Drug safety versus a "Constitutional right" to access to experimental drugs

[Note: There is a followup to this post here.]

I’ve been writing a lot about dichloroacetate (DCA) lately, perhaps even to the point of becoming repetitive and risking boring my readers. Fortunately, this post is not primarily about DCA. Unfortunately, it’s about a question that is related to the recent hype over DCA in that it pits the desperation of dying cancer patients who want to try out the latest drugs, even if they haven’t been demonstrated to be safe or efficacious, versus the what remaining ability the FDA has to regulate drug safety and, some might argue, the scientific method itself. It’s about a ruling that set a very disturbing precedent that patients have a “Constitutional right” to the being able to obtain potentially life-saving drugs even in the early stages of development. Because the article comes from a newspaper whose web articles expire rather rapidly, I’ll be fairly generous about quoting:

WASHINGTON— Abigail Burroughs fought head and neck cancer for 18 months, desperately seeking access to promising experimental drugs after chemotherapy and radiation therapy failed.

She was unable to get into a clinical trial for ImClone’s now widely available Erbitux because it was for colon cancer patients only, and she failed to meet the clinical trial inclusion criteria for Iressa, an AstraZeneca cancer drug that later proved largely unsuccessful.

At the end of May 2001, Burroughs was finally accepted into a clinical trial for OSI Pharmaceutical’s subsequently approved cancer drug Tarceva, but she was too ill to travel from Virginia to the Texas testing site. She died two weeks later at age 21.

“It was a horrible, horrible nightmare. When your child is terminally ill, you want to do everything you can,” said her father, Frank Burroughs of Fredericksburg, Va. “People just want a chance to live when they are facing death.”

Burroughs soon formed the Abigail Alliance, an organization dedicated to helping cancer patients and others with life-threatening illnesses break down barriers imposed by the Food and Drug Administration and the pharmaceutical industry to obtaining potentially helpful experimental drugs outside the clinical trial setting.

His relentless campaign has resulted in a court ruling that threatens to shake the foundations of the FDA’s regulatory authority covering pharmaceuticals and lead to greatly expanded use of unapproved medications that haven’t been fully tested for safety or effectiveness.

The legal battle, ironically, comes as medical experts, members of Congress and consumer groups have been criticizing the FDA for letting problem drugs on the market and then not properly monitoring their safety.

In a case to be reargued March 1 before 10 members of the U.S. Court of Appeals for the District of Columbia, a three-judge panel last May ruled dying patients have a constitutional right to purchase unapproved experimental drugs that have completed the initial Phase I human clinical testing if their doctors say there are no other viable options.

Just as terminally ill patients have a right to die by refusing medical treatment, the court said in a 2-1 decision, individuals have a fundamental right to “self preservation” that includes being able to obtain potentially life-saving drugs in early stages of clinical development.

The FDA is vigorously contesting what it calls “a profoundly troubling ruling,” arguing the appeals court has placed its ability to ensure patient safety in “a constitutional straight jacket.”

By weakening its discretionary authority, loosening the standards and allowing large numbers of patients to take drugs after small Phase I trials, the FDA said, the court’s ruling could create unacceptable risks, hasten patient deaths and undermine the science-based clinical trial system.

Oddly enough, I hadn’t been aware of the Abigail Alliance. I can fully sympathize with the parents who had to watch their child die of a horrible disease. I can even understand that they might believe that Erbitiux or Iressa may have saved her, even though in retrospect we know that it’s unlikely that either drug would have. Unfortunately, the ruling that the Abigail Alliance is pushing for could potentially have a very grave effect on the ability of the FDA to regulate drug safety, and it’s no surprise that the FDA is appealing it vigorously. Worse, it could jeopardize the development of the very drugs that it purports to want to make more widely available.

Before you can understand why, you need to understand what a Phase I clinical trial is. Basically, Phase I clinical trials represent the very first time a promising new substance is ever given to humans. The intent is not really therapeutic. Rather, it is to gather toxicity data and to determine the optimal dose. Basically, what is done is something called a dose escalation, where increasing doses are tried until toxicity is observed. The usual patients enrolled in these trials when done for cancer drugs have advanced disease that is incurable with present modalities. One reason for this is that in many cases it would be unethical to try such drugs out in patients who could expect to have a chance at long-term survival using conventional treatments, and that healthy volunteers would be unlikely to be willing to undergo the risk of toxicity from these very powerful drugs. Another reason is that sometimes we can see anti-tumor activity even in a phase I trial. However, it is not expected that antitumor activity will be observed, and not observing activity would not preclude moving on to a larger, randomized Phase II trial, in which the drug is tested against specific tumors.

