MILLER: A worsening medical condition

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COMMENTARY:

A cornerstone of American medicine is physicians' ability to prescribe drugs for not-yet-approved uses, based on findings in the medical literature and their own clinical judgment.

This "practice of medicine" by physicians traditionally has not been constrained by federal drug regulators; and with the exception of certain "controlled substances," such as narcotics, generally drugs have been freely prescribed and advertised.

During the last several years, however, the increasingly risk-averse Congress and the FDA have been gradually moving toward "conditional," or limited, approvals of new drugs that place various restrictions on prescribing, distribution, sale and advertising.

At the same time, legislators and regulators have imposed additional requirements for the demonstration of safety and efficacy to obtain even those limited approvals. That combination has delivered a devastating double-whammy to patients and has damaged one of the nation's most innovative and successful industries.

As a result, at a time when drug development should have been spurred by huge increases in research and development expenditures - which tripled to more than $45 billion between 1995 and 2007 - and by the exploitation of numerous new technologies, drug approvals have actually dropped. The 19 approvals in 2007 were the lowest in 24 years, and the 2008 count is running behind last year's.

Bringing a new drug to market now requires, on average, 12 to 15 years and costs more than $1.2 billion (in direct and indirect expenses). Several recent developments at the FDA will further increase the time and cost of drug development - bad news for the developers of medicines and for the sick and infirm who need new therapies:

(1) One such development is an agreement between two groups within the FDA's Center for Drug Evaluation and Research. It specifies that the drug review and drug safety offices will have equal responsibility on "significant safety issues" for medicines that are under review or already have been approved for marketing. Examples include: changes in labeling that pertain to safety; establishment or revision of a drug's risk management plan (which can range from educational programs for physicians and pharmacists to highly restrictive limits on prescribing and advertising); withdrawal of a drug from the market; and the requirement for post-approval clinical trials or epidemiological studies.

This shift of responsibility is critically important. Officials in the FDA's Office of Surveillance and Epidemiology (OSE) are focused so narrowly on "safety" that they ignore the fact that because all drugs have side-effects, safety cannot be evaluated in a vacuum but must be part of a complex cost-benefit judgment. Their motto might be, "If you don't approve any new drugs, you don't have safety problems with any."

Worse still, some of them are true-believers - not in the need for new drugs, but in the venality of drug companies and the inherent dangers of their products. A former FDA senior official summarized the inherent bias of the drug safety minions this way, "OSE has a vested interest in finding problems." Up to now, the drug safety staff has had an advisory, largely subordinate role, but the new arrangement compounds the already high risk-aversion of the FDA's new drug review divisions with the blinkered, safety-obsessed views of the OSE.

(2) Another troubling development, related to the first, is that the 2007 FDA Amendments Act gave the agency new regulatory authority for drugs that are under review or already marketed, including the ability to require Risk Evaluation and Mitigation Plans (REMS). REMS can include a medication guide, patient package insert, communication plan, an implementation system, and also must include a timetable for assessment of the REMS.

Another required component is "elements to assure safe use," which may include strict restriction of the drug to specified patient populations, distribution only by certain specialty pharmacies, required laboratory findings and/or monitoring, advertising permitted only to certain physician specialists, and patient enrollment in a central registry.

Those limitations and requirements, in effect, constitute "conditional" approvals that reduce the primacy of the physician-patient relationship by creating new obstacles to patients' getting needed medicines.

(3) A third development is an FDA advisory panel's recommendation that regulators require studies of the long-term cardiovascular risks of new diabetes drugs before they can be marketed, even if they show no sign of such problems in the usual large trials performed to demonstrate safety and efficacy. If regulators accept this recommendation, it would add tens of millions of dollars and years of delay to drug development. Ira Loss, who tracks the drug industry for Washington Analysis Corp., an independent investment research firm, was quoted in a Bloomberg wire service article as predicting a major impact on research and development of new diabetes drugs: "It would be a major setback to drug development. Anybody who is developing a drug for diabetes is at risk. If they put new burdens on the industry, it could in the worst case bring to a halt any new diabetes drugs for some time." And diabetes drugs are only a microcosm of all medicines in development.

(4) The advisory panel recommendation follows recent FDA guidance to two drug companies that their new lipid-lowering drugs would need to show not only the ability to exert a favorable effect on laboratory values - such as lowering LDL cholesterol - but that clinical trials would need also show a positive effect on "genuine" clinical outcomes, such as fewer heart attacks and strokes or even longer survival.

(5) The FDA appears to have begun to require that new drugs are not merely effective but are actually superior to existing therapies, a new standard. Wyeth chairman and CEO Robert Essner described the implications: "If you're the first company to get approved in a certain area and competitors can't get on the market, the FDA is now establishing monopolies. And that's certainly not their mandate."

Even critical cancer drugs have been treated shabbily by regulators. In a 2007 commentary in the Wall Street Journal, oncologist Richard A. Miller decried the FDA's unwillingness to grant even limited approvals to five potentially important cancer drugs that had shown significant evidence of efficacy. "In each case, the FDA overlooked substantial evidence of the drug's positive impact in slowing the progression of killer cancers and improving quality of life - evidence that should have been at least sufficient to warrant conditional approvals under established regulations that have been eroded by the Agency's bureaucratic intransigence."

The bottom line is that the new conditional approvals diminish the ability of physicians to exercise discretion and will worsen the condition of patients and drug companies. At a time when the U.S. population is aging and needs innovative new medicines for a wide spectrum of degenerative and infectious diseases, these developments are not what the doctor ordered.

Henry I. Miller is a physician and a fellow at Stanford University's Hoover Institution. An FDA official from 1979 to 1994, he is the author of "To America's Health: A Proposal to Reform the FDA."