The ethics of using placebo in hypertension clinical trials

USE OF PLACEBO CONTROLS: Placebo controls can enhance the value of two types of hypertension trials: measurement of the blood pressure-lowering efficacy of antihypertensive treatment and determination of whether therapeutic interventions can affect clinical endpoints. However, the possibility of adverse outcomes in hypertensive patients allocated to placebo therapy raises ethical concerns. EFFICACY STUDIES: Placebo controls in efficacy studies are particularly helpful in thoroughly quantifying the effect of treatment. The hazard to patients can be minimized by exposing them to placebo for the least possible amount of time and, assuming that blood pressure is itself the primary variable, reducing the probability of cardiovascular events by excluding subjects with severe hypertension or major concomitant risk factors. ENDPOINT STUDIES: Endpoint studies present a more difficult challenge, for they are designed in anticipation of cardiovascular events and patients at high risk are often enrolled in order to more rapidly achieve the required number of endpoints for statistical analysis. In such circumstances, positive therapeutic controls, despite the complexities of analysis, must be preferred to placebo. EARLY-STAGE HYPERTENSION: Important questions regarding the management of early-stage hypertension remain, and despite official treatment guidelines recommendations, currently based chiefly on extrapolation and judgement, many physicians routinely withhold therapy in mild hypertension, even when other risk factors are present. With appropriate safeguards, placebo-controlled trials may be necessary to examine potential benefits of therapy in such patients. Indeed, resolving therapeutic uncertainty and creating well founded recommendations for the future management of the many patients with milder forms of hypertension can make placebo controls both ethical and appropriate.     

Dose-ranging in clinical trials: rationale and proposed use with placebo or positive controls

Drugs are currently released for general use without substantial knowledge of their minimum and maximum effective dose and their dose-related side effects. There are several plausible explanations for this situation, but in some cases this has resulted in patients receiving larger than necessary or smaller than effective doses and experiencing adverse reactions. A concurrent problem with drug evaluation is the rising concern with the use of placebo controls and the growing pressure to utilize positive-control studies. Such studies have many problems, however, some of which are subtle but nonetheless counterproductive in terms of proving efficacy through rigorous scientific investigation. The use of dose-ranging in clinical trials provides more information regarding a drug's TI and can circumvent some of the problems of placebo- and positive-controlled studies. Thus, such dose-ranging studies should be a feature of the development of most new drugs.     

Ethics of placebo use in pediatric clinical trials: the case of antihypertensive drug studies

Industry-sponsored pediatric clinical trials of antihypertensive medications have greatly increased in number since passage of the Food and Drug Modernization Act of 1997. This development should ultimately benefit the treatment of hypertensive children by increasing the amount of scientific knowledge regarding the efficacy and safety of antihypertensive agents in children. However, the designs of many of these trials raise ethical questions related to the inclusion of placebo controls, a practice that has largely been abandoned in trials of antihypertensives in adults because of the well-known adverse consequences of untreated hypertension. This is an especially important issue in pediatric hypertension, as many hypertensive children have either secondary forms of hypertension or hypertension-induced target organ damage, potentially increasing the risk of harm during exposure to placebo. Against this background, and with a strong emphasis on protection of this vulnerable patient population, a strict set of conditions for use of placebos in pediatric antihypertensive trials is proposed.     

In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials

The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.     

Safety of placebo controls in pediatric hypertension trials

Many clinical trials, including those in pediatric populations, use a placebo arm for medical conditions for which there are readily available therapeutic interventions. Several short-term efficacy trials of antihypertensive medications performed in response to Food and Drug Administration-issued written requests have used a placebo arm; whether the use of a placebo arm is safe in children with hypertension is unknown. We sought to define the rates of adverse events in 10 short-term antihypertensive trials to determine whether these trials resulted in increased risk to pediatric patients receiving placebo. We combined patient-level data from 10 antihypertensive efficacy trials performed in pediatric patients that were submitted to the Food and Drug Administration from 1998 to 2005. We determined the number and type of all of the adverse events reported during the placebo-controlled portion of the clinical trials and compared these numbers between the patients who received placebo and those who received active drug. Among the 1707 children in the 10 studies, we observed no differences in the rates of adverse events reported between the patients who received placebo and those who received active drug. Only 5 patients suffered a serious adverse event during the trials; none were thought by the investigators to be related to study drug, and only 1 occurred in a patient receiving placebo. Short-term exposure to placebo in pediatric trials of antihypertensive medications appears to be safe.     

