Why ethnic minority groups are under-represented in clinical trials: a review of the literature

Randomised controlled trials (RCTs) are considered to be the gold standard in evaluating medical interventions; however, people from ethnic minorities are frequently under-represented in such studies. The present paper addresses a previously neglected debate about the tensions which inform clinical trial participation amongst people from ethnic minorities, in particular, South Asians, the largest ethnic minority group in the UK. In a narrative review of the available literature, based mainly on US studies, the present authors aim to make sense of the issues around under-representation by providing a theoretical reconciliation. In addition, they identify a number of potential barriers to ethnic minority participation in clinical trials. In so doing, the authors recognise that the recent history of eugenic racism, and more general views on clinical trials as a form of experimentation, means that clinical trial participation among people from ethnic minorities becomes more problematic. Lack of participation and the importance of representational sampling are also considered, and the authors argue that health professionals need to be better informed about the issues. The paper concludes by offering a number of strategies for improving ethnic minority accrual rates in clinical trials, together with priorities for future research.     

The role of social work in HIV/AIDS clinical trials.

The social worker can facilitate screening, retention and patient adherence in HIV/AIDS clinical trials. This paper introduces the process and its key vocabulary, and uses three case studies to demonstrate how social workers can assist clients who may wish to participate in, or are already enrolled in a clinical trial. After examining five major issues that affect the client in a clinical trial (informed consent; treatment vs. research; risks and side effects; altruism; the role of family members; and gender, race and class issues), the authors elaborate on interventions at the screening level, and concrete services and psychosocial interventions for study participants.     

带状疱疹疫苗临床研究进展

带状疱疹（herpes zoster,HZ）好发于中老年人,是由潜伏于感觉神经节的水痘-带状疱疹病毒（varicella-zoster virus,VZV）复发感染所致。近年由于种种原因,尤其是中国人口老龄化愈发严重使中国HZ发病率急剧上升。虽然HZ具有自限性,但其并发症会降低患者生活质量并加重患者家庭及社会的经济负担,为减少发病率、提升老年人的晚年生活质量,研发安全有效的HZ疫苗可能是一种重要而有效的措施。本文旨在对HZ疫苗临床研究进展作简要综述,为中国HZ疫苗的使用及带状疱疹疾病的防制工作提供参考。     

Real world TB vaccines: clinical trials in TB-endemic regions

The first 4 years of the 21st century have been an exciting time for tuberculosis (TB) research. After more than a half-century, the first new vaccines for TB are beginning to enter human clinical trials. Based on advances in proteomics and genomics, new vaccine candidates are filling the preclinical pipeline and our understanding of the natural history of M. tuberculosis infection is expanding rapidly. This review summarizes the developing consensus on the BCG vaccine and its limitations and discusses clinical trials of some of the new vaccines intended to supplement or replace it.     

Long-term safety analysis of preventive HIV-1 vaccines evaluated in AIDS vaccine evaluation group NIAID-sponsored Phase I and II clinical trials

This report evaluates long-term safety data from 3189 human immunodeficiency virus type 1 (HIV-1) uninfected, healthy volunteers who were enrolled into 51 National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Phase I and II multicentred, randomized, double-blind trials of recombinant HIV-1 subunit vaccines (23 studies), synthetic peptide vaccines (7 studies), live vaccinia-vector recombinant envelope vaccines (7 studies), canarypox vector recombinant vaccines (13 studies), a DNA vaccine (1 study), and a Salmonella-vector vaccine (1 study). During the 12,340 person-years of follow-up, participants were monitored for adverse events including immune dysfunction/autoimmunity, anaphylaxis, cancer, death, and vaccine allergy. The analysis provides evidence that a preparation of a C4-V3 polypeptide vaccine emulsified in incomplete Freund's caused serious toxicity, but otherwise no safety problems considered serious were identified for any of the vaccines and adjuvants studied. These data serve to solidify the growing safety base of current vaccine technologies utilized in candidate vaccines for HIV-1 infection.     

Fowlpox virus vaccines for HIV and SHIV clinical and pre-clinical trials

DNA prime and recombinant fowlpox virus (rFPV) boost vaccines were designed to express multiple HIV or SIV antigens for use in human clinical trials and in pre-clinical trials in macaques. Three sets of vaccines with matching HIV or SIV antigen sets, modified for vaccine safety considerations, were constructed and shown to express the relevant proteins. The rFPV vaccines with inserts at up to three sites, were stable on passage in chick cell culture, including during GMP manufacture of vaccines for human Phase I clinical trials. Cellular and humoral immunogenicity in mice was demonstrated using a DNA prime/rFPV boost and vaccinia virus challenge model. These data establish a preliminary safety and efficacy profile for these multigenic vaccines suggesting they are suitable for advanced development as candidate HIV vaccines.     

Multiple factors affect immunogenicity of DNA plasmid HIV vaccines in human clinical trials

Plasmid DNA vaccines have been licensed for use in domesticated animals because of their excellent immunogenicity, but none have yet been licensed for use in humans. Here we report a retrospective analysis of 1218 healthy human volunteers enrolled in 10 phase I clinical trials in which DNA plasmids encoding HIV antigens were administered. Elicited T-cell immune responses were quantified by validated intracellular cytokine staining (ICS) stimulated with HIV peptide pools. HIV-specific binding and neutralizing antibody activities were also analyzed using validated assays. Results showed that, in the absence of adjuvants and boosting with alternative vaccines, DNA vaccines elicited CD8+ and CD4+ T-cell responses in an average of 13.3% (95% CI: 9.8–17.8%) and 37.7% (95% CI: 31.9–43.8%) of vaccine recipients, respectively. Three vaccinations (vs. 2) improved the proportion of subjects with antigen-specific CD8+ responses (p = 0.02), as did increased DNA dosage (p = 0.007). Furthermore, female gender and participants having a lower body mass index were independently associated with higher CD4+ T-cell response rate (p = 0.001 and p = 0.008, respectively). These vaccines elicited minimal neutralizing and binding antibody responses. These findings of the immunogenicity of HIV DNA vaccines in humans can provide guidance for future clinical trials.     

