Abigail Alliance and the Future of Drug Regulation in America

On Thursday, March 1, the D.C. Circuit will rehear en banc, the case of Abigail Alliance v. Eschenbach.   If the panel decision is upheld (and further S. Ct review is not sought or is denied), this case has the potential to radically reconfigure the way FDA regulates drugs (and as Eugene Volokh has argued in a forthcoming publication, might represent a significant change in constitutional law more generally).  The case has drawn a lot of attention from all quarters, including an article in the New Yorker and in JAMA (subscription required).  I think it is fair to say it is the most significant food and drug law decision in the past 10 years

[Disclosure: I was one of the lawyers who drafted the government's rehearing petition in this case while at the Justice Department; Disclaimer: Any views expressed herein are my own, and do not represent those of FDA, the Justice Department, or any entity of the federal government].

In the rest of this post, I'll describe the litigation and its implications.

For those who have not read the (now-vacated pending rehearing) original panel opinion, here is a summary of it (drawn from a longer summary I did for the American Society for Bioethics and Humanities, available at page 5 of this publication)): 

The D.C. Circuit (Judge Rogers authoring, joined by Chief Judge Ginsburg. over a dissent by Judge Griffith) announced that the the due process clause of the federal constitution provides a fundamental right that prevents the Food and Drug Administration (FDA) from blocking competent, terminally ill patients from having access to potentially lifesaving drugs that have cleared Phase 1 clinical testing but have gone no further in the drug approval process, when usage is based on the advice of doctors.

The Federal Food, Drug, and Cosmetic Act (FDCA), prohibits the distribution and marketing of new drugs before a new drug application has been submitted and the FDA has determined that the drug is both safe and effective for each intended use. The statute and accompanying regulations require drug manufacturers to undergo a three-phase testing process. Phase 1 involves a small initial study, usually with less than 100 subjects, and focuses on toxicity. Phase 2 involves a well-controlled, closely monitored evaluation of thedrug in a larger (but still small) group of patients, usually no more than several hundred, and focuses on effectiveness. Phase 3 involves the evaluation of the drug in a large clinical trial ortrials, usually with several hundred to several thousand subjects, and focuses on dosage. Although safety issues are most obvious at Phase 1, according to FDA (backed up by data on safety-related non-approval of drugs that have cleared Phase 1), safety is at issue in all the testing phases (although this is a point of dispute between the litigants and panel majority and dissent.

Abigail Alliance for Better Access to Developmental Drugs (“Alliance”), a nonprofit association representing several terminally ill patients who would like to have access to Phase 1 drugs, sued to enjoin FDA from enforcing its ban on on unapproved drugs insofar as it prohibits terminally ill patients with no other treatment options from purchasing investigational drugs.  The Alliance claims a fundamental right under the due process clause to obtain access to potentially beneficial investigational new drugs that have completed Phase 1 trials.

The D.C. Circuit panel majority held that the due process clause creates a fundamental “right of a mentally competent, terminally ill adult patient to access potentially life-saving post–PhaseI investigational new drugs, upon a doctor’s advice, even where that medication carries risks for the patient.” The majority found this right to be “deeply rooted in this Nation’s history and tradition," as reflected in various common law doctrines (the defense of necessity, the freedom from battery, the tort of intentional interference with a rescue).

The Court also found the right to be “implicit in the concept of ordered liberty” such that it satisfied the the two-part substantive due process analysis described inWashington v. Glucksberg, 521 U.S. 702 (1997) (the assisted suicide decision). The majority also relied on what it perceived to be an absence of federal regulation for drug effectiveness until 1962 and drew an analogy between the right it recognized and the Supreme Court’s decision in Cruzan v. Director, Missouri Department of Health, 497 U.S. 261 (1990), that suggested a right to refuse life-sustaining medical treatment. The panel remanded the case for the district court to determine whether the FDA’s restrictions on the treatment use of investigational drugs are “narrowly tailored to serve a compelling governmental interest.”