Thai study success affects ongoing placebo trials

The AZT trial in Thailand, using lower doses of the drug than are normally given in the United States, will change the design of several placebo-controlled trials. The study showed that less than a full dose of AZT was effective in preventing transmission. This will be of great benefit in areas where the drug is not available or is too expensive to administer. However, researchers are concerned that the results will be misinterpreted to mean that the regimen used in the United States is not necessary. An immediate implication is that several placebo studies will stop; it would be unethical not to administer AZT to those patients. Early results show that nevirapine, less costly than AZT, may also be effective in preventing perinatal transmission.     

Major vaccine trials begin

March 8 marked the beginning of the first HIV vaccine effectiveness trial in the San Francisco Bay Area, being conducted by the San Francisco Department of Public Health and the University of California at San Francisco. This phase III trial is expected to run four years in more than 50 locations, and enroll 5,000 participants in the U.S. The study will test a recombinant vaccine known as AIDSVAX B/B, developed by VaxGen. A similar trial will enroll 2,500 injection drug users in Thailand. In related news, the National Institute of Allergy and Infectious Diseases launched a vaccine trial in Africa in February. The phase I trial will enroll 40 HIV-negative participants in Uganda and will test Alvac, a vaccine produced by Pasteur Merieux Connaught. Contact information for the San Francisco Bay Area trial is provided.     

Motivators of enrolment in HIV vaccine trials: a review of HIV vaccine preparedness studies

HIV vaccine preparedness studies (VPS) are important precursors to HIV vaccine trials. As well, they contribute to an understanding of motivators and barriers for participation in hypothetical HIV vaccine trials. Motivators can take the form of altruism and a desire for social benefits. Perceived personal benefits, including psychological, personal, and financial well-being, may also motivate participation. The authors performed a systematic review of HIV VPS using the Cochrane Database for Systematic Reviews, Medline, PubMed, Embase, and Google Scholar. The authors independently searched the literature for individual HIV VPS that examined motivators of participation in a hypothetical HIV vaccine trial, using the same search strategy. As the denominators employed in the literature varied across studies, the denominators were standardized to the number of respondents per survey item, regardless of their willingness to participate (WTP) in an HIV vaccine trial. The authors retrieved eight studies on social benefits (i.e., altruism) and 11 studies on personal benefits conducted in the Organization for Economic Co-operation and Development (OECD) countries, as well as 19 studies on social benefits and 20 studies on personal benefits in the non-OECD countries. Various different forms of altruism were found to be the major motivators for participation in an HIV vaccine trial in both the OECD and the non-OECD countries. In a large number of studies, protection from HIV was cited as a personal motivator for participation in a hypothetical HIV vaccine trial in the OECD and the non-OECD countries. Knowledge of motivators can inform and target recruitment for HIV vaccine trials, although it must be remembered that hypothetical motivators may not always translate into motivators in an actual vaccine trial.     

The current status of cholera vaccine development and experience with cholera vaccine trials in volunteers

In recent years notable advances have been made in the development of improved vaccines to prevent cholera. These new vaccines are administered orally to maximally stimulate intestinal secretory immunity. Killed vibrios, given in conjunction with purified B subunit or administered alone, in three spaced doses, caused no adverse reactions and have conferred significant protection in volunteer challenge studies and in field trials. Two attenuated mutants of V. cholerae, prepared by recombinant DNA techniques, CVD 103 and CVD 103-HgR are well-tolerated and elicit prominent immune responses and protective immunity after ingestion of a single oral dose. Other modern approaches being pursued include the development of auxotrophic strains and of modifying attenuated S. typhi strain Ty21a to express V. cholerae Inaba and Ogawa LPS antigens.