Are NDA Laws Constitutional?

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This month the current drug approval process is being challenged on three fronts: On March 1 a Federal Circuit Court began a review of the decision by the court's own three-judge panel that the new drug approval (NDA) process violates the Constitution. Then March 14 will see the end of the public comment period of the FDA's proposed new rule on expanded access to unapproved drugs. Meanwhile the Brownback/Shea ACCESS bill, which takes a far more radical approach to the same objective, will again be pending in Congress.

The pharmaceutical industry has a lot at stake in the outcomes. So does the American public. To understand what brought about this convergence, we need to go back to go back to 2001.
A young woman who was being treated for cancer at Johns Hopkins had not been helped by any of the then available drugs. Her oncologist thought that an experimental agent (now marketed as Erbitux) might save her life, but was unable to obtain it for her. On June 9, 2001, Abigail Burroughs died.

Her father, Frank Burroughs, says that “after the most horrible tragedy I could have ever imagined, I decided that I would continue my efforts.” Together with a father whose son had come to a similarly tragic end, he founded the Abigail Alliance. Its mission is to help cancer patients and others with life-threatening diseases who have run out of conventional treatment options “to find clinical trials, expanded access programs, and…compassionate use programs.” Thus, says the Alliance, thousands of lives a year could be saved, and toward that end it has encouraged both legislation (hence the Brownback bill), and gone to court (hence the decision pending in the Circuit Court).

So far the Alliance has scored some successes:
It has obtained wide publicity for its cause, including editorial support by the Wall Street Journal.
It has persuaded the National Institutes of Health to add a mention of the clinicaltrials.gov Web site in its recruiting ads so as to spread the word of drug trials that patients might enter.
Most important, by suing FDA and HHS (with the help of the Washington Legal Foundation), it has won a ruling by a three-judge Circuit Court panel that “FDA's policy prohibiting the sale of investigational drugs to… patients with no other treatment options” is unconstitutional.
And finally, it has lined up Congressional backing: the bills introduced by Sen. Sam Brownback in 2005 and Rep. Christopher Shays in 2006 would accomplish the Alliance's goal, no matter how the court case comes out.

The Alliance was, however, disappointed by the FDA's proposed new rule to expand availability of experimental drugs. The Alliance claims that the proposal does little more than confirm the current system.

A critical difference is that the FDA proposal would apply to drugs that have cleared Phase II, whereas the Alliance wants patients to have access to all drugs that show substantial evidence of safety and efficacy in Phase I. It also cuts some of the red tape when a doctor wants an investigational drug for patients who are failing therapy by, for instance, making it possible to file a single application for a small group of patients, rather than a separate one for each. And it clarifies how companies can charge to cover their costs (but still not to make a profit), and sets up a sliding scale for supporting evidence based on the size of the population and the level of disease.
The timing of the FDA's proposal might make it seem as if it had been drafted in response to the unfavorable court ruling, but Peter Pitts says no, and he is in a position to know, for Pitts was FDA associate commissioner until 2004 and he recalls that the proposed new rule was being drafted before the court decision.

Pitts, who is now a VP at Manning, Selvage & Lee, understands both the dying patients' frustration and the reluctance of FDA to give the Abigail Alliance everything it wants. Desperate as patients are, he says, “the agency still has to do the right thing, which is to act responsibly. It's appropriate to cut through red tape, but not simply for the patient to say I want this drug and have the FDA say, ‘OK.' You still need to have strict regulatory controls. If you don't, you're putting people at risk.” Decisions should still be made on a case-by-case basis and not, as the Brownback bill proposes, to give entire groups access to investigational drugs. “You can't legislate science,” says Pitts, “and you can't legislate what is safe and what isn't. Once you begin to give authority to prescribe investigational drugs to people who are removed from responsibility, you open the floodgates to very dangerous things.”

