Potential Trial Participants Research Articles

Depression treated by homeopaths: a study protocol for a pragmatic cohort multiple randomised controlled trial

The most commonly recommended treatments for depression are psychological/psychotherapeutic treatments, and antidepressant drugs. However, 38 percent of patients with depression do not use these recommended treatments. Some patients seek homeopathic treatment for depression, but insufficient evidence exists to conclude as to the effectiveness, cost-effectiveness and safety of treatment by homeopaths for patients with depression. The aim of this trial is to evaluate the acceptability and comparative clinical and cost-effectiveness of the offer of adjunctive treatment provided by homeopaths for patients with self-reported depression. This pragmatic randomised controlled trial is embedded within the population based South Yorkshire Cohort (SYC) of whom nine percent self-report long-term depression. The SYC is designed to facilitate 'cohort multiple' randomised controlled trials (cmRCT). A self-completed questionnaire will be used to both screen and collect baseline data from potential trial participants. The primary outcome is PHQ-9. One-hundred-and-sixty-two participants will be randomly selected to the intervention group (Offer of treatment by a homeopath). The results of the Offer and the No Offer groups will be compared at 6 and 12 months using both an intention to treat (ITT) and complier average causal effect (CACE) analysis. Cost-effectiveness analysis will involve calculation of quality adjusted life year (QALY). In order to help interpret the quantitative findings a selection of up to 30 patients in the offer group will be invited to participate in qualitative interviews after the first consultation and after a minimum of 6 months. Interviews will be assessed by two researchers and results will be analysed using thematic analysis. Triangulation will be used to combine results from qualitative and quantitative methodologies at the interpretation stage, to see if results agree, offer complementary information on the same issue or contradict each other.

Influences on recruitment to randomised controlled trials in mental health settings in England: a national cross-sectional survey of researchers working for the Mental Health Research Network.

BackgroundRecruitment to trials is complex and often protracted; selection bias may compromise generalisability. In the mental health field (as elsewhere), diverse factors have been described as hindering researcher access to potential participants and various strategies have been proposed to overcome barriers. However, the extent to which various influences identified in the literature are operational across mental health settings in England has not been systematically examined.MethodsA cross-sectional, online survey of clinical studies officers employed by the Mental Health Research Network in England to recruit to trials from National Health Service mental health services. The bespoke questionnaire invited participants to report exposure to specified influences on recruitment, the perceived impact of these on access to potential participants, and to describe additional positive or negative influences on recruitment. Analysis employed descriptive statistics, the framework approach and triangulation of data.ResultsQuestionnaires were returned by 98 (58%) of 170 clinical studies officers who reported diverse experience. Data demonstrated a disjunction between policy and practice. While the particulars of trial design and various marketing and communication strategies could influence recruitment, consensus was that the culture of NHS mental health services is not conducive to research. Since financial rewards for recruitment paid to Trusts and feedback about studies seldom reaching frontline services, clinicians were described as distanced from research. Facing continual service change and demanding clinical workloads, clinicians generally did not prioritise recruitment activities. Incentives to trial participants had variable impact on access but recruitment could be enhanced by engagement of senior investigators and integrating referral with routine practice. Comprehensive, robust feasibility studies and reciprocity between researchers and clinicians were considered crucial to successful recruitment.ConclusionsIn the mental health context, researcher access to potential trial participants is multiply influenced. Gatekeeping clinicians are faced with competing priorities and resources constrain research activity. It seems that environmental adjustment predicated on equitable resource allocation is needed if clinicians in NHS mental health services are to fully support the conduct of randomised controlled trials. Whilst cultural transformation, requiring changes in assumptions and values, is complex, our findings suggest that attention to practical matters can support this and highlight issues requiring careful consideration.

A nested randomised controlled trial of a leaflet, containing information on research, to increase the recruitment rate of reform (reducing falls with orthoses and a multifaceted podiatry) trial participants

Background Poor recruitment is a major problem in randomised trials. Although pre-notification has been demonstrated to be an effective strategy for increasing response rates to postal questionnaires (Edwards et al, 2010), the usefulness of this approach to aid trial recruitment has never been evaluated. This study, nested within the NIHR funded REFORM Trial, aimed to identify whether increasing understanding of research in potential trial participants, prior to being approached for consent, can increase trial recruitment.