The prospects for AIDS vaccines

Several vaccine strategies against HIV are under study in phase 1 clinical trials. Many involve recombinant subunit preparations, and the question is which of these components of the virus may be immunogenic. Immune effectors and mediators that protect against HIV are also undefined. Vaccines may ultimately be used to treat as well as prevent AIDS.     

Chronic hepatitis B: Immunological profile and current therapeutic vaccines in clinical trials

More than 250 million people worldwide are chronically infected with hepatitis B virus (CHB), and over half a million die each year due to CHB-associated liver complications such as cirrhosis and hepatocellular carcinoma. The translation of immunological knowledge about CHB into therapeutic strategies aiming to a sustainable hepatitis B virus (HBV) clearance has been challenging. In recent years, however, the understanding on the immune effectors required to overcome chronicity has notably increased thanks to preclinical and clinical research. Therapeutic vaccination may prove to be useful for treating CHB patients when coupled with current antiviral agents and other immunomodulatory strategies. This review summarizes current data and future perspectives on therapeutic vaccination. Other treatment alternatives that could be combined with vaccines for a complete cure from hepatitis B virus infection are also discussed.     

Falsificationism and clinical trials.

The relevance of the philosophy of Sir Karl Popper to the planning, conduct and analysis of clinical trials is examined. It is shown that blinding and randomization can only be regarded as valuable for the purpose of refuting universal hypotheses. The purpose of inclusion criteria is also examined. It is concluded that a misplaced belief in induction is responsible for many false notions regarding clinical trials.     

Burkholderia pseudomallei and Burkholderia mallei vaccines: Are we close to clinical trials?

B. pseudomallei is the cause of melioidosis, a serious an often fatal disease of humans and animals. The closely related bacterium B. mallei, which cases glanders, is considered to be a clonal derivative of B. pseudomallei. Both B. pseudomallei and B. mallei were evaluated by the United States and the former USSR as potential bioweapons. Much of the effort to devise biodefence vaccines in the past decade has been directed towards the identification and formulation of sub-unit vaccines which could protect against both melioidosis and glanders. A wide range of proteins and polysaccharides have been identified which protective immunity in mice. In this review we highlight the significant progress that has been made in developing glycoconjugates as sub-unit vaccines. We also consider some of the important the criteria for licensing, including the suitability of the “animal rule” for assessing vaccine efficacy, the protection required from a vaccine and the how correlates of protection will be identified. Vaccines developed for biodefence purposes could also be used in regions of the world where naturally occurring disease is endemic.     

Efficient and robust method for comparing the immunogenicity of candidate vaccines in randomized clinical trials

In randomized clinical trials designed to compare the magnitude of vaccine-induced immune responses between vaccination regimens, the statistical method used for the analysis typically does not account for baseline participant characteristics. This article shows that incorporating baseline variables predictive of the immunogenicity study endpoint can provide large gains in precision and power for estimation and testing of the group mean difference (requiring fewer subjects for the same scientific output) compared to conventional methods, and recommends the “semiparametric efficient” method described in Tsiatis et al. [Tsiatis AA, Davidian M, Zhang M, Lu X. Covariate adjustment for two-sample treatment comparisons in randomized clinical trials: a principled yet flexible approach. Stat Med 2007. doi:10.1002/sim.3113] for practical use. As such, vaccine clinical trial programs can be improved (1) by investigating baseline predictors (e.g., readouts from laboratory assays) of vaccine-induced immune responses, and (2) by implementing the proposed semiparametric efficient method in trials where baseline predictors are available.     

Starting over. Why remarriages are more unstable

Previously divorced and remarried couples have a higher probability of divorce and decline in marital quality. Models which have explained this behavior focus on: willingness to leave marriage; selection; socioeconomic status; the remarriage market; and incomplete marriages. Each model is examined among a population of marrieds and remarrieds to distinguish attributes and the extent to which these attributes increase the probability of decline in marital quality or divorce. Data were obtained from a sample of 2033 marrieds 55 years old who were interviewed over the telephone in 1980, 1983, and 1988 in the Marital Instability Over the Life Course Study. Incomplete marriage was measured by whether and to what extent parents or parents-in-law made contact and the number of relatives that party was close to. Willingness to leave was based on attitudes to divorce and the ability to handle emotion and financial affairs if the marriage ended. Selection referred to poor marriage material (drugs or alcohol, criminal conduct, mismanagement of money, immature behavior. Socioeconomic status was reflected in occupational status, educational levels, and income. The marriage market was a measure of age, education, and religious differences. Marital quality was examined in terms of happiness, interaction, disagreement, and divorce proneness. Multiple classification analysis was used to compare attributes by marital history. The methods of Kessler and Greenberg were used to examine changes in marital quality over time in first time marriages and remarriages. The results indicate that individuals in remarriages have relationships with attributes which potentially lower marital quality and increase the probability of divorce. When both individuals have prior marriage and divorce experience, there is even lower social integration, greater willingness to leave marriage, higher probability of marrying as a teen, lower socioeconomic status, and greater likelihood of age differences. Remarriage variables and marital quality variables both showed linear relationships. Remarriage variables and marital quality variables both showed linear relationships. In the cross sectional analysis of the 1980 data there is a statistically significant relationship with attributes which potentially lower marital quality in 1980 indicates remarried persons are more prone to lower marital quality than people in first marriages.