Clinical Trials Of New Drugs Research Articles

The placebo effect in heart failure

Many patients who are enrolled in controlled clinical trials of new drugs for the treatment of heart failure show favorable hemodynamic and clinical responses to placebo therapy. This “placebo effect” results from both the creation of a supportive therapeutic environment and the spontaneous improvement that is commonly seen when measurements of symptoms and cardiac function are repeated frequently over long intervals of time. Three months of treatment with a placebo produces a reduction in symptoms in 25% to 35% of patients, an increase in cardiac output and a decrease in pulmonary wedge pressure, and an increase in exercise tolerance of up to 90 to 120 seconds. Physicians commonly seek to maximize the “placebo effect”, since the goal of treatment in the clinical setting is to improve the quality of the patient's life. On the other hand, clinical investigators seek to minimize the “placebo effect,” since the goal of a research study is to test the hypothesis that the new drug is superior to a placebo.

Virology, immunology, and natural history of HIV infection

Human immunodeficiency virus-1 infects and damages or destroys several types of cells, most importantly helper/inducer (CD4+) lymphocytes. In the majority of infected persons, the loss of CD4+ lymphocytes leads to a progressive reduction in both cell mediated and antibody mediated immunity. Early during infection most adults are asymptomatic, but after several years many develop symptoms representing a moderate degree of immune suppression. Eventually, most of these individuals become susceptible to the life-threatening opportunistic infections and cancers which define the acquired immunodeficiency syndrome. Recent advances in management, including earlier diagnosis, the use of maintenance or suppressive therapies, and specific anti-retroviral therapy with zidovudine (AZT) has nearly doubled the life expectancy for persons with AIDS. Clinical trials of new drugs, sometimes in combination with AZT, are underway. Vaccine development is proceeding, but many obstacles must be overcome before a successful vaccine can be identified.

Representation of American Blacks in Clinical Trials of New Drugs

Investigations that have revealed racial differences in drug response and disposition indicate the need for adequate representation of racial minorities in clinical drug trials. There is concern, however, that there may be a disproportionate use of racial and ethnic minorities in clinical research due to the inner city location of most university hospitals. To examine this issue, we reviewed the representation of American blacks in 50 recently published clinical trials of new drugs. This survey revealed that investigators do not seem to adequately take into account racial differences as a potential source of variability. It also was found that in the majority of studies, the proportion of black subjects is less than their proportion in the general population. This underrepresentation in clinical trials suggests that insufficient data exist to accurately assess the safety and efficacy of many new drugs in American blacks.

Representation of American blacks in clinical trials of new drugs

Representation of American blacks in clinical trials of new drugs

Modelling the liver function data in diabetes.

We have enrolled diabetic patients into a long-term follow-up study that entails visits to the eye clinic every six months at which time use of a classification scheme determines whether or not the patient is normal regarding liver function. Since the study is still in progress, not all patients have complete follow-up data. We fit models of complete symmetry to the multi-visit binary data with supplemental margins and also investigate the data as stationary Markov chains with testing for stationarity and determination of the order of chain. The final model, a synthesis of both approaches, has potential use in future clinical trials of new drugs for diabetic patients.

Progress toward a more ethical method for clinical trials.

Methodology for conducting clinical trials of new drugs and treatments on people need not be regarded as fixed. After reviewing the currently most popular method (randomization) and its ethical problems, this paper explores the possibilities of a new method for conducting such trials. It relies on new Bayesian technology for eliciting the opinions of medical experts. These opinions are conditioned on specific predictor variables, and are held in a computer. At any stage in a trial, these opinions can be updated in the computer using the information collected in the trial up to that point. Consider as an admissible treatment for a patient having specific values of predictor variables only those treatments that at least one expert regards as best (in the computer model) for this patient. It is proposed that only admissible treatments, so defined, be allowed to be assigned to the patient. The ethical and statistical consequences of this principle are explored. Experience to date with a trial at Johns Hopkins designed on this principle is reported.

The Safety of Medicines: Evaluation and Prediction

Professor Folb is professor of pharmacology at the University of Cape Town and chief physician at Groote Schuur Hospital in Cape Town, South Africa, with research interests in mechanisms and animal models of drug toxicities. From this authoritative perspective the author has prepared a series of six informative essays describing and commenting on, in layman's language, the subject of drug safety. The underlying theme of the work is that no drug is completely safe and that everyday therapeutics always involves a risk-benefit assessment in clinical practice. The overriding principle in the development of new drugs should be reasonableness rather than wasteful overregulation (and disincentives to drug developers) in an attempt to assure the impossible: a completely safe medication. General principles of drug safety are defined in terms of preclinical animal studies and their extrapolation into early clinical trials of new drugs; these include teratogenic potential, drug dependence, carcinogenic potential, potential

New procedures affecting the conduct of clinical trials in the United Kingdom.

Changes have recently been introduced to facilitate the conduct of clinical trials of new drugs in the United Kingdom. These changes became necessary because early developmental work on new drugs was going abroad to the detriment of British industry and with a loss of skill in our departments of clinical pharmacology. The scheme also gives formal recognition to the part played by ethics committees in considering approval of the ethical aspects of clinical trials of new drugs.

