A Bold Proposal for FDA Reform

A Bold Proposal for FDA Reform

Review of Free to Choose Medicine, by Bart Madden (The Heartland Institute, 2010)

In Free to Choose Medicine, veteran market analyst and Heartland Institute Policy Advisor Bart Madden describes the governmental dysfunction that has given rise to the lengthy development times and vast expense now required to bring new drugs to market, and the resulting human misery and mortality that result from regulatory delays.

Madden correctly characterizes the Food and Drug Administration (FDA) as a bottleneck that prevents the pharmaceutical industry from offering “better drugs, sooner, at lower cost,” and he proposes a remedy based on consumer choice and competition that would end the current government regulatory monopoly.

Madden recounts how “prior to 1962, after passing a drug safety test, drugs could be sold and were evaluated for effectiveness in actual use by doctors and patients.” In that year, Congress dramatically changed the regulation of new medicines, requiring for the first time that manufacturers test for efficacy as well as safety.

He notes a vestige of the pre-1962 situation can be found in the treatment of off-label drug use (that is, prescribing of an approved drug for uses not sanctioned by the FDA), and he suggests the widespread use of drugs for off-label indications shows doctors and patients need not rely on FDA-supervised efficacy testing in order to benefit from new treatments.


Challenges of Safety Testing

However, perhaps in an effort to keep the book brief and readable, Madden does not address fully some essential nuances about the real world of drug development and medical practice. First, there is no such thing as an absolute standard for a “drug safety test.” Safety is always relative, not absolute. It requires a subjective judgement that takes into consideration not only the frequency, severity, and reversibility of side effects but also the intended use of the drug. In addition, “safety trials” are seldom distinct from those that ascertain efficacy.

Second, although it is an appealing concept, the effectiveness of individual physicians making independent, systematic judgements about the safety and efficacy of unapproved drugs remains largely unproven. For one thing, unlike in clinical trials, the number of patients they treat with a given drug is usually small and the patients not comparable, and the doctors’ ability to draw conclusions may be confounded by other drugs taken by the patients.

Another possible difficulty is that the average primary care doctor or specialist in internal medicine will see many patients who develop common maladies such as diabetes and high blood pressure and who will suffer heart attacks and strokes. How is he to ascertain whether these are caused by a drug that the patient might be taking, or by other factors?


Questionable Trial Results

It is noteworthy that even formal clinical trials sometimes yield misleading results. For example, the results of a large study announced on November 14 showed a heart-failure drug called nesiritide (brand name Natrecor) was not effective for the major symptom (fluid in the lungs) that small studies had found it benefited. Likewise, it failed to replicate small studies that seemed to indicate an increased risk of kidney problems and an increased death rate.

Madden criticizes the prevailing reliance on randomized clinical trials (RCTs) as the “gold standard” for judging safety and efficacy, praising instead the alternative of “observational data (with associated inferences of cause and effect).”

But the value of observational data is limited, and the current laissez-faire regulation of herbal dietary supplements—which might better be described as non-regulation—serves as a cautionary tale about patients’ ability to make decisions about drugs. In order to exempt them from regulation, these products were classified by Congress as foods, but many are drugs by any reasonable definition—they are used primarily to cure, treat, or prevent symptoms or diseases.

Only two or three of the hundreds available have been shown to have any efficacy at all (and even those are less effective than “real” drugs), while many have severe side effects, ranging from dangerous elevation of blood pressure and allergic reactions to life-threatening interactions with prescription medicines.


Three Elements

Criticism of the 1962 drug amendments is not new, but what makes Madden’s Free to Choose Medicine proposal to reform drug regulation unique is an innovative way to share clinical trial data with doctors and their patients. Unfortunately, the proposal could be stymied by various practical and political obstacles. It has three elements:

(1) A Free to Choose track distinct from FDA regulation for people willing to accept the possibility of higher risk in return for access to unapproved drugs that might benefit them. Patients would be able to choose drugs from a pool of medicines that “have successfully passed their safety trials and generated preliminary efficacy data.”

(2) The creation of a Tradeoff Evaluation Database (TED) available on the Internet so that “patients and their doctors have access to up-to-date information about the risks and comparative effectiveness of approved and not-yet-approved drugs.” It would include all clinical trial data (not just selected favorable results) as trials were completed. Patients and their doctors would thereby have access to as much information as the FDA.

(3) “Conditional” FDA approval, a new level of regulatory sanction that would be based on “a combination of results from clinical trials and Free To Choose Track use.”


Obstacles to Success

Some things stand in the way of each of the program’s success, however. Having reviewed applications for approval as an FDA official, I can testify that pre-Phase III data are extremely difficult to interpret, even for experts—they are disjointed, come from trials of varying designs, and often are the results of testing for many different indications. And because many of the trials are small, statistical considerations can be confounding; the number of safety and efficacy events may be insufficient to instill confidence the results do not arise by chance.

Madden argues a second track for the availability of new drugs that would compete with the FDA would spur regulators to streamline their review and approval procedures, reduce drug development costs, and ultimately lower prescription drug prices. The FDA, however, has proven highly resistant to external pressure, and Congress has in recent years moved regulation in the opposite direction of Madden’s approach, markedly increasing the FDA’s mandates, power, and risk-aversion.

As Competitive Enterprise Institute public policy scholar Gregory Conko has pointed out, drug developers may not be quick to opt in to Madden’s proposed system. (Participation in the Free to Choose track would be voluntary.) Participation may be undermined by concerns about tort liability; the need to reveal confidential business information in the publicly accessible database; and early access making it harder to enroll patients in placebo-controlled clinical trials.


Turning the Tide

As Nobel Prize winner Milton Friedman and coauthor Rose Friedman observed, “once a tide in opinion or in affairs is strongly set, it tends to overwhelm counter-currents and to keep going for a long time in the same direction. The tides are capable of ignoring geography, political labels, and other hindrances to their continuance.” However, the Friedmans continued, the very success of these tides “tends to create conditions that may ultimately reverse them.”

No matter how obvious and persuasive the arguments for reform of the drug approval process, the fundamental changes needed to turn the tide will occur only if the public demands them. By proposing changes in drug regulation, Madden would like to stimulate grassroots demand for reform that will become “one of the most popular and vocal movements of our times.” I wish him success.

Henry I. Miller (think@heartland.org), a physician and molecular biologist, is a fellow at Stanford University’s Hoover Institution. He is the author of To America’s Health: A Proposal to Reform the FDA (Hoover Institution Press, 2000).

Internet Info:

Free to Choose Medicine Web site:


Bart Madden discusses Free to Choose Medicine: