fda's new drug evaluation process: a general overview

Vol. 52, No. 6, Special Issue 1992 333

FDA’s New Drug Evaluation Process: a General Overview ~ _ _ _ _

Philip G. Walters, MD Deputy Director Division of Medical Imaging, Surgical and Dental Drug Products Center for Drug Evaluation and Research Food and Drug Adrninistration-HFD-I60 5600 Fisher’s Lane Rockville, MD 20857

Abstract A general overview of the FDA new-drug evaluation

process is presented with special emphasis on the regulatory requirements as outlined in the federal Food, Drug, and Cosmetic Act and the interpretive New Drug Regu- lations. Included is a description of the administrative/scientific makeup and functions of the new-drug evaluation divisions within the Center fur Drug Evaluation and Re- search. Some specifics relating to the investigative development of anticaries and plaque/gingivitis new drug products are discussed.

Key Words: Food and Drug Administration, anticaries, plaque, gingivitis, new drug.

Perhaps a brief history of the development of the Food, Drug, and Cosmetic Act, which is the legal mandate under which the FDA new-drug evaluation operates, would be of interest. Prior to 1906 the United States had essentially no effective regulation of the development, nor marketing approval, of drug products for human use. In 1906 legislation was passed authorizing the FDA to remove a drug product from the market, provided the agency could prove the product was adulterated or mis- branded. In 1938 new legislation required a drug manufacturer to provide the FDA with evidence that a new drug product was safe before that product could be placed on the American market. In 1962 the newdrug amendment required a manufacturer not only to establish the safety of a new drug product, but, in addition, to provide scientific evidence that the product was indeed effective for the claims made in the product labeling. This evidence of effectiveness was to be established through ”. . . adequate and well-controlled investigations, includ- ing clinical investigations, by qualified scientific ex- perts....” The legal mandate of the Food, Drug, and Cos- metic Act is carried out through a series of New Drug Regulations promulgated by the FDA and published in the Code of Federal Regulations.

The act and the regulations refer repeatedly to ”new drugs.” From the legal standpoint, a new drug is defined as ” . . . any drug that is not generally recognized as safe

and effective under the conditions prescribed, recommended, or suggested in the labeling ....” This pertains to drugs that have entered to the US market since 1938 or that do not have the same labeling as they had prior to 1938. In other words, a drug product could have been on the market prior to 1938, but due to post-1938 changes in the product’s labeling, it could be considered to be a new drug product. These changes include anew indication for use, a different dosage regimen, or an alteration in the dosage form.

With that brief legal background we can now take a closer look at the actual new-drug evaluation process within the FDA. This activity is carried out by the Center for Drug Evaluation and Research, which is one of six centers, the othersbeing the Center for Biologics Evalua- tion and Research, the Center for Food Safety and Ap- plied Nutrition, the Center for Devices and Radiological Health, the Center for Veterinary Medicine, and the Na- tional Center for Toxicological Research.

The Center for Drug Evaluation and Research, headed by the center director, is composed of several different offices, each having its specific areas of responsibility within the new-drug regulatory process (Figure 1). The actual evaluation of new drug products is the major responsibility of two such offices: the Office(s1 of Drug Evaluation I and 11. These offices are each composed of several new-drug review divisions-the Division of Medical Imaging, Surgical, and Dental Drug Products being one such division within the Office of Drug Evalu- ation I. In addition to the new-drug review divisions there are scientific support groups with expertise in the fields of biometrics and epidemiology, bioequivalence, biopharmaceutics, and drug advertising, to name a few.

Each of the new-drug review divisions is composed of a scientific review staff consisting of medical/dental of- ficers, pharmacologists/ toxicologists, and chemists, wi th additional legal and clerical support staffs (Figure 2). Each division is headed by a director and deputy director, who are physicians. Each review division also has an assigned biostatistician, who works with the other scientific reviewers, as well as an assigned biometrician who also works in close harmony with the other scientific reviewers. The Division of Medical Imaging, Surgical,

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334 Journal of Public Health Dentistry

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FIGURE 1 Center for Drug Evaluation and Research

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and Dental Drug Products also has a microbiology review staff that deals with, among other areas, the anti- microbial aspects of various drug products handled by the division (such as products aimed at treatment of gingivitis and periodontal disease).

