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When is Compassion Not Compassionate?

The medical community debates the ethics of compassionate use
March 15, 2018 | Comments

In 1986 the first drug was approved for the treatment of a then invariably fatal illness, now known as Human Immunodeficiency Virus (HIV) infection. This approval by the US Food and Drug Administration (FDA) occurred just 25 months after the first human clinical trials of the drug zidovudine (also known as AZT) were initiated, one of the shortest approval times ever.

Despite the fact that people were dying from AIDS, the result of severe HIV infection, the FDA required the drug company that owned the patent for zidovudine to conduct a randomized controlled trial (RCT) of the new drug compared to placebo before granting approval. Jack was the recipient of research funding from the NIH at the time to study the neuropsychiatric aspects of AIDS and remembers hearing grumbling that the RCT should be dispensed with and zidovudine made immediately available. After all, what did a person about to die from HIV infection have to lose from taking an untested drug? There were rumors at the time that some participants in the zidovudine clinical trial opened the capsules they were given and figured out which had real zidovudine in them and which had placebo. Those randomized to placebo supposedly then stopped taking it. If true, that would of course have compromised the validity of the clinical trial. Fortunately, zidovudine was superior to placebo and sufficiently safe to be put into widespread clinical use in 1986. Today, even better antiretroviral drugs have turned HIV infection into a manageable chronic illness.

Jack also spoke with scientists in the late 1980’s who worried that there should have been more testing of zidovudine before it was approved. There weren’t enough data to determine the best dose of the drug, for example, and indeed zidovudine was originally administered at much higher doses and more frequent intervals throughout the day than turned out to be needed, increasing the risks for poor adherence and adverse effects. Usually, FDA does not approve drugs until careful dose range testing in animals and humans have been completed so that optimal doses are known before general use of the new medication. But back in 1986 there was great pressure to get zidovudine out there and prescribed.

This tension between carefully studying a drug to be sure it is safe and effective and getting life-saving medications into clinicians’ hands as soon as possible is perhaps the major one that has always faced the FDA’s drug approval process. Whenever a drug is approved that later turns out to have serious adverse effects (remember Vioxx?), politicians and advocacy groups criticize the FDA for letting it through in the first place and sometimes also blame pharmaceutical companies for covering up the evidence of potential harm. But when there is a deadly disease without a known cure, those same individuals are likely to attack the FDA’s rigorous and time-consuming clinical trials requirements before approving a new medication.

Today, this dilemma is front and center with the introduction to Congress of proposed Right-to-Try legislation. This proposed new law, already passed by the Senate and awaiting House action, would allow patients with life-threatening illness to obtain experimental medications without FDA involvement. Right now, physicians may apply to the FDA for “compassionate use” of a yet unapproved drug and, with FDA permission, the drug company may provide it. Right-to Try laws, already in effect in 38 states, would bypass the FDA approval step and allow doctors and their patients to deal directly with a drug company that owns an experimental drug. Proponents of the bill, which include President Trump, argue that this will cut down on the time needed for dying patients to get potential life-saving drugs.

The proposed law also has two incentives for drug companies to provide investigational drugs to dying patients. First, the FDA would be barred from using any data from patients who access drugs this way in making ultimate approval decisions. Thus, for example, if a patient using a drug via the Right-to-Try pathway experiences a severe adverse effect, that event could not factor into the overall adverse side effect rate the FDA uses to determine if an experimental drug is safe enough for general use.

Second, drug companies would be protected from liability when providing medications under Right-to-Try.

At first glance, it is hard to see what could be wrong with this approach. After all, even if an experimental drug later turns out to be ineffective or to have serious—even fatal—adverse effects, a dying person and his or her family and physicians might make the very logical decision that the drug is worth a try. This seems indeed like the compassionate choice.

So why then are there vociferous objections to Right-to-Try legislation from doctors and ethicists? In their January article in the New England Journal of Medicine, Steven Joffe and Holly Fernandez Lynch explain the two main potential drawbacks of Right-to-Try:

  1.     Is it really true that the patient has “nothing to lose?” Even a person who is not likely to survive an illness wants to prolong survival as long as possible, avoid pain, and maximize quality of life. An investigational drug might cause painful side effects and physical and mental impairment and even hasten death. In the absence of valid scientific data, there would be no way to know how likely such outcomes would be.
  2.     Although the Right-to-Try law would require that a patient be ineligible to participate in a clinical trial of the experimental medication, there are concerns that this won’t be enforced strictly, thus reducing the supply of patients to participate in trials and delaying formal FDA approval of new medications for use by the affected general public.

Joffe and Fernandez note that the new law probably would not have a large effect because most compassionate use applications are actually approved now by the FDA. Still, there are legitimate concerns that Right-to-Try laws undercut the principle that people should not be exposed to medications until rigorous testing has proven they are safe and effective. “Are we prepared to abandon the FDA’s gatekeeping role in favor of unfettered patient autonomy and market forces,” Joffe and Fernandez ask, “risking precisely the problems that prompted Congress to grant the FDA its present authority?”

So which approach is actually compassionate? The emotional appeal of providing whatever has a sliver of a chance of helping a dying patient is clear. Clearly, we don’t want bureaucracy to stand in the way of saving a life.

On the other hand, Right-to-Try legislation might still harm the patient in unanticipated ways. Equally important, it runs the risk of preventing us from knowing whether an experimental drug is actually useful. Thousands of patients could presumably be denied getting an experimental drug if a handful try it outside the clinical trial structure and delay the drug’s approval.

For these reasons, many scientists, doctors and ethicists opposed federal Right-to-Try legislation. It seems that when we step back, think about the whole population of people suffering with life-threatening disease instead of individuals, and consider the scientific basis for the drug approval protocols we now use, Right-to-Try no longer seems as compelling a concept. It may be that compassionate use in this case is not unequivocally compassionate.

 

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