The development and regulation of new medications.

The unmet needs of many patients make the successful search for new and better drugs an urgent goal. Increasing regulatory demands have generated delays in the availability of new drugs and concerns about the long-term profitability of the innovative pharmaceutical industry. A rational and flexible approach to drug regulation could ease some of the most worrisome constraints without jeopardizing the public welfare. Changes in our national drug regulatory policy and in the performance of the Food and Drug Administration will serve our society better than drastic legislative mandates intended either to emasculate the FDA or to grant the agency broad new powers.

Problems in publication of clinical trial methodology.

The literature on analgesic testing in man reveals a series of informational gaps. These include a failure to document the occurrence of "trials that failed", the problems associated with recruiting patients and in dealing with dropouts, the relative advantages and disadvantages of different methods of assessing relief from pain, the importance of baseline variables, and the utility of global and comparative judgments by patients. A trial is described in which only 100 subjects of a total of over 8,000 patients theoretically available for study proved suitable. Significant differences between consenters and nonconsenters and selection factors that are used in choosing an experimental population have implications for the generalization of a study. Such conclusions have been largely ignored both in and out of the scientific literature.

Clinical trials of drugs from the viewpoint of the academic investigator (a satire).

Dr. Lasagna was unable to attend the workshop in person, and therefore delivered his remarks by videotape, in the assumed role of the newest "Secretary of Human Experimentation" at the Department of Health, Education, and Welfare addressing a public television audience. There is no difficulty in sensing the serious truths underlying the satire in his address.

Patient package inserts. II. Toward a rational patient package insert.

Analysis of the response to a questionnaire on various aspects of drug information showed several significant trends. The importance of the physician as an information source varied directly with age and inversely with educational level of patients. The doctor's importance as a source of information was also greater for those who visited physicians' offices or clinics more and if they were on long-term treatment. Younger persons, those with higher levels of education, and those who were not in regular contact with a physician placed greater importance on non-physician sources. Persons consulting physicians regularly desired less information and knew less about drugs than those who did not regularly see a physician. These findings suggest that the educational role of the physician could be improved and should be directed particularly at the low-income, older patient. In the design of the package insert, particular attention should be given to self-prescribed medications where no other information sources will be operating.

Commentary: Patient package inserts. I. Nature, notions, and needs.

A total of 137 completed questionnaires were obtained from several population samples in an attempt to assess drug knowledge, information sources, and views on drug information with particular attention to the possible role of a patient-oriented package insert. The results indicated that the study population was variably informed and could make fairly accurate assessments by this knowledge. Responders placed great importance on the doctor and pharmacist as preferred and actual drug information sources. The mass media were accorded little prominence. Great emphasis was placed on the adequate provision of information, and this appears to be a crucial function in an adequate doctor-patient relationship. The results appear to indicate a favorable climate for establishing a patient-oriented package insert that should have summarized as well as detailed information to complement the doctor and pharmacist as primary information sources.

Evaluation of current clinical trial methodology in analgesimetry based on experts' opinions and analysis of several analgesic studies.

There is general agreement that the controlled clinical trial is the best method for analgesic evaluation. Current practice in clinical analgesimetry, however, varies considerably with regard to design, measurement of pain, and statistical analysis. We attempted to assess the degree of this diversity by a questionnaire survey of a sample of investigators who are currently conducting clinical pain studies. To examine how various statistical methods perform in practice, we reanalyzed data from four of our published analgesic studies using a number of standard methods.

Toward the operational identification of adverse drug reactions.

The evaluation of adverse drug reactions in clinical practice is somewhat arbitrary and is characterized by considerable differences of opinion. This report presents a decision table algorithm approach toward the development of an operational system for the identification of adverse drug reactions. The algorithm incorporates an estimate of the certainty of the link between the untoward clinical event and the suspect drug, and examines the underlying causes of the identified drug reactions. Use of such a system is a first step toward reducing ambiguity in the evaluation of adverse drug reactions.

Estrogen patient package insert: medication acceptance despite negative attitudes.