What the Abigail Alliance is arguing for is to be allowed access to drugs that have only passed Phase I. At this point, there is usually no evidence of efficacy yet, and only the nastiest of the drug’s side effects are known. As the article points out, nine out of ten drugs tested in Phase I trials end up being abandoned, either because of excessive toxicity or because they don’t work. One example is amonifide for advanced breast cancer, which was discontinued after safety concerns emerged in a phase 2 trial. The trial demonstrated that amonifide resulted in serious hematologic toxicity (severe and life-threatening leukopenia and thrombocytopenia) and systemic allergic reactions. Expanding access to drugs that have passed Phase I would be likely to harm far more patients than it would potentially help, something the judges seem not to have considered. Indeed, they went so far as to infer that drugs showing success in phase 1 trials would “probably have a medical benefit with sufficiently minimal risk,” an inference that is breathtaking in its arrogance and ignorance.

However, there is a deep strain in American society between individual autonomy and the needs of society, and where that struggle is resolved often shifts over time. Peter Jacobsen describes the conflict and the dilemma:

Peter Jacobson of the University of Michigan Center for Law, Ethics and Health said the Abigail Alliance case presents a classic conflict between individual rights and the broader needs of society.

“Do I want to be the doctor telling a dying patient he has nothing to offer? No. Do I want to be the regulator saying you are not eligible for compassionate use of an experimental drug? No,” said Jacobson “But if I am a regulator and I say you can have anything you want, how do I protect patient safety?”

Jacobson said he believes “the future of pharmaceutical regulation is at stake,” with affirmation of the court decision opening the floodgates to “snake oil” remedies, offering “false hopes” and unleashing dangerous, unproved medications on the public. He said the integrity of the scientific and regulatory processes must take precedence over individual demands, no matter how heartbreaking.

This is particularly true because violating the integrity of these processes to make essentially untested drugs more widely available, is far more likely to harm the individual patient than to help him. If there’s anything worse than dying of a terminal illness. It’s dying of a terminal illness and suffering unnecessary complications or pain for no benefit and having to pay for the medications causing the complications yourself. In addition, we would risk seriously undermining the scientific basis for evidence-based medicine by undermining the whole system of clinical trials that studies efficacy and safety. After all, if early stage experimental drugs were available outside of clinical trials and were taken for a wide variety of cancers, it the signal-to-noise ratio would become very low, and it would become very difficult to tell which drugs were working and for which cancers (and which were not), particularly since it would be reasonable to expect that such a policy would result in enrollments in clinical trials plummeting. And what would be the potential payoff for this shredding of patient protections? Little at best, if even any at all. In reality, the likelihood of saving the lives of even a few cancer patients by giving them access to early experimental drugs is quite low and hard to justify on a moral and practical basis, given the likelihood of potential harm or premature death to so many other patients through the damage or destruction of a system that has been built up at such cost over several decades.

The entire ruling also seems to rest on a misperception that there are “miracle drugs” out there that we will have to wait years for because the FDA is too slow to approve them. However, if there really were such a “miracle drug” that was amazingly effective compared to anything we have now, a large randomized phase III trial would not be necessary to detect its efficacy. Indeed, its efficacy would almost certainly show up in even a small phase I trial. There’d be examples of amazing tumor shrinkage or even outright cures. In reality, we don’t see these things in Phase I trials, because there are no miracle drugs, at least not yet. Because the effects of most new drugs against various tumors tends to be less than miraculous, we need Phase III trials to determine safety and efficacy. It would be truly fantastic if we didn’t, but we do. If the ruling stands, the FDA really will be hamstrung. This seems a truly odd thing to want to do, given the high profile failures of the FDA to assure the safety and efficacy of various drugs. Indeed, in September, the Institute of Medicine released a report that was highly critical of the FDA and a rule passed by Congress in 1992 that allows pharmaceutical companies to pay the agency substantial fees to expedite reviews of their drugs. The report also criticized Congress for failing to fund FDA adequately for post-approval drug monitoring, citing Vioxx, the arthritis drug that was withdrawn in 2004 after it was found to double the risk of heart attack. For those out there who think that the FDA is a lapdog of big pharma, if this ruling stands it won’t have to be a lapdog to be totally ineffective. Worse, in a spectacularly misguided action, Senator Sam Brownback (R-Kansas) is pushing a piece of legislation that would in essence grant access to experimental therapies to patients with “serious or lifethreatening” illnesses.

Indeed, if it is ruled a “Constitutional right” to be able to use any experimental drug that has passed Phase I testing or if Senator Brownback’s bill passes, it could open the door to all sorts of dubious therapies being marketed:

Brownback’s bill stipulates that drug companies cannot be held liable for a patient’s adverse reactions to an experimental medication. But this may not be enough to reassure pharmaceutical companies, and it could inadvertently encourage retailers of alternative therapies that have little or no basis in science. “The bill opens the space for products that are sold by charlatans,” said David Parkinson, an oncologist who worked at the National Cancer Institute for many years and is now a senior vice-president at the biotech company Biogen Idec. One of Parkinson’s tasks at the N.C.I. was to evaluate herbal remedies and animal extracts, such as shark cartilage, that are sold in health-food stores and on the Internet, accompanied by testimonials from patients about their anti-cancer benefits. Some of these products could pass Phase I trials, Parkinson said, and, under Brownback’s bill, the F.D.A. would be compelled to approve them.

