Drug safety versus a "Constitutional right" to access to experimental drugs, part 2

[Note: Part I is here.]

I tell ya, I stay up all night putting the finishing touches on a grant, and what happens? Mark Hoofnagle over at Denialism.com finds a real hum-dinger of stupidity published in the editorial pages of the Wall Street Journal. Unfortunately (or fortunately, given the rampant stupidity that appears to be going on in this article), I do not have a subscription to the WSJ; however, a little Googling found the whole text here. I've written about this conflict before, and it's a recurring theme in the multiple posts that I've done regarding dichloroacetate (DCA), the small molecule inhibitor of pyruvate dehydrogenase targeting the Warburg effect that showed promise in rodent models of cancer, a result reported back in January. This led to a huckster by the name of Jim Tassano selling bootleg DCA to desperate cancer patients, an activity that was finally shut down by the FDA in July. Although Mark did a good job in deconstructing a lot of the fallacies in the article, given my longstanding interest in this, there's always something left for me to pick over:

Last week, the full D.C. Circuit Court of Appeals reversed an earlier decision by its own three-judge panel and ruled 8-2 against a dying patient's right to pursue life by taking investigational -- but as yet FDA-unapproved -- drugs.

The case was filed in 2003 by the Abigail Alliance for Better Access to Developmental Drugs and the Washington Legal Foundation. We argued that terminal patients with no options left but death have a constitutional right to such therapy in the care of a qualified physician.

I'm with the Angry Toxicologist on this one. It is indeed fortunate for cancer patients that the Abigail Alliance lost this case. The question is: Is there such a "right"? The court ruled no; so at least legally there is not. But what about the other arguments? One of the most common attacks against me when I wrote about DCA was that dying cancer patients have a "right" to try anything they want to save their lives. It's a compelling argument, at least on an emotional level, when it's framed that way. After all, who would advocate denying a dying cancer patient their last shot at life? Who could be so cold, so callous? Who am I to castigate Jim Tassano for his "efforts"? After all, he's just trying to help, right? After all, I'm not dying of cancer myself (never mind that I have had family members battle with cancer and lose). People forget, however, the reasons that our current regulatory system, whatever flaws it has, came about.

Let's look at the WSJ article again. Basically it's the same basic argument repeated over and over again ad nauseam. A promising cancer drug is described, with the statement that it was "obvious" how effective it is while the FDA was dealing with its approval. How long it took for the FDA to approve it is then castigated, after which the authors state how many cancer patients died of the particular cancers against which the drug is effective died during the period of time the FDA was supposedly diddling around with the approval. It is then argued that those patients didn't have to die and that many of them wouldn't have died if the FDA had been quicker. Here are a couple of examples from the article:

Gleevec set a tragic standard for loss of life at the hands of FDA bureaucrats. Coming out of Phase I testing in 1998, it was known beyond any reasonable doubt to be safe and effective. The Alliance started requesting access to the drug for chronic myelogenous leukemia (CML) patients in June 2001. By the time FDA approved Gleevec in March 2003, approximately 3,600 patients had been denied access to the drug. Many died waiting. More than 80% of the small number of patients who got Gleevec in clinical trials before the drug was approved are alive today.

Eloxatin, for advanced colorectal cancer, was summarily rejected by the FDA in March 2000 despite its being approved in at least 29 other countries. In January 2002, we started to ask the FDA to allow patients access. The agency delayed approval until August. In between, about 40,000 Americans died without ever getting the drug.

As Mark pointed out, Gleevec was (and is) a true breakthrough drug. A therapy targeted at the bcr-abl fusion protein that drives chronic myelogenous leukemia, it was one of the first successful therapies targeted at a specific genetic derangement. Indeed, it is rare for an anticancer drug to be that effective against cancer. It's also one of the rare anticancer drugs whose efficacy became apparent during phase I clinical testing. Remember, because it is the first time that an experimental compound with activity against cancer in cell culture and animal models is ever given to humans, the purpose of a phase I clinical trial is to demonstrate safety, not efficacy. Generally, in a phase I trial, an experimental drug is given to patients according to a dose escalation scheme in order to determine the maximum tolerated dose and to identify side effects. Sometimes evidence of efficacy is found, but more frequently it is not at this stage. In the case of Gleevec, 53/54 had complete hematological responses, an amazing figure for a phase I trial, while 7/54 (13%) of patients had complete cytogenetic remissions, meaning that the bcr-abl protein and RNA could no longer be detected.

