FDA advisors delay decision on Premarin alternative

Drug Store News, August 21, 1995 by Ken Rankin

Drug manufacturers seeking approval to market a generic version of Wyeth-Ayerst's Premarin say they're a step closer to their goal despite the refusal of key Food and Drug Administration (FDA) advisors to resolve the scientific controversy surrounding these products.

At stake in the dispute: a share of the fast-growing market for conjugated estrogen drugs, which Wyeth-Ayerst has had to itself for decades due to the difficulty of formulating a generic equivalent for the company's $600-million-a-year Premarin.

At issue in the controversy: Wyeth-Ayerst's contention that the generic versions now awaiting FDA approval are not truly equivalent to Premarin because they lack a substance present in the reference product--delta 8,9 dehydroestrone sulfate. The manufacturer maintains that delta 8,9 is not merely an impurity in Premarin, but a "concomitant component" that contributes to the drug's therapeutic effect.

Although the Food and Drug Administration dismissed that argument as lacking scientific evidence four years ago, it has resurfaced as a key element in Wyeth-Ayerst's effort to block approval of generic conjugated estrogens. If the manufacturer is right and the generic versions are not effective in preventing osteoporosis, the damage may not become apparent for a decade.

That argument attracted support from a diverse assortment of groups--from the National Consumers League to the American Pharmaceutical Association--during a recent meeting of the FDA's expert advisory committee on Fertility and Maternal Health Drugs.

Testifying on behalf of APhA, University of the Pacific pharmacy professor Alice Jean Matuszak warned that if the FDA approves generic versions without first "convincingly" addressing the therapeutic equivalence issue, the agency will provoke a "crisis of confidence" in generics among the nation's pharmacists.

Generic Pharmaceutical Industry Association scientific affairs vice president Alice Till, however, characterized these arguments as "legal double-talk, speculation and scare tactics." Refusing to approve a generic without requiring Wyeth-Ayerst to prove its theories "would set a dangerous precedent for the misuses of the regulatory process to preserve a monopoly," she said.

If anything, the FDA's panel of experts appeared more confused at the end of the hearings than at the start. After listening both sides of the argument for two straight days, the advisory panel concluded that it had "insufficient data to assess whether" delta 8,9 "must be present to achieve safety or efficacy" in conjugated estrogen drugs.

That finding cheered generic firms. Officials at Duramed, the first manufacturer to seek approval for generic Premarin, called the panel's indecisiveness "welcome news," while Barr Labs, another firm awaiting FDA approval of its application, described the committee's action as "a giant step forward for generic conjugated estrogens."

As Barr CEO Bruce Downey put it, "the burden of proof that delta 8,9 should be reclassified from an impurity to a concomitant component was on Wyeth-Ayerst, and clearly they were unable to make their case."

Now, FDA Commissioner David Kessler will have to decide the fate of the conjugated estrogen market without the advice--or the political cover--of his "expert" advisors.