Participants’ perspectives on safety monitoring in clinical trials

Minimizing the risk to study participants is an essential requirement of ethical research. Respecting the rights of subjects is also paramount, which includes respecting their autonomy by making available important information about the evolving safety profile of an investigational product as the trial progresses. Little is known about what trial participants understand and expect regarding monitoring and communication of serious adverse events during the conduct of a trial in which they have agreed to participate. To explore understanding and expectations of potential trial participants concerning monitoring and communication of serious adverse events during a clinical trial. A professional moderator led four 90-min, in-person focus groups: two groups with individuals who had never participated in a clinical trial and two groups with people who had. After relevant research terms were defined and existing regulations were explained, discussion focused on how participants expected safety to be monitored and communicated during the conduct of a clinical trial. Group comments were video-recorded and transcribed and then analyzed by the investigators. The 27 racially diverse focus group members were largely unaware of existing safeguards and regulations to manage risk in clinical trials. Many people expressed a desire for increased transparency about serious adverse events during the trial as well as shortened reporting deadlines. Focus group members also spontaneously expressed concerns about potential financial conflicts of interest in monitoring and reporting serious adverse events. This was a single-site, qualitative study and is not meant to establish the prevalence of beliefs. Potential trial participants have limited understanding and a wide range of expectations about how safety monitoring in clinical trials should be managed and communicated. The overall tenor of opinion suggests unease about participant safety and a desire to have more information conveyed by sponsors to investigators and, in some cases, by investigators to participants. Additional study in other regions and settings may be useful to more broadly explore the range of participants' beliefs and expectations. In the meantime, engaging patient advocates in the design of clinical trials and clearly communicating to trial participants the plan for oversight of their safety may help ease the types of concerns expressed in this study.

Assessing Whether Consent for a Clinical Trial Is Voluntary

Voluntary and informed consent are necessary for the ethical conduct of clinical research, but ensuring that consent is both voluntary and informed is challenging in resource-poor settings. Prior efforts to improve consent have focused on participant comprehension. (1) We report the results of an assessment of the voluntariness of consent for an HIV vaccine trial conducted at the GHESKIO Center in Haiti. The Step Study was a randomized HIV-1 vaccine trial in participants aged ≥ 18 years at high risk of HIV-1 acquisition. (2) The study was approved by Institutional Review Boards (IRBs) at Cornell University and GHESKIO. Potential participants reviewed the informed consent form during three educational sessions. A counselor, not involved in the trial, tested participants' comprehension of the consent form. If participants passed, they underwent an individual assessment of voluntariness. The assessment of voluntariness was designed with community members, former research volunteers, and Haitian IRB members and consisted of five open-ended questions about 1) the purpose of the study, 2) reasons for volunteering, 3) hopes for study participation, 4) “bad things” that could happen, and 5) reaction if something in the study made them unhappy. Responses were content coded and analyzed for emergent themes. A total of 596 potential vaccine trial participants attended three education sessions and completed the assessment of comprehension, and 529 (89%) passed. Of the 529 who passed, 492 completed the assessment of voluntariness. The median age was 27 years; 392 (80%) were female, and the median income was less than one dollar/day. Of the 492, 22 (5%) were separated from their sexual partner, and 219 (45%) were in plasaj, an unstable sexual relationship, commonly not monogamous, and not formalized by ceremony. Of the 492 potential vaccine trial participants, 54 (11%) gave at least one “red flag” response suggesting involuntary consent, (Table). The “red flags” were: 1) perceived financial benefit; 2) expectation of an effective HIV vaccine, 3) belief that doctors would never expose participants to risk, and 4) belief that a “volunteer” is a person who has the willpower to remain in a study. Of note, the word “volunteer” translates to “volonte” in Haitian Kreyol, and similar to many romance languages, also means “willpower” or “fortitude”. Table Questions and Responses Suggesting Involuntary Participation Multivariable analysis found that these “red flag” or ethically problematic responses were associated with participants being separated from their sexual partner (p < .001) or being in a “plasaj” unstable sexual relationship (p = .025). Of note, prior studies in Haiti have shown that women in “plasaj” are more likely to suffer domestic violence and acquire sexually transmitted infections. (3) Neither education level nor performance on the assessment of comprehension (4) was significantly correlated with providing “red flag” responses. Our assessment identified 11% of study participants enrolling in an HIV vaccine trial whose voluntary consent was in doubt, even after they had attended three educational sessions and demonstrated good comprehension of the consent form. These participants expressed hope of financial benefit, expected to receive an effective HIV vaccine, deferred to medical authority, or viewed a “volunteer” as one who makes an irreversible commitment to remain in the study. The association between being separated from one's sexual partner or being in an unstable sexual relationship and providing an ethically problematic response on the assessment of voluntariness suggests that social vulnerability may impair voluntary consent for clinical research. An assessment of comprehension during the informed consent process has become the standard for clinical trials conducted in resource poor settings. We recommend the addition of a few open-ended questions to assess voluntary participation and to identify volunteers with unreasonable expectations of financial or therapeutic benefit or other misperceptions that may compromise voluntary consent. (5)

