The FDA Should Add A Comparative Effectiveness Arm To Its Final Trials

Merrill Goozner

First published 6/16/11 on Gooz News

The Food and Drug Administration’s Prescription Drug User Fee Act is up for reauthorization next year, and so is the consumer and drug industry face-off over the contentious issue of comparative effectiveness research (CER). Consumers, patients and some physicians are demanding that CER be required of all new drugs coming to market when there are already FDA-approved therapies for the same condition. They say it will give payers and patients immediate feedback on the relative worth of the latest drugs, which are always more pricey than what preceded them, especially if the older drugs are coming off patent.

Industry opposes including CER arms in final efficacy trials. The companies claim it will place additional costs on the already expensive new drug development process; provide inadequate information for actually divining the relative worth of two competing therapies; and dissuade companies from investing in follow-on drug research, which can turn up drugs that are significantly better than older drugs.

The American Enterprise Institute’s Scott Gottlieb, who served in the FDA during the Bush administration, this week offered a lengthy brief in support of the industry position. Unfortunately, he sets up a straw man in order to knock down what could be a very effective tool for lowering the cost of medicine. It behooves industry leaders to ignore his advice, and to ignore the bleating of their marketing departments’ incessant demand for follow-on drugs.

Requiring comparative arms in Phase III trials in situations where it is appropriate will encourage companies to channel their scarce research-and-development dollars into more medically significant opportunities – therapies for previously untreatable conditions or better drugs where the current options are inadequate. A CER requirement at FDA could go a long way toward turning around the sharp decline in drug industry innovation that has occurred over the past decade.

Phase III trials are also the right time to carry out CER from a societal perspecctive. Physicians and patients are demanding this information, not only because of cost concerns but because they very often they don’t know what works best. The Affordable Care Act created the Patient Centered Outcomes Research Institute and gave it a half billion dollars a year to carry out CER. Given the hundreds of competing therapies that were developed over the last half century when there was no comparative research, PCORI already has a lot on its plate. It makes no sense to add to its burden by not collecting information about the relative medical value of future drugs. The drug development process is when CER is the easiest and cheapest to carry out, since it only requires adding one more arm to an already planned trial — not starting all over from scratch as government-funded CER will have to do.

Gottlieb claims consumers and patient advocates are demanding that “new medicines should demonstrate that they offer clear advantages over older, often cheaper drugs” before they are approved. Some may say that, but it’s a red herring. The FDA standard now for efficacy is that a new drug has to be better than nothing; in other words, it must be tested against placebo (unless it is for a life-threatening condition where there is already an approved therapy on the market; then the new therapy must be tested against that therapy, or added to it, because denying the already-approved therapy in a placebo arm in a trial would be unethical).

I do not support the position of advocates like former New England Journal of Medicine editor Marcia Angell who think new drugs should have to be proven better than what exists before they are approved. If companies want to bring comparable therapies to market, that’s their business. It may even be the case that some me-too drugs work in some sub-populations, but not in others. So if one drug fails to achieve lower cholesterol, or offer arthritis pain relief, for instance, the doctor can switch her patient to the newer drug. But if the new drug is not proven to be better than what exists in a large Phase III trial, then physicians, patients and payers will have the information they need to insist that people start on the cheapest, comparably effective medicine that is available. For most drug classes, that will mean a generic.

These non-inferiority trials do not have to be inordinately more expensive. If companies do not opt to try to prove superiority, it only requires adding a third similarly-sized arm to the final trials. While this could in theory add close to 50 percent to the cost of a final trial (going from two arms to three arms), it won’t require exponentially larger arms since they’re not trying to prove superiority. PCORI could even consider allowing companies to apply for grants to underwrite the comparative arm in a new drug trial. If it is in a therapeutic class or for a condition that the new agency has deemed important, adding the comparative arm or arms to a trial that was largely industry-funded would be substantially cheaper for the government than starting over from scratch.

A word of caution is in order before the FDA requires comparative arms in non-inferiority trials for new drugs. If the condition isn’t life-threatening, it should still require a placebo arm or insist on an adequately sized trial to avoid the “dumbing down” of new drugs. That has been a problem in the antibiotics field, where a succession of non-inferiority trials without placebo arms may have created a situation where new drugs have been approved even though their efficacy is in doubt. This is a fluke of statistics where each succeeding drug is near the bottom of the band that defines statistically significant non-inferiority. Adequately-sized trials with clear endpoints can usually avoid this problem.

Merrill Goozner is an independent health care journalist who blogs at Gooz News.

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