The Role of the Food and Drug Administration

Russell Katz

The views expressed in this article are those of the author and do not reflect an official position of the Food and Drug Administration.

Introduction

Legal authority for the regulation of drug and biologic products moving in interstate commerce in the United States and for granting approval to market drug and biologic products rests with the Food and Drug Administration (FDA), an agency of the Public Health Service in the Department of Health and Human Services. Practically speaking, this means that an investigator who wishes to administer an unapproved drug product to a human being must do so under an Investigational New Drug (IND) application that has been submitted to the FDA. Although any qualified individual may submit such an application (and a large number of such applications are submitted by individual investigators), this chapter is largely concerned with issues of drug development faced by commercial sponsors intending to bring a drug product to market. The relevant laws and regulations governing research with investigational drugs, as well as standards for marketing of new drugs, have been described in detail elsewhere.¹^,²^,³

Although many of the issues encountered in the development and evaluation of antiepileptic drugs also pertain to drugs of other classes, epilepsy does present a number of relatively unique problems for the regulatory agency, as well as for the sponsor. These problems range from the general, such as the choice of the appropriate clinical trial designs, to the specific, including such fundamental aspects of trial conduct as the appropriate collection of the basic data on which an adequate interpretation of the study depends. Most of these issues and problems have arisen in the context of the three most recent New Drug Applications (NDAs) acted on by the FDA.

Clinical Trials

Add-on Trials

The most fundamental question that needs to be addressed is the appropriate design for the adequate and well-controlled clinical investigations required by law in determining the effectiveness of a treatment. By far the most commonly employed clinical trial design currently being utilized by sponsors is the so-called add-on design, in which patients not adequately controlled by optimal therapy with currently available treatments are randomized to have the investigational therapy added on to their current treatment regimen, or to have placebo added on to their current treatment regimen. This trial design has great appeal for two reasons: First, ethical concerns regarding the use of placebo do not arise, because those patients who receive placebo continue to receive their standard treatment. Second, the trial is designed to demonstrate the superiority of the investigational treatment over the placebo treatment; in other words, the trial is designed to demonstrate a difference between treatments. Studies designed to demonstrate an equivalence between treatments (e.g., a study comparing the effects of an investigational antiepileptic drug with a standard antiepileptic drug) ordinarily cannot be interpreted unambiguously.⁴^,⁵

The standard add-on trial is not without problems, some of them structural, and therefore not fixable, and some related to study conduct, which can be handled. In the first place, this type of study can be relied on to offer conclusions about the new treatment only in combination with other antiepileptic drugs; that is, it is incapable, by design, of addressing the question of whether the treatment in question is effective when given alone, as monotherapy. It is possible that a therapy, because of pharmacodynamic interactions, is effective only in the presence of other antiepileptic drugs, but not by itself. Some consider a demonstration of effectiveness only in add-on trials to be an inadequate basis for the approval of a proposed new treatment for epilepsy; however, as of this writing, it is clear that the FDA is willing to permit marketing solely on the basis of data from add-on trials.

Add-on trials pose other difficulties. Beyond any potential pharmacodynamic interactions, most investigational antiepileptic drugs have pharmacokinetic interactions, often complex, with standard antiepileptic drugs. Unless the plasma levels of the (unbound) standard treatments are tightly controlled in a clinical trial, any apparent effect (beneficial or negative) of the new treatment may simply be the result of an alteration in the plasma level of one or more of the concomitant antiepileptic drugs. Unfortunately, sponsors ordinarily do not adequately characterize or quantify the possible kinetic interactions between their treatment and individual standard antiepileptic drugs, let alone the highly complex interactions that may occur when a new treatment is added to a regimen consisting of several concomitant antiepileptic drugs, before these same combinations are used in definitive clinical trials. Then, once the trials begin, plasma levels of the standard antiepileptic drugs are often not monitored with sufficient frequency or rigor to provide assurance that they are indeed constant. Given these conditions, it is often impossible to address this crucial question with adequate data.

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