The development of a new drug product in the United States, whether it be a new molecular entity, a new com- bination of known ingredients, or a new use for an al- ready marketed product, is neither a short-term nor an inexpensive process. It requires literally years of preclinical and clinical research and development prior to final

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marketing status, plus further postmarketing surveillance. Consider, for example, the overall development scheme for a new molecular entity. Such a "drug" would usually undergo one to three years of initial synthesisand animal testing before the product would be ready for its initial introduction into clinical testing. Once actual clinical testing begins, the new drug product would typically complete two to ten years of clinical evaluation, which would include three separate phases of trials, before data adequate to support a New Drug Application could be gathered and analyzed. Once a New Drug Application is submitted to the FDA for evaluation, another period ranging from two months to seven years is required before the product gains final marketing approval.

The phases of clinical trials that a new drug product goes through are referred to as phases I, 11, and I11 (Figure 3). Phase I, or the clinical pharmacology phase, has as its primary purpose identifying the basic safety profile of the drug in humans and involves as many as 50 normal volunteers. Phase 11, the controlled study portion of the clinical development scheme, involves as many as 200 patients with the actual disease or condition to be treated; the basic objective of this phase of study is to evaluate the efficacy of the product. Phase I11 may involve both a continuation of the controlled phase I1 trials, but may also involve open-label trials; phase I11 may involve up to 1,OOO or more patients and has as its basic objective

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FIGURE 3 Clinical Studies

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PHASE I - CLINICAL PHARMACOLOGY STUDIES USUALLY 1-10 MALE VOLUNTEERS (CAN BE AS MANY AS 50)

PHASE II - CONTROLLED STUDIES IN PATIENTS WITH DISEASE OR CONDITION 50 - 200 PATIENTS

PHASE 111 - BOTH CONTROLLED & OPEN TRIALS UP TO 1,000 OR MORE ADDITIONAL PATIENTS CLOSELY MONITORED BY SPONSOR FOR ADVERSE REACTIONS AND INFORMATION TO BE USED FOR SElTlNG DOSAGE REQUIREMENTS AND LABELING

TREATMENT USE INVOLVES PATIENTS WITH A SERIOUS, LIFE THREATENING, OR TERMINAL ILLNESS WHEN ALTERNATIVE TREATMENT IS NOT AVAILABLE OR NOT EFFECTIVE AND PROPOSED TREATMENT USE HAS SOME EVIDENCE OF EFFECTIVENESS

PRIMARY PURPOSE

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continued gathering of effectiveness data, as well asgath- ering of adverse-reaction data and other safety information to be used for setting dosage requirements and other important labelinginformation. In addition to these three basic phases of study, there is a phase IV postmarketing phase, which involves the continued study of a drug product in order to continue to elucidate long-term and /or rare adverse reaction potential of the product and also to identify new or broader patient populations in whom the drug may be used (such as pediatric use of a drug originally approved for use in adults only). There is also the ”treatment use” of investigational drugs, which allows for treatment of patients with serious or immedi- ately life-threatening disease when alternative treatment is not available and where the investigational drug has shown some evidence of effectiveness in early trials.

Let us now take a hypothetical new dental drug product and trace it through the FDA new drug evaluation process. What I will describe is what we would consider to be the most desirable path a hypothetical product would follow.

Prior to becoming involved with the clinical aspects of the newdrug evaluation process, the developer of the new drug product would characterize the drug from a chemical /manufacturing standpoint in order to determine the basic stability of the active ingredient and its other significant chemical characteristics. Also, certain basic animal pharmacology/ toxicology evaluations would be performed to characterize the basic preclinical

safety profile of the product (which would include acute- toxicity studies, mucosal irritation studies, etc.), which will be used to guide the clinical evaluations. If we are dealing with a new molecular entity, there will be some animal pharmacokinetic/pharmacodynamic evaluations, as well; thesestudies will also serve toguide similar clinical evaluations of the new-drug developmental pro- gram.