Experimental designs for small randomised clinical trials: an algorithm for choice

BackgroundSmall clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple.MethodsPubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs.ResultsWe identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs.ConclusionsThe algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.

Improving understanding of clinical trial procedures among low literacy populations: an intervention within a microbicide trial in Malawi

BackgroundThe intervention reported in this paper was a follow up to an empirical study conducted in Malawi with the aim of assessing trial participants’ understanding of randomisation, double-blinding and placebo use. In the empirical study, the majority of respondents (61.1%; n=124) obtained low scores (lower than 75%) on understanding of all three concepts under study. Based on these findings, an intervention based on a narrative which included all three concepts and their personal implications was designed. The narrative used daily examples from the field of Agriculture because Malawi has an agro-based economy.MethodsThe intervention was tested using a sample of 36 women who had been identified as low scorers during the empirical study. The 36 low scorers were randomly assigned to control (n=18) and intervention arms (n=18). The control arm went through a session in which they were provided with standard informed consent information for the microbicide trial. The intervention arm went through a session in which they were provided with a narrative in ChiChewa, the local language, with the assistance of a power point presentation which included pictures as well as discussions on justification and personal implications of the concepts under study.ResultsThe findings on the efficacy of the intervention suggest that the 3 scientific concepts and their personal implications can be understood by low literacy populations using simple language and everyday local examples. The findings also suggest that the intervention positively impacted on understanding of trial procedures under study, as 13 of the 18 women in the intervention arm, obtained high scores (above 75%) during the post intervention assessment and none of the 18 in the control arm obtained a high score. Using Fischer’s exact test, it was confirmed that the effect of the intervention on understanding of the three procedures was statistically significant (p=0.0001).ConclusionsPotential trial participants can be assisted to understand key clinical trial procedures, their justification and personal implications by using innovative tailored local narratives.

Using an internet consumer marketing strategy to reach men who have sex with men for participation in a preventive HIV vaccine clinical trial

Methods Between 12/1/2011 and 1/3/2012, the HVTU contracted with a consumer marketing company to recruit potential trial participants. For $3000, the company emailed MSM a scripted message inviting them to participate in a clinical HIV vaccine trial, and the company provided the trial site with contact information for those who responded. Site staff emailed and phoned each respondent to provide study information and conduct a phone-screen interview for the trial. Those eligible were scheduled for in-office screening appointments.

Innovating information-delivery for potential clinical trials participants. What do patients want from multi-media resources?