The Brownback bill, he feels, would not only undercut the drug review process, it would also be bad for industry. “It's a double whammy,” he says. First, it would likely short-circuit controlled studies and thus jeopardize ultimate approval; second, it could—despite the bill's provision requiring patient waivers—lead to expensive liability litigation. He finds it particularly surprising that “at a time when politicians are thumping their desks about drug safety they would even look at such a bill.” Furthermore, it would not be fair to patients by giving them false hope, since the drugs they want might not work or even be available. He is optimistic in one sense, though: he does not believe that “the Brownback bill stands a chance of passing.”

But even if it doesn't, all these risks might still be encountered if the full District Court confirms the decision of its three-judge panel that patients have a constitutional right to obtain unapproved drugs. The judges seemed to contemplate the consequences of their ruling with equanimity. After all, they pointed out, before 1906, when the first Food and Drug Act was passed, we didn't need government permission to take any drugs. Depending on your frame of reference, you can consider that the ultimate libertarian paradise regained—or a disaster for the pharma industry and quite possibly the nation's health.

Frank Burroughs has answers to critics of the Abigail Alliance's agenda (elicited in separate interviews). First of all, he stresses that ideally patients could enter controlled trials; only if they were unable to do so would other access methods apply. But as he points out, patients and even doctors often don't know that a potentially helpful drug is being studied, so that more has to be done to publicize clinical trials. Second, manufacturers would not be forced to make their products available. Instead they would be “incentivized” to ramp up production by being able to charge for them. Since presumably hundreds or even thousands of patients would want to be treated, the profits might be substantial.

He also makes it clear that even if the Alliance wins its case in the Court of Appeals and then in the Supreme Court (where it is likely to wind up, no matter who wins), his group will continue to push for adoption of the ACCESS bill. After all, court decisions are not self-enforcing; somebody has to spell out the implementing rules. One option is for FDA to draft them, but if the proposed regs didn't go far enough, the bill would override the agency's interpretation. So let's look at the bill.

Its premise is that current drug approval standards “deny the benefits of medical progress to seriously ill patients who face morbidity or death from their disease,” and that “the use of available investigational products… is the responsibility of the physician and the patient.”

The bill would therefore set up a tiered approval system. It is Tier I that represents the most radical departure since it affects products studied only in Phase I, which is designed to detect gross toxicity and usually involves fewer than 100 patients—sometimes as few as 20. Applications for Tier I approval could be based not only on evidence of safety and effectiveness in Phase I, but also on “preliminary evidence…based on uncontrolled data such as case histories, information about the pharmacological mechanism of action, data from animal or computer models…or other preliminary information…” The application would have to be submitted by the sponsor, which presumably could be anyone who thinks a product could help patients or make money.

With Tier I approval in hand, the product could then be advertised and charged for. All patients, the draft continues, shall provide written informed consent and a written waiver of the right to sue, while the sponsor shall submit “copies of all advertising and promotional materials related to the product…” until it receives final approval, and such materials “must prominently disclose the limited approval.” There is also a provision for an Accelerated Approval Advisory Committee, including two voting members representing “patient interests.”

Additional changes from the current standards are (1) that there can be no placebo-only or no-treatment controls, and (2), that applications cannot be disapproved “solely on the basis of a statistical analysis or the rigid use of the 95% confidence level convention.”

No wonder that two experts on FDA regulations that spoke to MM&M for this article use the same phrase to describe the impact of these proposals: that they would open the floodgates.

Bill Vodra was associate chief counsel in the early '90s, when protease inhibitors for AIDS were first being developed. Patients, knowing that in the absence of effective treatment the disease was in effect a death sentence, were understandably enraged when told they could not be treated until drug reviews had been completed. Like the Alliance, ACT-UP and other patient groups called placebo studies unethical. But, says Vodra, who is now a partner at the DC law firm of Arnold & Porter, once they understood that in the absence of scientific testing, development of improved forms of therapy would stop, “they turned around and came out very strongly in favor of controlled trials,” in fact helped to recruit volunteers.

The Alliance proposals, Vodra feels, have the same flaw. Once a drug is allowed into the marketplace, “the whole system would break down. Approval after Phase I means the whole ball game. Not only would you never again be able to study these new drugs in controlled trials, it would be like Gresham's Law of bad money driving out the good, with cheaper drugs driving out the good. Nobody is going to pay $70,000 a year for a new cancer drug if they can buy Laetrile for 75 cents.” (See sidebar on Laetrile, page 50.)

