Should terminally ill patients have the right to take drugs that pass phase I testing? No

Abstract

The United States is considering allowing experimental drugs to be given to people at the end of life. Emil J Freireich believes patients should be able to judge the risks for themselves, and Dean Gesme counters that use o such drugs outside trials will damage both individuals and science

Partially tested therapies cannot be allowed to substitute for good medical care. Hippocrates stated that our role as doctors is always to help or, at least, to do no harm. Those precepts apply equally to patients with minor ailments and those with terminal conditions.

In the United States, the Food and Drug Administration has proposed expanded access to investigational drugs for patients with terminal illnesses after initial safety (phase I) trials but before final approval for marketing.¹ This would apply to selected drugs already in phase II and III testing. The much publicised legal action filed against the FDA by the Abigail Alliance also seeks to make available drugs for which phase I safety data are known.² The US Supreme Court is yet to consider this legal action.

However, the use of drugs after phase I testing and outside clinical trials may still subject patients to toxicities while offering no reasonable expectation of benefit. Phase I trials are intended to evaluate dose safety, while effectiveness of drugs is assessed in phase II and III clinical trials. More than 90% of drugs entering phase I trials are found unacceptable,³ and, of those approved, most provide incremental improvements rather than lifesaving treatments.

The allure of promising new drugs continues to engender false hope, which has all too often diverted time, resources, and attention from more appropriate efforts to minimise symptoms and enhance the quality of life for terminally ill patients and their families. Inappropriate expectations for untested new drugs are commonly promulgated by investigators eager for grant funding, companies searching for capital, writers eager for a good storyline, and uncomfortable practitioners who would rather avoid dealing directly with the complexity of end of life issues.

Damage to clinical trials

Patients may prefer to take partially tested drugs outside trials to avoid the constraints of a larger protocol study. However, this would subvert accrual of patients to phase II and III trials and ultimately delay the approval of those new drugs. Thus the needs of the many may become subservient to the desperate desires of the few.

False hopes for unproved drugs can also erode the clinical trials system by substituting clinical enthusiasm and wishful thinking for evidence based medicine. The best analogy may come from the many years in which autologous bone marrow transplant was considered standard treatment for advanced breast cancer despite the lack of data concerning efficacy. Well designed clinical trials failed to find willing participants as both patients and many doctors were convinced that this procedure was life saving. We now know that thousands of women experienced unnecessary toxicities, prolonged hospital stays, and lost time with families for what has now been shown to be inappropriate care.⁴ Rather than repeating this tragedy with each promising new drug, we should focus our clinical energies on the optimal use of existing treatments and the enhancement of the current clinical trials system.

Access problems

Investigational drugs may not be accessible to patients even if government authorities grant patients the freedom to access them. Most doctors are likely to be unwilling or unable to assume the responsibility of obtaining adequate informed consent from patients who are desperate for treatment and often unable to dispassionately assimilate the possible risks involved.

Similar issues of liability and oversight may stop institutions from allowing open access to partially tested drugs. The issue of defining who is, or is not, terminally ill⁵ can be most difficult, let alone delineating when existing therapies might offer no possible benefit. Indeed, who will decide which of the many investigational drugs would be best for an individual patient? Do we allow the marketplace to substitute for best practices and evidence based medicine?

Many drug firms have opted not to join current expanded access programmes for drugs in later stages of development and are opposed to providing investigational products outside of approved phase II trials.⁶ The costs of drug production can be high, with limited production early in a drug's life. More importantly, there is concern that anecdotal toxicities for drugs used outside structured trials might lead to delayed approval, additional expensive testing, or adverse publicity that could jeopardise a process on which costs and profits of hundreds of millions of dollars are in the balance.

Who will bear the costs of open access to these partially tested drugs? Will government and other payers who are now seeking to minimise payments for marginally beneficial therapies be willing to pay for unproved drugs outside of formal clinical trials?

Finally, while all doctors dream of the miracle cure for each of their terminally ill patients, we must accept the duty and responsibility to conform to both the principles of evidence based medicine and the precepts of appropriate end of life care. This includes the identification of false hopes and the substitution of realistic goals, enlightened hopes, and attainable expectations. This may be the greatest test for the truly caring and compassionate physician.