To discover whether the provision of clinical trials information via a multi-media platform could better meet the needs, preferences and practices of potential cancer trial participants. A mixed qualitative and quantitative questionnaire was delivered to 72 participants from cancer support groups to elicit views on the provision and design features of multimedia resources in delivering clinical trials information. Perceived lack of information is an expressed barrier to clinical trials participation. Multimedia resources were viewed positively as a way to address this barrier by most potential clinical trials participants; in particular by helping to align information to individual needs, promote active engagement with information, and by allowing more control of the learning experience. Whilst text remained the most valued attribute of any resource, other highly rated attributes included the resource being simple to use, easily accessible, having a clear focus, incorporating examples and visual aids, and being interactive. Provision of support for the learning resource was also rated highly. As in other areas, such as education, multimedia resources may enhance the delivery and acceptance of information regarding clinical trials. Better alignment of information may have a positive impact on recruitment and retention into clinical trials.

Haematological and Biochemical Reference Values for Healthy Adults in the Middle Belt of Ghana

BackgroundReference values are very important in clinical management of patients, screening participants for enrolment into clinical trials and for monitoring the onset of adverse events during these trials. The aim of this was to establish gender-specific haematological and biochemical reference values for healthy adults in the central part of Ghana.MethodsA total of 691 adults between 18 and 59 years resident in the Kintampo North Municipality and South District in the central part of Ghana were randomly selected using the Kintampo Health and Demographic Surveillance System and enrolled in this cross-sectional survey. Out of these, 625 adults made up of 316 males and 309 females were assessed by a clinician to be healthy. Median values and nonparametric 95% reference values for 16 haematology and 22 biochemistry parameters were determined for this population based on the Clinical Laboratory and Standards Institute guidelines. Values established in this study were compared with the Caucasian values being used currently by our laboratory as reference values and also with data from other African and western countries.ResultsReference values established include: haemoglobin 113–164 g/L for males and 88–144 g/L for females; total white blood cell count 3.4–9.2×109/L; platelet count 88–352×109/L for males and 89–403×109/L for females; alanine aminotransferase 8–54 U/L for males and 6–51 U/L for females; creatinine 56–119 µmol/L for males and 53–106 µmol/L for females. Using the haematological reference values based on the package inserts would have screened out up to 53% of potential trial participants and up to 25% of the population using the biochemical parameters.ConclusionWe have established a panel of locally relevant reference parameters for commonly used haematological and biochemical tests. This is important as it will help in the interpretation of laboratory results both for clinical management of patients and safety monitoring during a trial.

ENROLLING IN DEEP BRAIN STIMULATION RESEARCH FOR DEPRESSION: INFLUENCES ON POTENTIAL SUBJECTS' DECISION MAKING

Ethical concerns regarding early-phase clinical trials of DBS for treatment-resistant depression (TRD) include the possibility that participants' decisions to enroll might be motivated by unrealistic expectations of personal benefit or minimization of risks. Thematic analyses were conducted on a sample of 26 adults considering participation in two DBS trials. Influences on the decision making of these potential DBS trial participants were derived from responses to questions posed in the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), a semi-structured interview designed to evaluate decisional capacity to consent to research. Participants cited numerous factors as influential in their enrollment decisions, including perceived lack of other treatment options, desire to take initiative, beliefs about DBS as a novel treatment, possibility of DBS efficacy, hoped-for improvements, potential risks and disadvantages of DBS or clinical trial participation, and altruism. No individual expressed a set of motivations or influencing factors that suggested compromised decision-making capacity or diminished voluntariness of decision making. These results suggest that individuals make the decision to enroll in early-phase trials of DBS for TRD based on a number of complex and sometimes idiosyncratic considerations, and that the trials that were studied utilized sufficiently robust informed consent processes. These findings offer evidence that the emerging research area of DBS can be advanced in an ethically sound manner, provided that safeguards and processes for discussing trials with participants are carefully and proactively enacted.

Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C

Background Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C.Purpose We describe our strategy for a phased approach for studying the impact of silymarin in hepatitis C, in the context of the unique challenges of botanical product clinical trials and the development of specific and curative antiviral therapy.Methods This multicenter, randomized, double-masked, placebo-controlled trial was conducted with four clinical centers and a data-coordinating center in the United States, to assess the impact of silymarin therapy in patients with chronic hepatitis C who failed conventional antiviral therapy.Results Key aspects relevant to performing clinical trials of botanical products include early identification of an appropriate product with standard product chemistry, acquisition of pharmacokinetic and dosing information, selection of the appropriate study group, and choosing rigorous outcome variables.Potential limitations Trial participants were chronic hepatitis C patients who were nonsustained virologic responders to IFN-based therapy; therefore, the findings are not generalizable to all hepatitis C populations. Further, alanine aminotransferase, a biochemical liver test, rather than hepatitis viral RNA or liver histology was the primary end point.Conclusions The challenges identified and addressed during development of this United States multicenter Phase II trial to evaluate silymarin for treatment of patients with chronic hepatitis C infection who had failed to respond successfully to previous IFN-based therapy are common and must be addressed to conduct rigorous trials of botanical products.

Can user testing of a clinical trial patient information sheet make it fit-for-purpose? - a randomized controlled trial

BackgroundThe participant information sheet (PIS) provided to potential trial participants is a critical part of the process of valid consent. However, there is long-standing concern that these lengthy and complex documents are not fit-for-purpose. This has been supported recently through the application of a performance-based approach to testing and improving readability called user testing. This method is now widely used to improve patient medicine leaflets - determining whether people can find and understand key facts. This study applied for the first time a controlled design to determine whether a PIS developed through user testing had improved readability over the original, using a sheet from a UK trial in acute myeloid leukemia (AML16).MethodsIn the first phase the performance of the original PIS was tested on people in the target group for the trial. There were three rounds of testing including 50 people in total - with the information revised according to its performance after each of the first 2 rounds. In the second phase, the revised PIS was compared with the original in a parallel groups randomised controlled trial (RCT) A total of 123 participants were recruited and randomly allocated to read one version of the PIS to find and show understanding of 21 key facts.ResultsThe first, developmental phase produced a revised PIS significantly altered in its wording and layout. In the second, trial phase 66% of participants who read the revised PIS were able to show understanding of all aspects of the trial, compared with 15% of those reading the original version (Odds Ratio 11.2; Chi-square = 31.5 p < .001). When asked to state a preference, 87.1% participants chose the revised PIS (Sign test p < .001).ConclusionsThe original PIS for the AML16 trial may not have enabled valid consent. Combining performance-based user testing with expertise in writing for patients and information design led to a significantly improved and preferred information sheet. User testing is an efficient method for indicating strengths and weaknesses in trial information, and Research Ethics Committees and Institutional Review Boards should consider requesting such testing, to ensure that PIS are fit-for-purpose.

251 Effectiveness of the Practice of Yoga Therapy in Anxiety Disorders: A Randomized Controlled Trial

The most commonly recommended treatments for depression are psychological/psychotherapeutic treatments, and antidepressant drugs. However, 38 percent of patients with depression do not use these recommended treatments. Some patients seek homeopathic treatment for depression, but insufficient evidence exists to conclude as to the effectiveness, cost-effectiveness and safety of treatment by homeopaths for patients with depression. The aim of this trial is to evaluate the acceptability and comparative clinical and cost-effectiveness of the offer of adjunctive treatment provided by homeopaths for patients with self-reported depression.This pragmatic randomised controlled trial is embedded within the population based South Yorkshire Cohort (SYC) of whom nine percent self-report long-term depression. The SYC is designed to facilitate ‘cohort multiple’ randomised controlled trials (cmRCT). A self-completed questionnaire will be used to both screen and collect baseline data from potential trial participants. The primary outcome is PHQ-9. One-hundred-and-sixty-two participants will be randomly selected to the intervention group (Offer of treatment by a homeopath). The results of the Offer and the No Offer groups will be compared at 6 and 12 months using both an intention to treat (ITT) and complier average causal effect (CACE) analysis. Cost-effectiveness analysis will involve calculation of quality adjusted life year (QALY). In order to help interpret the quantitative findings a selection of up to 30 patients in the offer group will be invited to participate in qualitative interviews after the first consultation and after a minimum of 6 months. Interviews will be assessed by two researchers and results will be analysed using thematic analysis. Triangulation will be used to combine results from qualitative and quantitative methodologies at the interpretation stage, to see if results agree, offer complementary information on the same issue or contradict each other.

