NCES tested in man in 1959 may be a statistical Aluke that represents a chance variation: for instance. in this sample the number of NCES tested in man per company in the period 1958 to 1962 ranged from as few as one to as many as 32 a year. Alternatively, a specific scientific development may have come to a peak in that year, such as the culmination of activity in many firms searching for better semisynthetic penicillins. Another possibility is that 1959 was a high-water mark of industrial enthusiasm and financial commitment after the dramatic scientific and commercial successes of the 1940 to 1950 decade. Whatever the explanation for the peak in 1959, the following years unquestionably represent a marked and permanent decline in the number of NCEs entering human investigation.

Commentaries about both investigational NCES and NDA approvals during this period tend to assume that anything occurring before or during 1962 cannot be blamed on the Kefauver-Harris amendments passed in October of that year or on the implementing regulations that followed. The 1962 legislation, however. was the culmination of 4 years of congressional hearings that attacked the pharmaceutical industry, its products, and its advertising and pricing policies. Congressman Blatnik and, later, Senator Kefauver chaired extensive hearings over those years, and the actions of the FDA and industry during the period were subject to extensive media coverage. Added to this was the growing realization of the thalidomide tragedy in Europe. Indeed, the FDA itself had published proposed new IND regulations on Aug. 10. 1962-under the existing law-2 months before the Kefauver-Harris amendments were enacted. Thus it is obvious that a change in conditions and attitude existed well before the amendments passed and that this was one likely inhibitor of both the industry's clinical ́ ́ NCE studies and the FDA's NDA approvals.

The permanent decline in investigational NCEs in the early 1960s would be expected (if no compensatory factors operated) to have led to a decline in NDA approvals after a latency period corresponding to the average INDplus-NDA time. Analysis of the yearly NCENDA approvals obtained by the nine firms

showed that after the sharp decline in the early 1960s. there was indeed a further decline in approvals (Fig. 3), which was slower but of a considerable magnitude (49%), from the mid1960s until the mid-1970s. The later decline was even more marked (71%) in the case of self-originated NCES. In a separate paper dealing with the whole U.S. pharmaceutical industry. we discuss (1) wider aspects of this link between the flow of investigational NCEs and subsequent NDA approvals and (2) the possible future significance of the further NCE decline of the mid-1970s.

Other influences, perhaps more subtle but as fundamental. were also contributing to the reduction in NCE flow. Running through this whole period, but difficult to quantify, were changes in both philosophy and state of the art. Scientific attitudes are changed by many forces. including technologic progress. In the 1940s and 1950s many in industry believed that preclinical testing was not highly predictive of a drug's clinical utility and that after a modest amount of toxicity testing, a new drug should (and safely could) be tested promptly in man. However, the public's concern about adverse drug effects prompted the FDA and industry to add many preclinical tests that had not been routinely conducted previously (e.g.. tests for teratogenicity, carcinogenicity, and recently mutagenicity). Whether or not these tests vindicated the time and money spent on them is beside the point: it became almost unthinkable not to do them, and the result-for both scientific and economic reasons-would be fewer drugs left to enter clinical testing. At the same time. laboratory scientists were becoming more accurate in predicting therapeutic activity. Today, for example, it is rare for an NCE not to show the proposed therapeutic effect postulated by chemical theory and animal experimentation. Such methodologic progress justifies more nonhuman pharmacodynamic evaluation, and again the trend would be for fewer compounds to reach clinical testing.

Finally, the scientific rules for convincing scientists about efficacy were changing. The modern controlled trial became firmly established as the premiere method for demonstrating clinical activity in an unbiased and convincing

way. Such trials, however, are more time consuming than uncontrolled ones and more likely to end ambiguously. The economic consequence is that fewer drugs can be studied clinically for a given research effort.

The flight of early clinical research abroad that began in the late 1960s seems most readily explained as industry's reaction to regulatory and economic constraints in the United States and the eventual shutdown of drug testing in prisoners. The possibility of testing drugs abroad in a less cumbersome and less expensive environment was attractive. The reversal of this trend in the late 1970s was probably related to the economic and regulatory climate abroad, where changes were occurring to reduce the benefits of foreign testing that had seemed attractive a few years before.

In the early 1960s, product candidates were dropped and time was lost as drug companies struggled to satisfy the new statute and the developing FDA regulations. With time, however, the companies increased their regulatory affairs personnel and learned how to satisfy the new requirements and the FDA. These developments may help to explain not only the return of some early human testing to the United States in recent years but the recovery in the numbers of NDA approvals in the late 1970s. Other possible explanations for the recovery of approvals include an increase in the number of NCEs that U.S. firms license from abroad, a moderation of official policy and informal regulatory attitudes in the FDA. clearing of an accumulated backlog of aging compounds, and the pass-through effect of the large increase in development time that occurred in the 1960s.

In conclusion, our studies have shown that before and coincident with the enactment of the 1962 amendments, the number of new drug candidates entering clinical testing declined sharply and permanently, and subsequently the time required for them to reach the market increased. This caused a long-lasting reduction in the number of U.S. firms' new drugs reaching the market, in addition to the immediate, direct effect of the amendments on new drug approv als. The consequences of this are far-reaching. For example, the serendipitous discovery of valuable. although unpredicted, clinical uses of

NCEs can occur only when there has been some clinical experience with the drug." Consequently, if fewer new drugs are being tested in man, the probability of finding new therapies by this method is reduced.

14

Although many drugs continued to reach the market, certain pharmacologic areas have been neglected, and some believe there has been a definite shortfall in the introduction of important new drugs in both the United States and Europe. We consider that the decline in the number of new drugs introduced in the United States is attributable in part to the 1962 amendments and the regulations implementing them and in part to the other factors discussed. In the light of these profound and long-lasting changes in the levels of clinical drug investigation and approval that resulted, it will be important to monitor the course and outcome of the new decline we have observed in the number of investigational drugs in the 1970s.23 Such monitoring needs to identify the causes of this recent change in drug development and the ultimate effects.

In addition to the National Science Foundation. which supported this study, we wish to thank many people in the pharmaceutical firms who supplied us with data and also to thank experts in the Food and Drug Administration, industry, and elsewhere who suggested explanations of our findings.

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