Industry Airs Grievances Over FDA's NDA Review Process

Industry Airs Grievances Over FDA's NDA Review Process The New Drug Application (NDA) "re-writes" recently published by the Food and Drug Administration state that the agency intends to commit itself to an increase in fruitful communication with the drug industry. A meeting held in Washington, DC, on October 7, 1983 with representatives of the industry was supposed to serve as a sign that FDA means what it says. But while industry spokesmen and FDA officials could agree on the major premise-that everyone wants drugs that are safe and effectivethere was considerable conflict about how to achieve the minor premise: an even-handed and expeditious review of the NDAs for these drugs. FDA acknowledged that, in recent years, the different approaches to INDs and NDAs taken by the agency and drug manufacturers "have reached an adversarial relationship." It was hoped by FDA that the sort of town-meeting environment of the session would prompt industry to air its ' grievances openly and so help to make contact between FDA and drug companies "more harmonious and mutually supportive." The meeting concentrated on the highly technical area of the chemistry, manufacturing, and controls submissions in INOs and NDAs, in part because a good number of NDAs founder in the review process, sometimes for months, because of FDA reviewer questions about industry data on synthesis and manufacturing specifications. FDA repeatedly emphasized the difficulty of its position in examining a company's data on a new drug entity-it lacks the years of experience the company has had with the drug, and therefore must rely on an explicit and complete disclosure of information within the NDA. Second, it said, while industry necessarily views questions about methods and procedures from within

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Dice: Data obtained sequentially

its own private "corporate culture," FDA officials must utilize information and generate conclusions that have a literally global application. Thus, said FDA, there must be as much uniformity as possible in the format and content of submissions. Speaking for industry, John Dice of Parke-Davis gave some illuminations on a research firm's special perspective. "Developing a new drug substance," he noted, "is sort of like raising a noisy new puppy," since you can only learn about how best to treat it and use it as you interact with it. "Data are only obtained sequentially," he stressed, "and we'll never know everything about the drug." Other intra-company concerns that bear upon the NDA submission include the continuous need to balance quality control standards against manufacturing costs. Further, the synthesis of the drug for use in an experimental situation will nearly always differ from the final, large-scale manufacture of the compound. Then, at one point during the session, the previously abstract differences between industry and FDA finally came to focus on a single, clear-cu tissue: the choice of meth-

odology for determining the purity of a drug substance. A representative from HoechstRoussel asserted that while FDA purported to allow flexibility in industry's choice of methods, any firm that tested purity by anything but high-performance liquid chromatography was asking for trouble. The Hoechst spokesman then said that FDA had peremptorily rejected purity data from the company simply because company chemists had determined that a different method gave more precise results. As the meeting progressed, the outlines of the more fundamental problem that impedes the interaction between government and industry in the processing of INOs and NDAs slowly began to take shape. Although the top officials at FDA claim that their" guidelines" for IND and NDA submissions are just thatguidelines-and not ironclad regulations, industry feels that the individual reviewers of the applications seem to see things differently and tend to use the guidelines as a mandatory checklist. In the words of one industry spokesman, "guidelines become frozen into regulations." Any deviation from the guideline "menu" may signal the beginning of a seemingly endless round of point-counterpoint between the submitting firm and FDA, as the reviewer doggedly seeks literal compliance with the guidelines, and industry tries to explain why such literal compliance is not appropriate for the particular drug under review. And, for the rest of us, the availability of perhaps critically needed drugs may be delayed for years because of this sort of conflict. Nor does it appear that things are likely to improve much, until FDA, with industry, can arrive at a clearer agreement about exactly what is meant by the word "guidelines."

American Pharmacy Vol. NS23, No. 12, December 1983/612