When the new-drug developer feels that the product is characterized adequately from a chemistry and pharmacology standpoint, so as to provide a reasonable rationale and margin of safety for human exposure, the developer will begin to assemble an Investigational New Drug Ex- emption (IND) for submission to the FDA. This exemp- tion will allow the new drug to be placed into interstate distribution for the purpose of conducting clinical trials needed to support the approval of a New Drug Applica- tion. Ideally, the developer at this point will request to meet the FDA division personnel for a pre-IND conference. The purpose of this conference is to discuss the overall background of the product, the plans for the initial clinical trials with the drug, and the basic adequacy of the preceding chemistry and pharmacology evaluations that were conducted. A general overall discussion of the developmental plan for the product would also be part of this pre-IND conference.

Based on the discussions, comments, and recommendations that come out of the pre-IND meeting, the developer would then put together a formal I N D submission.

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This document will contain all of the background chemistry, manufacturing information, reports of all of the preclinical phannacology/toxicology evaluations that were conducted, and a detailed study protocol for the intended initial clinical trial that the developer proposed to carry out. The IND, when received at our offices, will be assigned to a reviewing dental officer, chemist, and pharmacologist. Within 30 days this review team will conduct a cursory review of the application to determine if, in the team’s opinion, it is reasonably safe for the proposed clinical trial to be initiated. If there is some reason the FDA staff feels the proposed studies should not be initiated, the IND sponsor will be so notified, in writing, of the specific reasons the IND is being placed on what is termed ”clinical hold.” If there are no such problems, the proposed studies may be initiated after that first 30day waiting period. Within 60 days of receipt of the original IND, the FDA staff will complete an in- depth review of the application and will notify the sponsor again in writing of any comments, recommendations, or deficiencies regarding to the various portions of the application.

Following the submission of the original IND, the sponsor is required to notify the agency of any additional studies that will be undertaken, any new investigators who will conduct clinical studies, and any adverse reactions identified during the drug studies. The sponsor is also obligated to submit to the agency an annual report on the progress of the studies being conducted under the IND, reported adverse reactions, etc.

When the phase I and phase I1 studies with the hypothetical drug are completed and the sponsor has drafted plans for the phase I11 studies, an end-of-phase I1 conference is held. At this conference the sponsor presents the data resulting from the phase I and I1 studies, pertinent preclinical data, pertinent chemistry data, and a detailed plan for upcoming phase 111 work. This conference gives everyone involved with the developmental project the opportunity to give serious consideration to the remaining areas to be addressed and to reach agreement on these matters. Formal commitments regarding the remaining data required to support a New Drug Application are made and basic study protocol designs are agreed upon.

The phase I11 clinical trialsare then mounted. The same reporting requirements are in effect as with the earlier phases of study. During the conduct of the phase I11 trials, it is not unusual for the sponsor‘s scientific staff and the division‘s scientific staff to hold one or more meetings during which the progress of the phase 111 trials is discussed. Also, the specific content of what will be contained in the product’s package insert is developed.

After the phase 111 clinical trials are completed and evaluated by the sponsor, a New Drug Application (NDA) is submitted to the FDA. This application contains all information known about the new drug product, in- cluding any foreign marketing experience, foreign label-

ing, pertinent literature citations, etc. The application contains the results of all of the clinical studies conducted with the new drug product, as well as all the preclinical evaluations and all of the specific manufacturing information. Biostatistical evaluation of the clinical data is presented along with any and all pharmacokinetic and pharmacodynamic data that were developed. Regula- tions no longer require that all of the raw data from the preclinical and clinical studiesbe submitted as part of the original NDA submission; the application must, however, contain adequate summarizations, which should include tabulations, of these data sufficient for an adequate scientific review to be accomplished. The applicant must have available all of these raw data for future submission upon request by the FDA’s scientific reviewers. Case report forms must be submitted, however, for each patient who died during a clinical study or who did not complete a study because of the Occurrence of an adverse event (whether or not actually related to the active drug). Prior to the submission of an NDA the applicant is encouraged to meet with the reviewing staff at a “pre-NDA” conference to discuss the specifics of the content of the NDA so far as formatting, tabulation con- tents, raw data submissions, etc., are concerned. This pre-NDA conference more often than not saves considerable time in the overall review process, which, obvi- ously, is beneficial to both the applicant and the FDA staff.