Of course, at the time, even though the drug clearly showed activity, it was not clear that it would prolong survival. Not all drugs that produce an initial anticancer response ultimately prolong survival, although it was admittedly unlikely that a drug with such a dramatic effect as Gleevec demonstrated in phase I trials would fail to produce an increase in survival. Even so, unless you do the trial, you can't know if it does or by how much. In a similar vein, phase I trials only test acute toxicities. They do not identify problems that may crop up after more prolonged use. Given the mechanism of action of the drug, it couldn't be known for sure whether it wouldn't inhibit other tyrosine kinase-class enzymes, producing adverse reactions. That it turned out to be such a safe and successful drug was truly scientific medicine at its best. Finally, whenever we test a new drug, it's important to know whether it's more effective, as effective, or less effective than the current standard of care. That's where phase III trials come in, in which a new drug is tested head-to-head with a standard of care regimen. In the case of CML, it's not as though there weren't any effective treatments; there were. They just weren't as effective as Gleevec, as clinical trials showed, clinical trials, it should be noted, that were halted early when it became apparent that patients in the Gleevec arm were doing much better.

The other drugs listed are not nearly as big an advance. Indeed, the usefulness of the drugs compared to the existing standard of care at the time the FDA was considering the drugs appears to decrease as the list continues. Eloxatin, for example, is not by any means a cure for metastatic colorectal cancer. It does, however, extend life by a few months when combined with the previous standard of care drug (5-FU), a combination known as the FOLFOX regimen. Most commonly, FOLFOX is now given as an adjuvant therapy after surgery of stage II and III colorectal cancer, where it increases three year recurrence-free survival rates from 72.9% to 77.8%, a significant result (in essence a 23% reduction in the risk of recurrence. This is a significant result but not exactly earth-shattering. In metastatic colorectal cancer, the FOLFOX regimen was an improvement over the standard of care (5-FU plus a drug called leucovorin) as well, improving median survival from around 12 months to approximately 16 months. Adding Avastin improves that further to nearly 20 months. Once again, significant but not earth-shattering and not a cure. Not a single patient who died of metastatic colorectal cancer during the period Eloxatin was being considered by the FDA would have been saved if the drug had been approved sooner, although a few might have had their lives prolonged somewhat. That, and the clearly incremental (and in some cases, marginal) improvements represented by the other drugs don't stop these guys from making a truly overblown pronouncement:

In sum, these 12 drugs -- had they been available to people denied entry to clinical trials -- might have helped more than one million mothers, fathers, sons and daughters live longer, better lives. We have actually underestimated the number of "life-years" lost at more than 520,000, because we have not included other safe and effective uses of these drugs that the FDA has yet to approve.

This is a truly astonishing claim, in essence that these 12 drugs would on average in the period of time that the FDA was considering them have prolonged the lives of 520,000 cancer patients by a year (or 260,000 patients by two years or 1,040,000 patients by six months)--particularly given that even the worst FDA approval processes complained about took three years, and most took between one and two years. That's not much time relative to such a grandiose claim to produce such a huge benefit in "life-years." Moreover, you really know that the authors of this are full of crap when they start appealing to as-yet-unknown "safe and effective other uses" of these drugs that the FDA has not yet approved. What, pray tell, are these uses, and what is the evidence that they would add even more "life years" for cancer patients?

The bottom line is that none of the drugs listed in this article other than Gleevec are cures (and even Gleevec, as great as it is, isn't a cure strictly speaking). They are all incremental improvements, and some are arguably not better than the standard of care at the time they were being evaluated. Being at best incremental, none of these drugs produce benefits compelling enough compared to the standard of care to justify bypassing the standard FDA approval procedures. On the other hand, it's not unreasonable to argue that there should be a mechanism to allow the early recognition of the occasional amazingly effective drug like Gleevec and allow it to be fast-tracked for approval. In fact there is such a mechanism, and Gleevec was approved on it. This is the same mechanism by which the FDA, stung by the criticism of AIDS activists a couple of decades ago that people were dying while promising new drugs were taking years to be approved, had implemented to speed access to promising drugs for rapidly fatal diseases. I'm not in any way saying that the mechanisms are foolproof or that they don't have room for improvement, but what the Abigail Alliance seems to want to do is to dismantle any approval process after a phase I trial, at least when it comes to cancer drugs, and allow patients to purchase any drug that's cleared that rather low hurdle.

Consider the final argument of the Abigail Alliance:

The American Cancer Society reports that some 550,000 cancer patients die annually, making the number of cancer deaths from 1997 to 2005 about 4.8 million. Over that same period, the FDA reports granting individual access to an investigational drug to not more than 650 people per year for all diseases and drugs -- a pathetic, even cruel, pittance. A few thousand more patients managed to gain access by enrolling in relatively small clinical trials or exceedingly rare expanded access programs.

