The drug lag revisited: comparison by therapeutic area of patterns of drugs marketed in the United States and Great Britain from 1972 through 1976.

This study describes rates and patterns of new drug introductions in the U.S. and Britain from January, 1972, through December, 1976, updating an earlier study that described the patterns over the previous decade. This comparative international approach enables overall effects of different regulatory, industrial, and other types of changes in drug research and development in the two countries to be evaluated. Numerical differences persisted. In the 1972 to 1976 period, 82 new drugs appeared for the first time in either country. Only 29% of these became mutually available in both countries, 2.4 times as many becoming available first in Britain as in the U.S. Of the 71% that became exclusively available, 2.6 times as many became available in Britain as in the U.S. More important than numerical data are clinical implications of differences between the countries. The largest differences have narrowed since the previous study, but important categories in which the U.S. still lagged behind Britain in December, 1976, included cardiovascular drugs, peptic ulcer drugs, and central nervous system drugs--including therapies for depression, epilepsy, and migraine. Several factors contributed to the narrowing of U.S.--British therapeutic differences, including more realistic regulatory practices and higher quality clinical studies in the U.S., more conservative practices in Britain, attention drawn by previous studies to anachronisms in the U.S., and industrial changes such as more efficient penetration of the U.S. market by foreign firms. It is difficult to determine the relative contribution of each of these factors to the narrowing of the international difference.

Drug discontinuations in the United Kingdom and the United States, 1964 to 1983: issues of safety.

Since the modern era of drug regulation began in the early 1960s, fewer new drugs have been approved for marketing in the United States than in the United Kingdom. We examined whether information can be obtained about the relative safety of higher and lower introductory rate policies by comparing each country's record of drugs that have been discontinued (removed from the market, withdrawn, or whose licenses were allowed to lapse) while a question of safety existed. We have compiled a list of both older (approved before 1964) and newer (approved in 1964 or later) chemical entities discontinued in the last two decades. With the aforementioned broad criteria to define "discontinuation," and to assess whether a question of safety was involved, our study showed that a total of 24 chemical entities have been discontinued in the United States or the United Kingdom. Nearly half (10 drugs) were products that had been approved in both countries, while the remainder (drugs that had been exclusively available in one country or the other) consisted of four drugs in the United States and 10 in the United Kingdom. Among the drugs introduced during the last two decades, five have been discontinued in the United States and eight in the United Kingdom. Each country's record of discontinuations has been remarkably similar for drugs introduced after 1974: Four have been discontinued in the United States and three in the United Kingdom. Since drugs discontinued while a safety question existed represent only 2% of the new chemical entities introduced, it appears that drugs that reach the market under the prevailing regulatory systems are seldom associated with unacceptable toxicity.

New drug development during and after a period of regulatory change: clinical research activity of major United States pharmaceutical firms, 1958 to 1979.

The 1962 drug amendments fundamentally changed the way in which U.S. pharmaceutical firms could test new drugs in man and receive New Drug Application (NDA) approval. Although it is well known that the amendments and associated events caused a profound decline in the annual number of new drugs receiving NDA approval, the amendments' effects on clinical research into new chemical entities (NCEs) have not been investigated because data were unavailable. To study this we requested drug development information dating back to 1958 from most major United States-owned pharmaceutical firms and obtained complete responses from nine. The results showed that the introduction rate of NCEs into human testing dropped sharply in the early 1960s and declined substantially thereafter. The number of NCEs entering human testing fell from a mean of 89 a year in 1958-1962, to 35 a year in 1963-1972 (a reduction of 61%), and to 17 a year in the last 5 years of the survey, 1975-1979--an overall reduction of 81%. The number of NDA approvals received by these firms fell sharply by 49% in the early 1960s and more slowly for 10 years thereafter, from the mid-1960s to the mid-1970s. In the case of self-originated NCEs, the size of this later fall was 71%. Causes of these changes in NCE flow include the amendments and the events that prompted them; changes in scientific philosophy, standards, and state of the art; and economic factors.

Methodology for demonstrating sustained efficacy of hypnotics: a comparative study of triazolam and flurazepam.

To test for sustained hypnotic efficacy, triazolam (0.6 mg) or flurazepam (30 mg) was given to chronic insomniac patients for 7 consecutive nights in parallel, double-blind design. Triazolam at this dose was an effective hypnotic by all usual subjective measures and did not produce appreciable hangover. Flurazepam performed similarly. For either drug, comparison of the mean scores for the first 2 nights with that for the last 2 nights for any of the parameters did not reveal any significant difference. Thus, both triazolam and flurazepam showed sustained efficacy for 1 week at these doses. Some interesting theoretical and practical questions about the measurement of sustained efficacy of hypnotics in situations of repetitive dosing were addressed by the study. While a placebo control is desirable, the results obtained may be uninterpretable. An acute-care hospital setting may not be the ideal setting for doing such studies. There were indications from the study that the first-night results in a hypnotic clinical trial may be atypical.

