pharmacologic types, and the subsequent fate of the NCES, to the point at which they either obtained NDA approval or were withdrawn from active research. Corresponding data on NCES tested from 1963 to 1979 were taken from responses to previous surveys.

The data on marketed NCEs were obtained from our earlier studies and from publicly available sources..

Quality of data obtained. Although this survey was more limited in scope than our earlier ones, the data we obtained on drugs investigated in the pre-1963 years was more variable and less complete. Approximately 5% of the values were either missing or ambiguous for the pre-1963 drugs because of the age of the data and the fact that, since there was no official requirement for external reporting prior to 1963, company internal records were the only source of information. We were able, however, to clarify a number of points in discussions with company personnel who compiled the information, and we believe that the data are now the best available on pre-1963 research. Although some NCES entering clinical trials in 1958 to 1962 have probably been omitted, such omissions would only cause us to underestimate the size of the large decline in NCEs entering clinical testing that we found to have occurred over the 1958 to 1962 period.

Terminology: IND-equivalent NCES. To avoid cumbersome terminology, the abbreviation "IND" is used to denote the first IND filing on an NCE from 1963 (when IND requirements were implemented) onward. The abbreviation "IND/eq" (IND equivalent) is

used to denote the first administration of an NCE to man in the United States before 1963. The abbreviation "IND/eqs" is used to refer collectively to both groups of NCES: those for which NDS were filed and those that were first tested in man in the United States before 1963.

Results

Number of NCEs under clinical investiga tion, 1958 to 1979. Table I summarizes data supplied by the nine major firms on their NCE research. Over the whole period from 1958 to 1979, 981 NCEs were investigated clinically, of which 804 (82%) were self-originated NCES and 174 (18%) were acquired. Nine hundred twenty-two IND/eq filings were made on the total NCE cohort, of which 749 were selforiginated NCES and 170 were acquired. Most of the remaining NCEs were not brought to the United States. By the end of 1979, 99 of the 111 NDAS submitted had reached approval; these consisted of 66 approvals from 76 submissions on self-originated NCEs and 33 approvals from 35 submissions on acquired NCES.

Table I also shows the number of NCEs investigated in the 5 years (1958 to 1962) that preceded enactment of the IND requirements and the number investigated in the 17 years that followed (1963 to 1979). This comparison reveals that the annual number of NCEs entering clinical testing was far higher in the pre-1963 years than it was thereafter. Nearly half (48%) of the NCES were first investigated in 1958 to 1962: whereas the remaining 52% were spread over the subsequent 17 years.

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A detailed picture of the annual rate of entry of NCES into clinical investigation between 1958 and 1979 is shown in Fig. 1. After the first observation in 1958. there was a steep rise in 1959. Then beginning in 1960, there was a sharp decline for 4 consecutive years with the largest drop (67%) from 1962 to 1963. Comparing the 5-year period 1958 to 1962 to the following decade, 1963 to 1972, there was a 60% overall decline from a mean of 89 a year to 35 a year. In the last 5 years of the survey (1975 to 1979) the mean rate declined further, to 17 a year—an 81% drop from the pre-1963 average level.

Fig. I also shows the number of selforiginated NCEs studied in man each year. Since self-originated NCES account for approximately 80% of the total sample, they fellow trends that are similar to those for all NCES. Entry of self-originated NCEs into clinical test

ing dropped sharply in the early 1960s and continued to decline thereafter.

From 1958 until the late 1960s, only 3% or less of self-originated NCEs were first tested abroad (Fig. 1). In the first half of the 1970s. however, a strong trend developed toward initial testing abroad. This trend peaked at 60% in 1975. The proportion has since fluctuated but in general has declined: in 1977 to 1978 only 21% of self-originated NCEs entered clinical trials abroad, although the percentage rose to 45% in 1979. The trends shown here for the nine firms are similar to those we observed for all U.S. firms over the period 1963 to 1979.23

Fig. 2 shows the number of IND/eqs filed on self-originated and acquired NCEs and the percentage of those that were self-originated. Although IND/eq filings by the nine firms have decreased over time, the self-originated percentage has remained at approximately 80%.

Time required to reach NDA approval. We compared the average time required for NCES to progress from IND/eq filing to NDA approval at the beginning and at the end of the observation period. Self-originated NCEs that entered clinical trials between 1958 and 1963 averaged 54 months from INĐ/eq filing to NDA approval, whereas those approved between 1972 and 1979 averaged 112 months."