He cites a parallel from his experience. “If you want to know what's going to happen, look at the dietary supplement market. Congress voted to exempt these supplements from the requirement to prove effectiveness. And look what's happened. The market expanded some 20-fold between 1984-2006 because these products can now be promoted without substantiation of good science. Yet study after study has shown that many of them simply do not work. Once the floodgates are open, there will always be a lot of people who are scam artists.”

Vodra's biggest concern is the court ruling that there is a constitutional issue in preventing patients from obtaining unapproved drugs. The entire NDA process could be ruled illegal. He points out that the Abigail Alliance petition refers not only to cancer patients but to those with other life-threatening diseases. “What about cardiovascular conditions?” he asks. “What about diabetes or AIDS or asthma? They don't threaten immediate death, but they can definitely shorten life. The practical definition of ‘terminal' is when a doctor says there is nothing more I can do for you. That is a very flexible standard that could lead to a substantial erosion of the efficacy requirement.”

Rep. Christopher Shays (Rep.-CT), who introduced the ACCESS act in the House last year and plans to reintroduce it, explains that “the legislations is based on the principle that many who are facing terminal illnesses are willing to accept the risk of serious side effects for the chance that a therapy might cure them. We also would eliminate the use of placebos for terminal patients because it seems to me this practice is unethical.” His staff adds that the congressman met with a number of constituents who lost loved ones to fatal illnesses and who advocated for more freedom to make personal healthcare decisions. Attempts to reach Sen. Sam Brownback were unsuccessful, but then he's running for president so maybe he has more pressing priorities.

Spokespersons for the American Cancer Society responded by saying “we have not been active on this issue.” PhRMA did supply this statement from Associate VP Alan Goldhammer. “We'll be submitting extensive comments directly to the Food and Drug Administration,” he says, adding that this is not a new issue. “The challenges companies face as they try to accommodate more patients include having enough of the potential new medicine to satisfy the demand…In addition, companies must be careful to make sure that after making experimental drugs available to more patients, they are able to find enough volunteer patients” for their clinical trials. “In the end,” he concludes, “companies try very hard to do what is best for patients, and they try to accommodate those in need of immediate treatment.”

That sums up the dilemma when personal compassion collides with a public benefit. Who wins? Or, more to the point, who loses? And how will the critical decisions to be made this month be resolved?

 The FDA is almost certain to finalize its proposed new rule, even if slightly modified. Also, having been given a good scare and now headed by an oncologist, the agency may become somewhat less rigid in implementing its regulations.

Another fairly safe prediction is that Congress, consumed by the agenda of its new Democratic majority, is unlikely to act any time soon on the Brownback/Shays ACCESS bill. That, in light of the unpredictability of courts, leaves the Abigail Alliance/WLF suit against FDA as the big unknown. If the plaintiffs win, it won't be a case of a slippery slope toward the unraveling of the drug approval system; it will be more like falling off a cliff. Ironically, based on Vodra's comparison with Gresham's Law, it could well turn out to be a Pyrrhic victory, for with quack and hoax products driving out the good, and with patients able to get treated without placebo controls instead of entering clinical studies, it could well be that the kind of promising new drugs that patients now fight to have access to will simply no longer be developed. That is such a disastrous outcome that someone may still have second thoughts.

Wayne Pines says: The present system “has the potential to work, but the reason it doesn't work is that doctors and patients are not aware of it. Instead of legislation or regulation, I believe that the next step should be better education of doctors and patients.” That's why Frank Burroughs of the Abigail Alliance urges pharmaceutical companies to add to their ads, both professional and consumer, a tagline or box to build awareness of the clinicaltrials.gov Web site, since right now neither the public nor physicians have sufficient awareness that such opportunities exist.

That still leaves the controversy about the use of placebos in controlled trials. Under current cancer protocols, no one goes untreated. The study group receives the best available approved drug plus the agent under study; the control group gets the approved drug plus a placebo. If that's unethical, the proposed solution simply introduces a new problem.

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