FDA and Drug Approval!

Gerald A. Faich MD, MPW

Index term: Drugs

JVIR 1995; 6:24S

1 Address correspondence to G.A.F., Phar­maceutical Safety Assessments, Inc, 104Foxhall Lane, Narberth, PA 19072.2 Paid consultant for Abbott Laboratories.

© SCVIR, 1995

DRUG regulation spans from ani­mal studies through the postmarket­ing period. Developmental studies(phases I-III), approval, labeling,and cost-effectiveness are exten­sively addressed by the U.S. Foodand Drug Administration (FDA).Unlabeled use, promotion, and cost­effectiveness claims have receivedparticular attention in recent years.

Typically, drug development re­quires 8-10 years including investi­gative (preclinical and clinical-IND)work and time for New Drug Appli­cation (NDA) preparation, submis­sion, and approval. There has beensome shortening of FDA review timefrom 24 to 19 months in the past 2years. Nonetheless, the process ofdrug development and approval isremarkably protracted, difficult, andexpensive. Some estimates are thatit costs over $300 million to bring anew drug to market.

Drug approval is dependent onsubstantiation of efficacy and safetybased largely on two well-performed,adequate, randomized, controlledtrials conducted by qualified experts.Clinical and statistical differencesbetween the active agent and pla­cebo, surgery, and/or another activeagent must be shown. The definitionof primary and secondary outcomemeasurements, power estimates,and monitoring for protocol adher­ence and data verification are cru­cial to the successful conduct oftri­also

Once the agent is approved, theproduct label (package insert) is de­veloped by the drug sponsor and ap­proved by the FDA. This describesindications, doses, efficacy, andsafety of the product. Such labeling

should be seen as a contract be­tween the FDA and the sponsor forthe allowable use claims of the prod­uct.

While initial marketing and label­ing are strictly regulated by theFDA, the agency does not regulatethe unlabeled use of marketed drugsby practitioners. However, pharma­ceutical manufacturers are prohib­ited from promoting off-label use.This prohibition extends to the needto ensure only "hands-off' involve­ment in continuing medical educa­tion where objectivity, fair balance,and independence of program con­duct must be maintained.

Cost-effectiveness studies and as­sociated claims have become in­creasingly important to both man­aged care and the FDA. Usual phaseIII trials examine drug effects in thehighly atypical setting of carefullyselected patients and investigatorswith intense monitoring of dosingand outcomes. While having high in­ternal validity, generalizing to "realworld" patients and use is often dif­ficult. Preapproval data may be lim­ited by duration oftrials, the exclu­sion of complicated patients, andcomedication. To obtain effective­ness data, larger simplified trialsare often needed. These may be con­ducted in late phase III or phase IVand must focus on outcomes, careutilization, and comparisons be­tween alternate therapies. Thisevolving area may be subject to FDAregulation because advertisingclaims will derive from such studies,and the FDA has said it intends toreview the scientific basis for suchclaims.

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