After receipt of the original NDA the FDA has, by statute, 180days tocompleteitsin-depth scientific review and to take a final action regarding the approvability of that application. During this review period, problems may be identified that the review staff feels need to be corrected prior to a final approval of the application, and that inall probability can be corrected ina timely manner. These recommendations are forwarded to the applicant in writing via what are referred to as ”information request” letters. An example of such a letter would be a discussion of certain manufacturing or chemistry con- trols information that may not have been contained in sufficient detail in the application, but that in all probability is readily available. During the overall review process, it is not unusual for there to be considerable inter- change between applicant staff and FDA staff. These contacts are by telephone as well as by formal confer- ences. We feel it is often possible to solve many problems that are identified with anapplication by discussing these with the applicant during the review process, thusavoid- ing unnecessary delays in the overall review time.

When our scientific and administrative reviews are completed, an action letter is sent to the NDA applicant. This letter is either a ”not approvable,” “approvable,” or an “approval” notification. A ”not approvable” letter will contain in specific detail the reasons the application can- not be approved and the additional data and information necessary for the application to become approvable. An

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“approvable” letter usually contains labeling revisions and any additional ”minor” deficiencies that need to be corrected prior to the final approval of the application. As the term “approval” indicates, this is the notification that the application contains adequate information to establish the safety and effectiveness of the new drug product so as to allow for the marketing of the product in the US as well as export of the product from the US. A final approval may contain certain commitments that must be met post-approval, such as additional clinical studies (phase IV studies), special adverse-reaction reporting, or special monitoring of specific patient populations.

After a New Drug Application hasbeen approved, the applicant is required to report periodically to the FDA. Adverse drug experiences must be reported at quarterly intervals for the first three years post-approval (this report includes a special ”15-day alert report” for each adverse drug experience that is both serious and unex- pected). In addition the applicant is required to report annually to the FDA on matters concerning such things as drug distribution data, current professional labeling in use, certain types of manufacturing changes, and clinical and nonclinical study reports that include literature reports of studies carried out with the new drug product.

I have given a brief encapsulation of the overall new- drug evaluation process for any product utilizing the new-application procedures in order to gain marketing approval, whether that new drug product is to be for OTC or prescription dispensing. In closing, let me pass on a few specifics that would relate to dental drug products.

If one is considering a new fluoride-containing denti- frice, all of the basic processes just discussed would, of course, apply. Any dental product containing fluoride is considered to carry an anticaries claim, either directly stated or implied, since this would be the only reason for fluoride to be included in such products. The drug developer would be expected to conduct the phase I11 studies both in areas that have fluoridated water and those that do not. Most anticaries phase 111 studies, as you know, are conducted on schoolchildren, who represent the basic

target population. These studies involve as many as 2,000 children to arrive at a statistically valid number for a meaningful final evaluation. These studies are camed out over a period of two years, with baseline and periodic examinations throughout the course of the studies. In anticaries studies each patient serves as his or her own historic control for baseline purposes and one of the FDA-approved anticaries dentifrices (Colgate with MFP, Extra Strength Aim, or Gleem-2) is recommended as a positive control product. Such studies are recommended to be of parallel design with appropriate double-blind techniques utilized.

When considering a new product for the treatment of plaque and gingivitis, again the basics of new drug development apply. These indications require studies of shorter duration and fewer numbers of patients initially. Such studies are of parallel or crossover design, double- blind, and placebo controlled; an active control group may also be included and would, of course, be required if comparative claims are to be made in the approved labeling. These studies are recommended to be of six- month duration (three months on drug followed by a three-month posttreatment observation period), with an additional six-month posttreatment observation period because of persistent alterations in the normal oral flora, for example. Microbiological evaluations of the oral flora and the effects during and following therapy are of par- amount importance in plaque and gingivitis studies. As noted in the ADA’s Council on Dental Therapeutics guidelines, microbiological evaluations should be conducted at baseline, periodically during treatment, and at the end of the study period to determine both the effects of the drug product on the normal flora and to determine whether pathogenic organisms have developed. Change in the oral flora is, of course, not the only parameter considered in determining the effectiveness of such products. The various plaque indices, both quantitative and qualitative, should be considered. Gingivitis scores relating to inflammation, bleeding on probing, and measure- ment of gingival cervicular fluid are additional clinical parameters to be considered when designing such studies.

fda's new drug evaluation process: a general overview

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