The rate of development of new drugs in the United States, 1963 through 1975.

Information was obtained on 1,103 new chemical entities (NCEs) first tested in man from 1963 through mid-1975 by 36 U. S.-owned and 10 foreign-owned pharmaceutical companies operating in the U. S. Of these NCEs 1,029 reached the stage of IND filing. The portion of the U. S. industry responsible for the NCEs was relatively concentrated; 7 of the 36 companies accounted for half of the NCEs and 4 of these accounted for one-third. Although the annual worldwide rate of testing of NCEs by U. S. companies appeared to rise and then fall from 1963 through 1966, since 1966 the rate has been fairly constant. With time, however, a higher proportion of U. S.-owned NCEs is being first studied in man abroad. The annual rate of IND filings for U. S.-owned NCEs generally declined from 1965 to 1972, whereas the rate was fairly constant for foreign-owned NCEs over the entire period. The overall success rate in drug development has been low; nearly 90% of the NCEs studied in man are dropped prior to NDA submission, but about 88% of the NDAs submitted are approved for market. The 1974-1975 data indicate that the mean durations of the IND and NDA phase were then 4 and 2 years, respectively. However, there were variations in the time required for DNA approval between different pharmacologic areas. The data described in this paper represent the first baselines against which future trends in the processes of drug development and approval can be measured.

New drug development by United States pharmaceutical firms with analyses of trends in the acquisition and origin of drug candidates, 1963-1979.

The average number of self-originated new chemical entities (NCEs) first tested in man by 39 United States-owned pharmaceutical firms in the 3-year period from 1977 to 1979 was 26 a year, approximately half the number investigated annually in the previous decade. Investigational New Drug (IND) Exemption filings on self-originated NCEs, but not those on acquired NCEs, were also comparatively low. Consequently, the contribution of self-originated NCEs to total IND filings fell from 81% in 1963 through 1975 to 68% in 1976 through 1979. (There was a similar decline, from 78% to 61%, in the proportion of compounds synthesized in the United States.) The relative increase in IND filings on acquired NCEs was greatest for smaller firms. By the late 1970s acquired NCEs accounted for almost 50% of the INDs filed by smaller firms, but only 10% to 25% of those filed by large and medium-sized firms. The importance of NCEs acquired from abroad has increased since the mid-1970s. The number of INDs filed on Japanese-originated NCEs rose from approximately one a year in 1963 through 1975 to an average of 3.5 a year in 1976 through 1979. Initial clinical testing of self-originated drugs abroad, which increased sharply in the early 1970s to reach a peak of 36% in 1976, declined to approximately 21% in 1977 through 1979. Self-originated drugs approved in 1977-1979 spent an average of 6 years in United States clinical testing and 2 in regulatory review, a total of 8 years from IND filing to NDA approval. The percentage of IND filings on self-originated NCEs that received New Drug Application (NDA) approval after 8 years or more was 9% overall, although ultimate success rates will be higher. There was a higher success rate for anti-infective drugs (17%) than for other pharmacologic categories (7%). For acquired NCEs, the overall approval rate was much larger (28%).

Analgesic efficacy of an orally administered combination of pentazocine and aspirin. With observations on the use and statistical efficiency of GLOBAL subjective efficacy ratings.

The analgesic efficacy of a combination of pentazocine and aspirin (PA) in the ration 1:13 was compared with that of 650 mg of aspirin alone (A650) and with placebo (PBO), in 98 patients with postoperative pain. Two dose levels of the combination were compared: the lower dose (PA-L) consisted of pentazocine 25 mg and aspirin 325 mg, while the higher dose (PA-H) consisted of pentazocine 50 mg and aspirin 650 mg. All active treatments performed significantly better than PBO. PA-L performed as well as A650, while PA-H performed significantly better than A650. In addition to the usual subjective measures of analgesia, we obtained in 74 patients an evaluation of the overall (GLOBAL) performance of the treatment. This was rated on an ordinal scale of 1 ("poor") to 5 ("excellent"). On the GLOBAL scale, PBO had a mean score of 2.4 (fair-good); A650 and PA-L had scores of 3.6 and 3.9 respectively (good-very good): and PA-H had a score of 4.5 (very good-excellent). In five of six comparisons between treatment means, GLOBAL had the best discriminating power of all six measures. In the two comparisons of greatest interest (A650 against PBO and PA-H against A650), GLOBAL was more than twice as efficient as the TOTAL (summed pain score) measure. In comparing the statistical efficiency of different measures of the same analgesic effect, there is a problem in determining what are "clinically equivalent differences" on the various analgesic scales employed. We propose the use of the observed sample differences and the safeguard of repeating the comparisons over several studies to minimize the effect of random-origin bias.