The other 4.7 plus million cancer patients, not to mention millions more with other diseases, were abandoned to die, denied access to progress by their own FDA when they needed it most.

Although I agree that compassionate use programs should be expanded, referring to all these patients as being somehow "abandoned to die" because they can't try any experimental regimen out there is, quite simply, ridiculous. Indeed, it's a blatant appeal to emotion over reason, very much like the classic alternative medicine lament that "doctors sent me home to die." These patients presumably received the standard of care for the treatment of their cancers. They were not "abandoned," although I can somewhat understand why they might feel that way. Finally, there are two huge unexamined assumptions underlying this hyperbolic, overblown, and offensive argument. The first is that these experimental protocols are the only treatment modality. They aren't; moreover, in most cases they are only slight or moderate improvements over the standard of care. A drug like Gleevec, alas, doesn't come around all that often. The second unsupported assumption is that allowing unfettered access to experimental drugs that have passed phase I trials would help more people than it would hurt. In actuality, because phase I trials only identify acute toxicities and do not identify adverse reactions that occur with longer use, physicians administering these drugs would be flying almost blind. The potential for harm is enormous, particularly when it is powerful chemotherapeutic agents that are being given. It is far more likely that widespread use of unapproved substances would harm far more patients than it would help. Indeed, at the level of the individual patient, trying such drugs is more likely to harm than help. If there's one thing worse than dying of cancer, it's making one's last days shorter and more miserable with toxicities from unapproved drugs or, even worse still, paying big bucks to do so.

Here's another problem. If a pharmaceutical company can sell its drugs to patients after only phase I trials, there would be far less incentive for them to do the hard phase II and phase III trials that determine specific toxicities, identify what kinds of patients benefit and what kinds do not, identify which cancers against which a drug is effective, and optimize treatment protocols and far less incentive for patients to enroll in clinical trials. Remember, nine out of ten drugs tested in phase I trials do not make it to market. 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. Finally, it's impossible to know if these drugs actually improve patient survival without randomized clinical trials. My discussions of DCA have shown how, without careful randomization scientific measurements, wishful thinking and confirmation bias lead patients to believe that the drug is working when there is no good objective evidence that it is. Worse, because no insurance company would pay for these drugs, only patients who could afford them could get them. At least under today's compassionate use program, patients usually don't have to pay for the drugs.

Although I sympathize with the emotions that drive the Abigail Alliance, it is clearly emotion rather than reason that is driving this campaign. It's also very difficult as a physician to tell dying patients that they can't have these experimental drugs. No one wants to do that; it would be far easier simply to say yes to them all. However, it is necessary to reiterate that allowing expanded access to such drugs has the potential to do far more harm than good, both to individual patients and to the entire integrity of the scientific process of clinical trials designed to determine which drugs do and do not work. Worse, it would allow pharmaceutical companies the opportunity to take advantage of such patients by selling them experimental drugs with even less oversight than is exercised now. I can just see viral marketing campaigns popping up for a drug partway through the FDA approval process aimed at cancer patients. In fact, one might even argue that the DCA Site is a good example of how such drugs would be marketed, except that it would be large pharmaceutical companies, rather than a small business person from California, who would be setting such sites up or quietly supporting them financially. Even better for the pharmaceutical companies, the patient would have to pay cash on the barrelhead. There would be no pesky requirement to provide free drugs for clinical trials, and, because insurance companies won't pay for experimental drugs, there would be no need to deal with insurance companies to pay for the drugs!

It is important for cancer patients to realize that the FDA is not the enemy. It may have real deficiencies, not the least of which is its chronic underfunding that keeps it investigating as many problems with drugs that need to be investigated as it should and, ironically, from processing new drug applications as rapidly as the law allows. It may need fixing, and its fast track system for approving drugs for life-threatening conditions could be fine-tuned, but by and large the FDA is there to protect the public from unsafe and ineffective drugs. The Abigail Alliance does not appear to view the FDA as the enemy, but to some the FDA is viewed as the enemy. (Cato Institute, anyone?) These forces are not above riding the wave of emotion provoked by the heart-rending stories publicized by the Abigail Alliance, all in order further their agenda of crippling the FDA. In the end, as with many issues, it is a delicate balance between individual liberty and the overall good. Allowing potentially dangerous experimental drugs to be widely available to cancer patients is far more likely to do a lot of harm in return for minimal benefits.