Such a bill or ruling could also put physicians in an ethically troublesome position, as Peter Jacobsen also points out:

In reality, that approach might prove problematic for physicians, leaving them caught between patient demands for ineffective or dangerous pharmaceuticals and physicians’ ethical obligation to do no harm. Perhaps even more troublesome, it would encourage the antithesis of evidence-based medicine.

The essence of the alliance’s clinical argument is that terminally ill patients should have the choice of using experimental drugs in consultation with physicians. “All [the plaintiffs] ask is that the government get out of their way, so that they can use their own private resources to fight for their own lives at the inherently uncertain frontiers of modern science.”20(p31) Consistent with current market theory, the panel’s opinion shifted the risks to the patient but also to the physician.

Physicians already face considerable pressure from patients who demand medications that are heavily marketed through direct-to-consumer advertising. As contentious as such advertising has been, allowing access to unapproved pharmaceuticals places physicians in the uncomfortable position of prescribing drugs with unknown risk profiles that may be more harmful than beneficial, explaining to patients why simply calling something lifesaving does not make it so, or being candid that medicine has nothing more to offer. While this is precisely the risk-benefit discussion that physicians should be having with patients, there is a substantial added burden when discussing drugs that have not completed appropriate clinical trials, especially when no data or published reports exist to support the physician’s professional opinion of safety and efficacy. As the government argued to the panel, terminally ill patients are particularly vulnerable to promises that unproven treatments will be effective.

Don’t even get me started on the liability issues involved. It’s impossible to give truly informed consent regarding a drug that hasn’t made it through at least Phase II testing. Given the litigious nature of the U.S., it’s highly unlikely that a blanket immunization from liability to physicians prescribing such drugs or drug companies making them would pass muster. And the flip side of the coin, of course, is that it is possible to imagine physicians being held liable for not pursuing experimental therapies.

Worse, none of this would prevent drug companies from advertising or publicizing their new drugs by word of mouth or viral marketing campaigns. Also, the Internet is a powerful tool that would almost instantly spread hype about new drugs far and wide. In essence, this policy would open the door not just to quacks and alties selling dubious remedies to cancer patients but to big pharma profiting from experimental drugs before they are even shown to be safe and effective. I point to the DCA kerfluffle again as further evidence for how hype and promises of a cancer cure can prey on desperate people. Here was a report of a drug that had shown promise in cell culture and in rat tumor models but had yet to be tested in humans against cancer, and the blogosphere goes wild. We have, as I pointed out, patients looking to buy the stuff, even though the sources cited as selling it aren’t selling pharmaceutical grade DCA, and I’ve even come across medical ignoramuses like David Springer (a.k.a. “DaveScot”) encouraging this behavior with a “wink-wink, nudge-nudge” disclaimer that he is “not encouraging anyone to self-medicate” and intends his message “solely to get the attention of established clinicians with experience in orphan drug testing.”

Yeah, right. Sure he isn’t and sure he does.

It could be argued that the FDA was too restrictive in the past in approving new drugs, but it can now be argued that it is in danger of moving too far in the other direction. For example, the FDA has moved, starting at the behest of AIDS activists and continuing under the urging of activists for various other diseases, to increase compassionate and expanded use programs and to developed an “accelerated approval” program for drug approval. The problem is that this “accelerated” program, originally intended to be used only for drugs designed to treat life-threatening diseases for which time is of the essence (such as AIDS) has now morphed to the point where it can be used for nearly any drug approval. (Indeed, Vioxx, hardly a drug designed to treat such diseases, was approved under the “accelerated approval” program, and look what happened there. There have been other problems with drugs approved under this program.)

The bottom line is that there will always be a conflict between wanting to do something now for suffering patients, damn the consequences, and following the scientific method to demonstrate efficacy and safety. Our nation has been at both extremes. Indeed, until 1906, pharmaceutical companies could make essentially any claims and sell essentially anything to the public as a drug without regulation. We all know how well that worked out. Early in the history of the FDA, as Dr Jerome Groopman points out, companies often tested new drugs by sending them to doctors to offer to their patients, asked for little information regarding side effects and complications, and had no standard criteria for efficacy. Do we really want to go back to those days? That’s where we seem to be heading. From my perspective, the National Organization for Rare Disorders seems to have a better and less dangerous summed it up well:

I understand the emotion that drives the Abigail Alliance, but this isn’t about emotion, it’s about saving as many lives as possible and not about getting as many drugs out as possible. It’s about doing the right research and making sure we have patient protections in place and making drugs available that are truly helpful.

As physicians, we must remember our charge, “First, do no harm.” Expanding the access to unproven drugs after only the minimal testing of a Phase I trial, many of which will turn out not to be efficacious and for which patients may have to pay out of pocket would be failing in that charge.

ADDENDUM: Walnut has posted his critique on Daily Kos as well.

All Orac posts on DCA:

Posts by fellow ScienceBlogger Abel Pharmboy:

Share this:

Related

By Orac

Discover more from RESPECTFUL INSOLENCE