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Executive Summary

AYERST's PROPOSED INDERENE TRIPLE COMPONENT COMBO NEEDS CLINICAL STUDY to establish safety and efficacy, FDA told the firm in a May 16 letter. In denying Ayerst's ANDA suitability petition for the proposed combo product containing propranolol, hydrochlorothiazide and triamterene, FDA Office of Drug Standards Director Peter Rheinstein, MD, said that "investigations are necessary," and that "the new combination cannot be adequately evaluated . . . on the basis of the information required to be submitted in an abbreviated application." Ayerst's December 1985 petition asked that the proposed combination be evaluated in reference to either of two other products, Inderal LA (long acting propranolol) or Lederle/Mylan's Maxzide (hydrochlorothiazide and triamterene). FDA responded, however, that the ANDA/patent restoration act did not authorize comparisons of a combo product to single ingredients, not did it authorize the ANDA approval route for new combination products. Rheinstein told Ayerst that "if the listed drug referred to in the ANDA has only one active ingredient (i.e., if the petition is deemed to refer to Inderal LA), neither substitution nor addition of different active ingredients is permitted." He added that "if the listed drug referred to in the ANDA has more than one active ingredient (if the petition is deemed to refer to Maxzide), substitution of one active ingredient for another active ingredient may be permitted, but addition of a new active ingredient to the existing combination is not." Rheinstein said that the act requires that where a substitution is proposed for one active ingredient for another, the two ingredients are to be of the "same pharmacologic or therapeutic class . . . or expected to have the same therapeutic effect." He noted that "such a showing could not be made where an additional active ingredient is added to the existing active ingredients in a listed drug." Rheinstein stated that "while your proposed product does represent the combining of one 'listed' drug product with another 'listed' drug product, it also represents a new combination which has never been tested or approved. Because the new combination has never been approved, the interactions of the proposed active ingredients raise questions of clinical effectiveness and possible adverse effects. The effectiveness of the new combination cannot be established without data showing that there is no negative (or positive) interaction among the ingredients of the proposed combination."

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