Comparison of pharmacologic types of NCEs under investigation in 1958 to 1963 and in 1975 to 1979. We compared pharmacologic types of the NCEs investigated in the

With a data base of this type that has fixed start and finish doses. in order to avoid biases because of start-up artifact and right censoring of the data, one must calculase values for the early years by the dase of IND/eq filing and values for the later years by NDA approval. This removes one rype of bins but makes the values not exactly comparable, so that the precise size of the increse cannot be obtained from these values.

first and last 5 years of the survey period (Table II).

The emphasis on certain pharmacologic areas has changed. In particular, psychotropic and neurotropic drugs, analgesic and anti-inflammatory drugs, and drugs acting on the motor system and on body fluids and electrolytes accounted for larger percentages of the pre-1963 NCES than the 1975 to 1979 NCES. On the other hand, cardiovascular, endocrine, and digestive system drugs accounted for smaller percentages in the pre-1963 period than they did in 1975 to 1979.

This comparison also highlights the decline in the number of NCEs entering clinical investigation. Although the 11 major pharmacologic areas in Table I accounted for approximately 90% of the NCEs under investigation both in the pre-1963 period and in the last 5 years, they

previously encompassed many more NCES (420 and 77).

New drug approvals, 1950-1980. In addition to studying the entry rate of drugs into clinical research, we also examined the approval rate of drugs for the market. The total number of NCE-NDA approvals granted to the nine firms each year from 1950 to 1980 and the number granted for self-originated NCES from 1963 to 1980 are shown in Fig. 3. This graph shows that the number of NCE-NDA approvals fell sharply in 1961 from a mean of 10.6 a year in 1950 to 1960 to a mean of 5.4 a year in 1961 to 1967 (a decline of 49%). The decline continued from the mid-1960s to the early 1970s, to a mean of three a year in 1968-1975, with an overall decline of 72% from, the 1950-1960 level.

The number of self-originated NCEs approved (shown in the dashed line of Fig. 3),

declined even more (71% from the mid-1960s to the early 1970s alone) to only one a year. Subsequently the numbers recovered, so that by 1980 they had returned to the levels of the early 1960s. These trends are similar to those shown for NCE drug approvals granted in the same period to all U.S.-owned pharmaceutical irms.

Discussion

The manner in which pharmaceutical firms in the United States could test their drugs in man and obtain NDA approval for marketing changed importantly with the passage of the Kefauver-Harris Drug Amendments on Oct. 10, 1962, and issuance by the FDA of procedural and interpretative regulations that came into effect on Feb. 7, 1963.168.9 Before 1963 the regulations governing clinical trials on INDS did not require either an initial notice to the FDA or

subsequent reports on ongoing trials. Under the new regulations a sponsor who wished to test a new drug or antibiotic in man had to file with the FDA a notice of claimed investigational exemption" (IND) before clinical trials could commence. For the first time the FDA required substantial information before clinical work could begin. This information included data on the nature of the new drug, the preclinical toxicity tests that had been performed, the proposed plans for clinical trials, and the identity and qualifications of the investigators who had to supervise and be responsible for the trials. Informed consent of clinical subjects was also required for the first time. The subsequent clinical research was to be closely monitored, and detailed reports on its progress were to be filed regularly with the FDA. If the FDA deemed the plans inadequate or the trials unsafe, it could require corrective action or termination of the studies.

The criteria for approving an NDA also changed in 1962.1.8.8.9.15.18 The provision in the 1938 act that had required the FDA to approve an NDA automatically 60 days after its submission was dropped: the requirement for premarket notification was changed to a requirement for premarket approval. A requirement was added that the manufacturer should pro

"Automatic approval was granted unless the FDA deemed within that time that the information supplied was incomplete or that more time was required (up to 180 days) to review the application.

vide "substantial evidence" through "wellcontrolled investigations" to show that a drug was effective, as well as safe, for its proposed indications. The impact of the efficacy provisions on drug development in 1962 and the years immediately following is not clear-cut. however, because it took almost 8 years for the FDA to establish detailed criteria for "wellcontrolled investigations:" these regulations were not made final until May 8, 1970.

Although the effects of the 1962 drug amendments on the number of drugs being marketed in the United States since 1962 have been analyzed extensively.12.11.12.18.19 there have been no previous studies of the other primary intent of the amendments, namely to control clinical drug research. Our study shows how large the impact was: the amendments were associated with a steep reduction (by 60% or more) in the number of NCEs entering clinical testing. In subsequent years there was a corresponding decline in the number of NCEs reaching NDA approval, an increase in the time required to do so, and a further reduction of NCES entering clinical testing.

The temporal changes described in this paper are complex, and the reasons for them are complicated as well. The peak in the number of

The 1938 law required that the drug be safe for its intended uses. Although proof of efficacy had not formally been required, the safery judgment had presumably been made in light of the drug's intended uses and information about its efficacy.