Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
C. WHITE PAPER ON THE THERAPEUTIC EQUIVALENCE OF CHEMICALLY EQUIVALENT DRUGS
WHITE J?APER ON THE THERAPEUTIC EQUIVALENCE OF CHEMICALLY EQUIVALENT⢠DRUGS Prepared by a Subcommittee of the Policy Advisory Committee Drug Efficacy Study Recent reports of considerable variation in the serum levels, and therefore in the probable biological activities, of equal doses of cer- tain drugs marketed by different manufacturers, focus attention upon an important determinant of drug efficacy. These variations indicate that therapeutic equivalence, or equal biological activity, cannot necessar- ily be inferred from equivalence in the chemical constitution of differ- ent formulations of the same drug. In the Drug Efficacy Study, it has been found that, in many cases, no data bearing on biological activity of chemically equivalent drugs is available other than those submitted by the manufacturer who originally filed a New Drug Application for his product. For this reason, the following qualifying addendum was approv- ed by the Policy Advisory Committee of the Drug Efficacy Study and was forwarded to the Food and Drug Administration with each of the 26 groups of reports of the Drug Efficacy Study: Drugs of identical chemical composition (so-called generic drugs) formulated and marketed by numerous individual firms under generic or trademarked names have been evaluated for efficacy as a group without consideration of "therapeutic equivalence". In the event that no evidence for pharmacological availa- bility or therapeutic efficacy in man can be pre- sented for any of the drugs in the attached listing, their classifications of effectiveness may need to be modified if future regulations of the FDA require such proof. This statement defines the problem but offers no solution. Theoret- ically, biological tests in man of every formulation of a drug would be needed in order to establish proof of therapeutic equivalence. In many, but not all, instances, blood levels might be a satisfactory index of therapeutic activity as well as of the absorption of oral preparations. Furthermore, if appropriate chemical or physical tests should be found to correlate consistently with serum concentrations, these in vitro tests might be substituted for the more burdensome tests in animals or man. Indeed, blood levels in animals can be acceptable tests only if they cor- relate with comparable observations in man. The more potent the pharma- codynamic action of the drug, the more imperative would be the need for ⢠Drugs that meet the current standards of identity, purity and quality of the active ingredients established by competent authority. 241
proof of the equivalence of biological and physical or chemical tests. The Policy Advisory Committee of the Drug Efficacy Study is aware that consistent evidence of therapeutic equivalence of oral preparations, even when based upon simple study of blood concentrations in man, might require the testing of each lot of each formulation and so become a large-scale clinical operation requiring consent of large numbers of patients and volunteers. A strict interpretation of therapeutic equiv- alence might even require biological tests of individual capsules or successive batches of the drug selected at random. Moreover, variations in biological response of individual subjects would seem likely to be greater than compositional differences among enteric-coated tablets or timed-release capsules. Let us not deceive ourselves: if tests in human subjects constitute the only reliable method of demonstrating therapeutic equivalence, an unacceptably large burden will be imposed on drug manufacturers. Such biological tests may represent the most valid measure of comparative therapeutic activi- ties, but the measure is one that is impossible of technical achieve- ment by the pharmaceutical and medical professions. What, in this less than perfect world, can be done? All producers of drugs should be required, as they are now, not only to provide evi- dence of ~omposition, purity, and quality but also evidence of physical availability as judged by tests of disintegration, dispersion, and dis- solution rates in appropriate solvents. In the majority of cases, this should suffice, but in every case in which there may be doubt of bio- logical equivalence (e.g., calcium added to tetracycline), biological tests should be required. The exploration of possible chemical, physical, and animal tests that might satisfactorily be substituted for biological tests in man has already begun, and this should most certainly be encouraged. Par- ticular attention is being paid to relatively insoluble drugs dispensed in solid forms as tablets or capsules. A Joint Panel of the United States Pharmacopeia and the National Formulary has been at work fqr some months on the development of standards and test procedures Ja~ that will permit better definition of physiological availability. Bio- logical data on the lack of therapeutic equivalence of various prepara- tions of chloramphenicol recently dramatized this problem ⢠Criti~al investigation of the chemical and physical properties of these prepara- tions is currently in progress, and such investigations should certainly be encouraged. The whole subject will require extensive scrutiny as well as close attention to process control of the uniformity of the chemical and phys- ical properties of both generic and trademarked preparations. Appraisal of problems concerned with particular drugs will represent various de- grees of medical, as well as technical, difficulty. For example, are high blood concentrations of short duration medically more desirable than lower, more prolonged, concentrations? The decision would be quite 242
- - ---·-- ... ~--·- -- different in the case of an antibiotic in contrast with an anti-epileptic preparation. What if a generic formulation turns out by such criteria to be biologically superior to the original proprietary? What if blood concentrations cannot be measured? With some drugs, there are reasonably good analytical methods for biological assays, whereas for others a meaningful test is virtually impossible at this time. Consequently, the problem of the biological equivalence of drugs should be approached expectantly and progressively. Critical evidence of chemical and physical equivalence is the first order of business. Obviously, new drugs and ac cepted drugs of greatest pharmacodynamic a ction or therapeutic importance may additionally re- quire careful biological scrutiny. It would seem reasonable for the FDA to require that the generic manufacturer submit, in addition to evidence of chemical equivalence and purity, data on dissolution rate and data from other in vitro tests demonstrating equivalency. However, if there is evidence that in vitro evaluation or animal tests do not correlate well with pharmacodynamic effects in man, there may be need to resort to clinical tests. In this way, the principle of generic prescribing based on therapeutic equiva- lence may become acceptable to the medical profession and be supported by the pharmaceutical industry. W. B. Castle, M.D., Chairman E. B. Astwood, M.D. Maxwell Finland, M. D. Chester S. Keefer, M.D. 243