We surveyed 100 women receiving short courses of estrogen post partum to suppress lactation. Thirty six had significant apprehension about estrogens, but took them. These women were significantly older and better educated and 92% of them were married. In contrast, only one third of the "nonapprehensive" women were married and they had significantly lower family incomes. More of the apprehensive women read the estrogen patient package insert (PPI) and almost 30% developed negative attitudes toward estrogens. The major concerns of these women reflected information in the PPI about cancer and thromboembolism. The reasons given for taking estrogens despite apprehension included the lower risk of short courses, assurance from physicians, nurses, or family members, and the desired therapeutic effect. These women should not be given the current estrogen PPI, which was designed to warn women of the risks of long-term estrogen use; a PPI should be written specifically for patients receiving short courses. Similar problems will arise with the PPIs for other medications that have different risks for different therapeutic indications.

The quantification of pain: an analysis of words used to describe pain and analgesia in clinical trials.

In this study 116 subjects were asked to quantify the descriptive pain terms commonly used in analgesimetry by using the visual analog scale as a tool. The results showed highly variable responses. Several words that have been assigned the same value on an ordinal scale do not convey the same meanings as on the visual analog scale. The words some and terrible are probably the least useful terms to quantify pain. The word complete for describing pain relief showed the least variation. The data on global ratings varied greatly; 10% of the participants gave the same values to the terms very good and excellent. The unequal differences between descriptive terms that are commonly considered equidistant on an ordinal scale are clearly demonstrated. We propose an approach to quantifying pain that takes into account the interindividual variations in interpretation of descriptive pain terms.

Oral ciramadol in the treatment of postoperative pain.

The efficacy and safety of single oral 15, 30, and 60 mg doses of ciramadol, an investigational agonist/antagonist analgesic, were studied in a postoperative pain model and compared with aspirin, 325 and 650 mg. Two visual analog pain assessment scales were also compared. Results showed that a pain relief score of moderate or better was reported at some time during the 6-hour observation period by 76% of the patients who took 15 mg ciramadol, by 60% of those who took 30 mg ciramadol, by 59% of those who took 60 mg ciramadol, and by 38% and 92% of the patients who took the low and high doses of aspirin, respectively. From 1 to 4 hours after drug dosing, 15 mg ciramadol generally produced higher scores, indicative of greater pain relief, on the three pain intensity efficacy scales used (verbal, linear analog, and curvilinear analog) than did the other two ciramadol doses, but these differences were generally not significant. The differences between 15 mg ciramadol and 650 mg aspirin were generally not significant, although the higher aspirin dose had some advantages over 15 mg ciramadol. The most frequently reported adverse effect was dizziness/vertigo in 22% of patients taking 60 mg ciramadol, in 17% of those taking 30 mg ciramadol, in 13% of those taking 15 mg ciramadol, in 4% of those taking high aspirin doses, and in none of those who received the low aspirin doses. The correlation coefficient for the linear and curvilinear pain analog intensity scales was 0.955, indicating a highly significant correlation (P less than 0.001).

A comparison of drug product information in four national compendia.

Four widely used compendia of prescribing information have been received to examine the way in which some drug companies recommend uses for several anti-inflammatory products and describe the major dangers in their use. The Physician's Desk Reference (PDR) cites the greatest absolute number of indications for steroids with systemic action, as well as the greatest number of contraindications, warnings and precautions, and adverse effects. The total number of precautions appearing in the PDR is three times the mean for the other compendia, and the number of adverse effects is four times the mean of the others. Together, these other compendia contain 70.5% of the number of words in the PDR. The PDR contains statements that are strongly directive for the physician and that do not appear in the other compendia. Regulatory and social differences may at least partially explain these discrepancies.

New indications for already-approved drugs: time trends for the new drug application review phase.