Judge Griffith wrote a lengthy dissent, in which he explained that “[b]alancing the risks and benefits found at the forefront of uncertain scienceand medicine has been, for goodreason, the historical province of the democratic branches[,] [and] I can find no basis in the Constitution or judicial precedents to remove that function from the elected branches.” He noted that claims of constitutional entitlement to the use of unapproved drugs have been repeatedly rejected by other courts. After reviewing the common law precedents invoked by the majority and the history of federal and state drug regulation, he concluded that the majority had “provide[d] no evidence of a right, deeply rooted in our Nation’s history and traditions, to procure and use experimental drugs.” He also took issue with the majority’s conclusion that the right of access to unapproved drugs is analogous to other rights deemed “implicit in the concept of ordered liberty.” Finally, he identified a series of legal and practical problemsthat will confront the parties and the district court on remand by virtue of the majority’s holding.

As I have told students who have asked me about this case, it actually presents two separate questions.

The first is the question at the root of the litigation, does the Constitution compel Congress and FDA to adopt a certain policy as to the regulation and approval of drugs as applied to terminally ill patients? My own (admittedly biased) view is that the original panel opinion, while quite inventive, does not withstand a close examination. I don't want to join the matter here, given the pending nature of the case. But the one thing I will say is that although the majority took great pains to repeatedly limit the right at issue in a way that would make its holding seem more plausible, it is hard to see why on the decision's own constitutional logic, the stopping point should be terminally ill patients rather than preventing FDA from regulating any drug for any individual who thinks an unapproved drug will, on balance, help him or her.

The second, and to me more difficult, question is the policy one. Even if we assume Congress and FDA have the power to regulate drugs for the terminally ill in the way they are already doing, should they switch to a system with increased access? In this regard, the amazing John Robertson (who always manages to be right there with thoughtful analysis when a major bioethics issue emerges) has a recent article in the Hastings Center Report, that lays out the major policy issues.

As I see it, to return to a theme in some of my earlier posts, the issue consists of a large share of pure paternalism vs. antipaternalism arguments, and a harder to quantify share of externality-based reasoning (the fear that increased access may make it harder to recruit subjects for clinical trials thereby hampering  the drug development process).  There is also a further question that even if FDA lifted its prohibition on the sale of these drugs to terminally ill patients under specified conditions, whether drug manufacturers would be willing to sell the drugs to these patients?

It is sometimes suggested that the paternalism argument is weak here because the patients in question are already terminally ill.  But having a terminal illness is not the same as being on death's door, and in any event particular drug being sought for its as yet unsubstantiated claims of cure may actually hasten death. 

How often does the gamble pay off?  According to a study done earlier in this decade, for new chemical entities that entered Phase 2 FDA testing between 1987 and 1992, only 30.8% made it to the next stage of clinical testing.  As Peter Jacobson and Wendy Parmet note in their JAMA article , the success rate is similar for cancer drugs in particular (a focus of the Abigail case): only 5% of all cancer drugs that enter clinical testing are ultimately approved for cancer use, and of those that make it to phase 2 trials, only 30% proceed to phase 3 (citing Kola I, Landis J, Can the pharmaceutical industry reduce attrition rates? 3 Nat. Rev. Drug Discov. 711-716 (2004)).

Something that is somewhat obscured by a lot of the dicussions of the case is that FDA already has programs in place to make drugs available to the terminally ill patients, which FDA calls Treatment Uses.   Moreover, as the AP has reported, in December FDA put a notice of a proposed rulemaking regarding expanded access to investigational drugs for treatment uses in the federal register, 71 Fed. Reg. 75147 (Dec. 14, 2006), which largely seeks to clarify and codify the agency's existing practices.  Thus the relevant policy question is whether the current system strikes the right balance, or whether we should favor a still more expanded access program.

One deeper question this entire controversy raises is whether FDA should be in the business of requiring the demonstration of effectiveness at all?  One gets the impression that there are some out there who think the cost of the current regulatory system (in dollars and delays in going to market) is not worth it.  While I think there are useful discussions to be had at the margins of how FDA conducts effectiveness review, I am among those who shudder at the idea of a return to a wild west where anyone can peddle medicine without showing it works.

However the case comes out, it is bound to be interesting.  If you find yourself in DC next thursday, I'd highly recommending trying to get a seat at this en banc argument.