Problems in Clinical Evaluation of Drug Therapy

PROBLEMS IN CLINICAL EVALUATION OF DRUG THERAPY MINDEL C. SHEPS, M.D* I. The Current Climate It is estimated that in the year 1959 retail pharmacists in the United States filled 712 million prescriptions (1)—an average ofnearly four for every man, woman, and child in the country. An additional, probably not inconsiderable, number ofdrugs are dispensed to patients in mental hospitals , in outpatient clinics, and bythe armed forces. A total estimate ofdrug use would also have to include the medications given to the 22 million patients admitted to hospitals in that year. In one general hospital, for example , medical patients received an average offour drugs daily, administered ten times per day (2). Drugshavealways beenanimportant aspect oftherapy, and strange and ineffective substances have been popular. During the rise ofscientific medicine , "the medical profession as a whole does not seem to have paid the slightest attention to the struggling science ofexperimental pharmacology. It chose to notice, not the heroic efforts ofmen like Wepler or Daries, but the thousands of fake or absurd 'remedies' listed in the vast collections of the sixteenth and seventeenth centuries called pharmacopoeias, dispensatories , and formularies. A German pharmacopoeia of the middle of the seventeenth century contained descriptions ofsix thousand drugs" (3). In the nineteenth and early twentieth centuries, unwarranted and irrational practices evoked "therapeutic nihilism," which decried most drug therapy. Whatever the influence oftherapeutic nihilism on practice in its time, the more recent discovery of dramatically effective remedies for a variety of diseases has led to a greatly increased use of pharmaceuticals. Since the technological revolution in the manufacture ofpharmaceuticals, * Department ofBiostatistics, Graduate School ofPublic Health, University ofPittsburgh. 308 Mindel C. Sheps · Clinical Evaluation ofDrug Therapy Perspectives in Biology and Medicine · Spring 1962 a constant stream ofnew products promoted according to the latest advertising methods has further stimulated their use (4). Despite the undisputed benefits ofmodern pharmaceutical preparations, many observers are concerned about the current situation (4-9). Besides questioning the need for the sheer volume ofdrugs used, they have cited undesirable prefabricated mixtures, the disquieting frequency ofiatrogenic diseases, and the fact that it may take years after a drug has been widely marketed before its advantages and disadvantages are evaluated. Particular attention has been paid to the confusing, unnecessary, and costly multiplication of similar drugs. In a paper which has already provoked at least one criticalcommentfrom the industry (10), Modell (7) stressed theharm done by the plethora ofhurriedly introduced products recommended for similar indications. To identify the few most desirable preparations and eliminate redundantagents before release, he proposed cross-licensing to allowlargescale co-ordinated clinical trials ofan entire group ofdrugs regardless of their commercial origin. Other suggestions include changing the patent laws (8) and assigning to the Food and Drug Administration responsibility for having independent outside agencies determine the clinical efficacy of new drugs before release on the market (8, 11). Legislation incorporating some ofthese suggestions is currently under consideration. Too often reports oftherapeutic tests published in medicaljournals fail to meet the criteria that are normally applied to scientific investigations. Consequently, it has been urged elsewhere that medical journals adopt more critical standards for clinical papers, that organized medicine enforce minimum standards for clinical trial of drugs generally and of nonapproved drugs particularly, and that physicians refuse to prescribe a preparation before they are convinced by published evidence that the product is the best available therapy for the patient (9). The practicing physician faces a dilemma. He is often subjected to conflicting claims without evidence from acceptable clinical evaluations sufficient for a reasonable choice. Furthermore, his education has not always instilled that critical approach to evaluating therapy which is needed now even as in the days ofblood-letting (12). He is not always immune to the fallacy of crediting a drug with improvement which may be related to some other concomitant factor (13), despite the emphasis on this fallacy since Gideon Harvey's aptly named book The Art of Curing Diseases by Expectation was published in 1689 (14). 309 The rise ofthe science ofpharmacology and the explosive rate ofproduction ofnew drugs have made the controlled clinical trial increasingly important in the search for valid evidence oftherapeutic efficacy. The scientific principles that should underlie the trial have...