Drug displacement from protein binding: source of the sulphadoxine liberated by phenylbutazone.

1. A quantitative study has been made of the redistribution of sulphadoxine produced by phenylbutazone in live sheep.2. From calculations based on plasma measurements, 73% of the sulphadoxine in the body can be accounted for as the sum of the plasma-bound, extracellular-free and intracellular-free drug in the whole animal. This sum is termed the accountable sulphadoxine.3. After the injection of phenylbutazone there was a large shift of sulphadoxine from the plasma-bound form into the free form. The gain in free drug significantly exceeded the loss of bound sulphadoxine from the intravascular compartment, but the discrepancy could easily be explained by displacement of some bound sulphadoxine from extravascular plasma protein.4. Phenylbutazone did not displace sulphadoxine from sheep erythrocytes in vitro, nor from homogenates of liver, kidney or skeletal muscle.5. Although the existence of other susceptible binding sites cannot be entirely excluded, this evidence strongly suggests that all the sulphadoxine liberated by phenylbutazone comes from binding sites on plasma protein.

Drug displacement from protein binding: isolation of a redistributional drug interaction in vivo.

1. The pharmacokinetic interaction between phenylbutazone and sulphadoxine has been studied in live sheep.2. Intravenous injection of phenylbutazone causes a rapid fall in the concentration of total sulphadoxine together with a simultaneous rise in the concentration of free sulphadoxine in plasma. Both processes are complete within 3 min of the injection of phenylbutazone.3. These reciprocal changes in the concentrations of total and free sulphadoxine in plasma do not depend on changes in the absorption, hepatic metabolism or renal excretion of sulphadoxine. By exclusion therefore, it is concluded that the effect of phenylbutazone in this interaction is solely to cause redistribution of the sulphadoxine.

Residual effects of hypnotics: triazolam, flurazepam, and nitrazepam.

The residual effects of three hypnotics were investigated by the method of 24-h polygraphy (EEG, EMG, and EOG). The drugs were triazolam 0.25 mg and 0.5 mg, flurazepam 15 mg and 30 mg, nitrazepam 5 mg and 10 mg, and placebo. The subjects were healthy volunteers, eight men and eight women with an average age of 34.3 years. The number of total polygraphic records was 77. Triazolam 0.25 mg and 0.5 mg, flurazepam 30 mg, and nitrazepam 10 mg showed definited sleep inducing and sleep maintenance effects in night recordings. Flurazepam 15 mg and 30 mg and nitrazepam 5 mg and 10 mg were followed by residual effects in morning, afternoon and evening recording periods on the day after the administrations of the hypnotics. However, no effects were seen on the day after the administration of triazolam 0.25 mg and 0.5 mg except for some slight residual effects in the morning. Thus triazolam 0.25 mg and 0.5 mg produces less residual effect than do flurazepam 15 mg and 30 mg, and nitrazepam 5 mg and 10 mg, and 24-h polygraphy is useful for measuring the residual effects of hypnotics.

Research activity on systemic contraceptive drugs by the U.S. pharmaceutical industry, 1963-1976.

The process of drug development and regulation in the U.S. is first reviewed, with special reference to contraceptives. We next summarize recent data on all pharmaceutical innovation in terms of new chemical entities (NCEs) developed by the U.S.-owned pharmaceutical industry from 1963-1976, and then examine the data on all contraceptive NCEs brought to the stage of clinical investigation by the U.S.-owned firms during that period. Of the 956 NCEs studied in man by 39 U.S.-owned firms, 20 NCEs from ten firms were identified as antifertility agents. Of these, 17 had INDs filed, three of the INDs reached NDA submission, and two of the submissions were approved. Since the mid-1960s there has been a decline in the number of antifertility NCEs taken into human testing anywhere in the world and in the number filed as INDs by U.S. firms. Apart from the approved NDAs, there were only two antifertility NCEs with active INDs at the end of 1976. There have been no marked differences between the oral systemic contraceptive NCEs marketed in the U.S. or Britain since 1963. However, taking both countries together, no true NCE has been introduced for systemic contraceptive use since 1968. Although this study shows declining activity in research on contraceptive NCEs by the U.S. industry, thus supporting to some extent Djerassi's prediction of a decade ago, it should be recognized that it does not include complete data on the research activities in this area by the U.S. government or other non-industrial organizations, or on research sponsored by any group on new contraceptive methods other than NCEs.