Glycylprolyl-p-nitroanilidase in hepatobiliary disease

The serum activity of glycylprolyl-p-nitroanilidase (GPN) has been compared with isocitrate dehydrogenase and with alanine and aspartate aminotransferases in patients with hepatobiliary diseases, myocardial infarction and chronic inflammatory bowel disease. Serum GPN was markedly increased in all hepatobiliary diseases, especially secondary carcinoma and chronic alcoholic hepatitis, but no abnormal values were seen in patients with chronic inflammatory bowel disease. Slightly elevated GPN activities were noticed in a few cases of myocardial infarction. It is suggested that serum GPN would be useful for monitoring hepatic function, especially in the clinical trials of new drugs.

The Search for Therapeutic Cell Controls by the Chemotherapy Program of the National Cancer Institute

The chemotherapy program of the National Cancer Institute functions in a major part as a drug development program. The program screens large numbers of compounds each year in a predominately in vivo screen utilizing mouse leukemia L1210 as its most important component. Input to the screen comes from the synthesis of cogeners of known active chemicals (rational base) and from heterogeneous classes of chemicals, uncharacterized antibiotics and plant products (empirical base). The determination of clinical activity and its correlation with the experimental screen depends significantly on an accepted definition of an adequate trial. The clinical trial of new drugs is divided into three phases and the chemotherapy program defines an adequate trial as the establishment of a maximally tolerated dose (phase I) and the evaluation on an adequate dosage schedule in at least six tumor types (phase II). As a minimum it would be unfair to label a drug as inactive until it has been adequately evaluated in at least 10–15 evaluable patients in the six signal tumor types(lung, breast, colon, acute lymphocytic and acute myelocytic leukemia and lymphosarcoma) and found to have insufficient clinical activity in all of them. Defining an adequate trial has to take into account the question of whether an adequate dosage schedule was used. The chemotherapy program has a defined protocol for schedule dependency testing of all of its drugs in experimental systems and in this way attempts to define which schedule might be optimal for usage in men. The positive correlation for such an approach has been shown with drugs such as methotrexate and arabinosyl cytosine.

Therapeutic innovation: ethical boundaries in the initial clinical trials of new drugs and surgical procedures.

This issue of Daedalus and the conferences from which it sprang seem to have been initiated by widespread concern over the pre cise details and clinical practices of experimentation in bio medical research. By human experimentation'' was meant either the intentional employment of normal subjects as volunteers for physiologic experiments, or the study of patients (in a way that would not directly benefit them) to gather information on a disease or its treatment. While both of these ethical problems are worthy of consideration, they do not appear to me to present any severe on going ethical or technical difficulty in American medicine today. There are far more severe ethical problems in the Armed Forces, where chemical and biological warfare systems are studied on nor mal volunteers who suffer the coercion intrinsic in military activity, or in the Space Program with its high lethality-potential in failed missions.

A Biuret Method for Determination of Protein in Normal Urine

Abstract A biuret method has been developed which provides quantitative measurements of protein in normal urine without interference from drugs or pigments. This method is intended for use in monitoring clinical trials of new drugs—to detect nephrotoxicity. Protein is precipitated from duplicate samples of urine by addition of cold ethanolic phosphotungstic acid. The protein precipitates are separated by centrifugation and washed with ethanol. Protein from one of the duplicate samples is dissolvel in biuret reagent. Protein from the second sample is dissolved in an alkaline tartrate reagent which is identical to the biuret reagent, excepting that copper sulfate has been omitted. After 20 min., the differential absorbance of the two samples is measured at 540 mµ. The limit of sensitivity for detection of protein in urine is 0.5 mg./100 ml. The coefficient of variation of replicate analyses of protein in normal urine is 4.2%. The recovery of protein added to urine averages 103 ± 3%. Analyses of urinary protein by the biuret procedure provide close correlation with measurements by an amido black staining method. Systematic search has failed to reveal interference from urinary pigments, compounds, or drugs which are normally or occasionally encountered in hospitalized patients. In 24-hr. collections of urine from 28 healthy adults, the protein concentrations averaged 6.2 mg./100 ml. (range 3.0-12.2), and the protein excretions averaged 77 mg./day (range 40-150).

Species differences and the clinical trial of new drugs: a review.

In recent years a great deal of new information has been published on the effects of drugs and poisons on different strains of the same species and on different species of animals. Strains and different species, including Homo, may differ in the rate of turnover and metabolic degradation of drugs. These differences can be measured by the methods of essential elimination, as well as by chemical or biochemical techniques. Such studies may permit a limited extrapolation from experiments on lower animals to drug effects in the human species.

Information Needed for Clinical Trials of New Drugs.

Information Needed for Clinical Trials of New Drugs.

Oral Toxicity of Certain Alkyl Resorcinols in Guinea Pigs and Rabbits.

Two alkyl resorcinols have recently been discussed in relation to the treatment of certain parasitic infestations: Lamson et al1 suggesting hexylresorcinol in ascariasis and uncinariasis, and Faust2 and Ratcliffe3 proposing heptylresorcinol (“di-hydranol”) particularly in amebiasis. We believe that clinical trial of new drugs in man may proceed with greater satisfaction than otherwise, if it is made after a critical study of the toxicity of such agents in various genera of mammals for the purpose of reaching an approximate quantitative estimate of the toxic range of the materials, and of determining what pathological effects for which it may be expedient to watch when used clinically and against which to guard. The data presented by Leonard and his associates,4 while indicating that the toxicity of these drugs is “clinically negligible,” do not seem to have been derived from a critical quantitative study. There is, however, a more significant reason from theoretical grounds for investigating quantitativel...