For 55 individual drugs, the time required for approval of the original new drug application (NDA) was compared with the time required for approval of supplemental NDAs. The mean time required for the original NDAs was 22.2 +/- 18.1 months; the mean for review of all 46 follow-on indications was similar (19.1 +/- 17.9 months). Since subsequent applications do not ordinarily require new assessment of clinical safety or animal toxicity studies, one would expect the subsequent applications to be processed more expeditiously. Such is not the case. The negative implications of these facts are discussed.

New drug development in the United States, 1963 through 1984.

This study is the fifth in a series that documents changes in the status of drug development in the United States based on a survey of the pharmaceutical industry. For example, the study shows that, although there has been a recent increase in the number of new chemical entities being tested by US firms, an increasing proportion are acquired from outside the firm. Moreover, a growing number of acquired new chemical entities are coming from sources outside the United States, particularly Japan. These and other trends suggest an overall decline in research activity in the United States. At the same time, foreign firms are becoming more active, foretelling greater competition in the United States for both market share and research resources. The analyses also show a continued increase in synthesis-to-approval time, surpassing 13 years in the early 1980s, and rising success rates, reaching about 12% by the late 1970s.

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.

Commentary. The normal volunteer in clinical investigation: how rigid should selection criteria be?

Twenty-nine healthy young male volunteers were screened by history, physical examination, urinalysis, 24 different blood tests, and electrocardiography for admission to a Phase I drug study. The protocol submitted to, and approved by, the FDA listed the normal ranges for the local laboratories and stipulated that the test results for any volunteers accepted should all be within these ranges. During screening 46 abnormal values were found in the laboratory tests. Only 4 subjects had all their test data within "normal" range, a result that could have been anticipated simply form the number of tests performed. These findings indicate the need for deciding on realistic protocol criteria for studies involving healthy volunteers.

The drug lag: an update of new drug introductions in the United States and in the United Kingdom, 1977 through 1987.

This report updates previous studies that documented the existence of a significant lag between new drug introductions in the United Kingdom and in the United States. During the 11-year period from 1977 through 1987, the United Kingdom led the United States in the number of first introductions of new drugs (114 versus 41), in average lead time for mutually available drugs (60.7 versus 28.9 months), and in the number of exclusively available drugs (70 versus 54). Analysis by therapeutic category indicated large United Kingdom leads in the introduction of respiratory (5.1 years), cardiovascular (3.2 years), central nervous system (3.2 years), and anti-cancer (2.9 years) agents, and shorter leads for anesthetic and analgesic (2.0 years), gastrointestinal (2.0 years), endocrine (1.4 years), and anti-infective (0.8 years) agents. A comparison of the 5-year period from 1983 through 1987 with the previous 5-year period (1978 through 1982) showed no change in the length of the lag time (1.9 years for each period). These results indicate that the United States continues to lag behind the United Kingdom in the availability of new drugs.

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.

Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo.

To investigate the value of anorexiant medications as an adjunct to other forms of weight control therapy, we studied 121 people in a 34-week, double-blind clinical trial of 60 mg extended-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Participants weighed 130% to 180% (154% +/- 1.2%, mean +/- SEM) of ideal body weight (1983 Metropolitan Life tables) and were in good health. By week 34, participants receiving active medication lost an average of 14.2 +/- 0.9 kg, or 15.9% +/- 0.9% of initial weight (n = 58), versus a loss of 4.6 +/- 0.8 kg or 4.9% +/- 0.9% of initial weight by subjects taking placebo (n = 54; p less than 0.001). On visual analog scales, participants rated fenfluramine plus phentermine as more helpful than placebo (50.3 +/- 0.5 versus 20.3 +/- 0.3) and not bothersome (fenfluramine plus phentermine, 17.4 +/- 0.3 versus 13.5 +/- 0.2). Blood pressure decreased and pulse remained unchanged in both groups. Dry mouth was the most common adverse effect in subjects receiving fenfluramine plus phentermine; all adverse effects decreased after 4 weeks. Only nine participants left the study in the first 34 weeks. Two subjects from each group left the study as a result of adverse effects. Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise aided weight loss and continued to be efficacious for 34 weeks.