the spread of some communicable disease.

But so too could standard surgeries which present that risk whenever physicians fail to wash their hands during a routine procedure—a topic that has been vividly illustrated in Atul Gawande’s 2007 New Yorker masterpiece The Check List. But that point proves too much: by its logic, it would allow the FDA to regulate the entire practice of medicine so long as the doctors used products brought in from out of state—which doctors always do.

In its 1997 report on Proposed Approach to Regulation of Cellular and Tissue-Based Products, the FDA sought, at least for the moment, to limit the potential scope of its power by insisting that it only sought to exert control over “the cells or tissues [that] are…more-than-minimally, manipulated,” which covers all autologous stem cell procedures. But that “more than minimally” language bears no relationship to any portion of the relevant statutory text. Nor does the use of that phrase explain why this stem-cell procedure is not a text-book instance of the practice of medicine.

Bad Policy

In addition to being bad law, the FDA decision represents bad policy. The stem-cell practice may well pose some patient dangers, but that is far more true of other forms of surgery that have life-threatening implications. Yet the FDA has not regulated other forms of surgery that have shown staggering advances at every level without its intervention. It is today bad enough that the FDA regulates medical devices, but it would be a serious setback to medical innovation if each stem-cell procedure had to go through the FDA gauntlet.

Surgery is half science and half art. The procedures that are used at any time will be modified countless times within very short periods. Right now, it is only a combination of hunch, experience, and collaboration that indicate which new techniques are applied and which older ones are rejected. And this is how it should be. The business would come to a screeching halt if the FDA took it upon itself to insist that each and every one of these changes could only be done with its imprimatur.

And it is all so unnecessary. At the time Ms. Malarkey wrote her letter, Regenerative Sciences had already built up a track record of performance that the FDA could have investigated before dropping its regulatory bomb on the company. But information like that is irrelevant to the FDA, which only thinks in terms of its powers, without bothering to ask whether there is actually a problem to fix.

A far better approach is for the FDA to stay its hand in all cases until there is some evidence of mishap that calls for its intervention. It is the same story all over again. The FDA is keenly cognizant of its own powers, but largely oblivious to its own institutional weaknesses. In dealing with drugs and medical devices it may take a revitalized Congress to rein it in. But the courts are well within their power in striking down the FDA’s unwise venture into the regulation of medical practice in stem cell cases.