Relative Versus Absolute Standards for Everyday Risk in Adolescent HIV Prevention Trials: Expanding the Debate

The concept of minimal risk has been used to regulate and limit participation by adolescents in clinical trials. It can be understood as setting an absolute standard of what risks are considered minimal or it can be interpreted as relative to the actual risks faced by members of the host community for the trial. While commentators have almost universally opposed a relative interpretation of the environmental risks faced by potential adolescent trial participants, we argue that the ethical concerns against the relative standard may not be as convincing as these commentators believe. Our aim is to present the case for a relative standard of environmental risk in order to open a debate on this subject. We conclude by discussing how a relative standard of environmental risk could be defended in the specific case of an HIV vaccine trial among adolescents in South Africa.

Accrual and drop out in a primary prevention randomised controlled trial: qualitative study.

BackgroundRecruitment and retention of participants are critical to the success of a randomised controlled trial. Gaining the views of potential trial participants who decline to enter a trial and of trial participants who stop the trial treatment is important and can help to improve study processes. Limited research on these issues has been conducted on healthy individuals recruited for prevention trials in the community.MethodsSemi-structured interviews with people who were eligible but had declined to participate in the Aspirin for Asymptomatic Atherosclerosis (AAA) trial (N = 11), and AAA trial participants who had stopped taking the trial medication (N = 11). A focus group with further participants who had stopped taking the trial medication (N = 6). (Total participants N = 28).ResultsExplanations for declining to participate could be divided into two groups: the first group were characterised by a lack of necessity to participate and a tendency to prioritise other largely mundane problems. The second group's concern was with a high level of perceived risk from participating.Explanations for stopping trial medication fell into four categories: side effects attributed to the trial medication; starting on aspirin or medication contraindicating to aspirin; experiencing an outcome event, and changing one's mind.ConclusionsThese results indicate that when planning trials (especially in preventive medicine) particular attention should be given to designing appropriate recruitment materials and processes that fully inform potential recruits of the risks and benefits of participation.Trial registrationISRCTN66587262

Addressing the Ethical Challenges of First in-Human Trials

Phase I clinical trials raise ethical challenges, particularly the Phase I trials that involve a novel therapy being tested in humans for the first time, usually termed first-in-human (FIH) trials. The ethical appropriateness of clinical research requires having a favorable risk-to-benefit ratio and protecting patients from excessive risk, but both of these standards may be difficult to assess and to achieve in Phase I trials. There are no widely accepted standards for judgments concerning risk, benefit, and value in Phase I trials. Also the question of how to conceptualize and compute benefit has been a subject of ethical debate, particularly for Phase I trials where the likelihood of therapeutic benefit to participants is very slight. Specifically, should regulators and institutional review boards approve Phase I trials in the absence of likely benefit to participants when these subjects are being exposed to an uncertain and potentially high level of risk. Then there is the question as to how to communicate accurate and meaningful information about the uncertainty, risk of adverse events, and the very limited, if any, prospect of therapeutic benefit to potential trial participants in order to promote a meaningful informed consent process. That FIH trials involving highly novel agents often enroll participants with serious unmet needs further complicates the process. Very serious adverse reactions that occurred in the first-in-human trial of the monoclonal antipody TGN412 in Britain led to the issuing of several reports on first-in-human studies and the European Medicines Agency published a guideline on first-in-human trials shortly thereafter. In the past two years the (United States) Food and Drug Administration (FDA) has approved Investigational New Drug applications for three Phase I first-in-human clinical trials of candidate therapeutics derived from human embryonic stem cells (hESCs). Neither the FDA nor the National Institutes of Health have developed their own guidelines for the safety and ethics of first-in-human trials or guidelines for first-in-human trials with hESC derivatives. The analysis in this paper highlights the need for more focused attention to the ethical issues that first-in-human, trials raise. The paper proposes identifying prerequisites for beginning trials with a novel and potentially high-risk intervention. Preferably, there should be clear-cut guidelines and/or review by a central body.

Health education through analogies: preparation of a community for clinical trials of a vaccine against hookworm in an endemic area of Brazil.

BackgroundObtaining informed consent for clinical trials is especially challenging when working in rural, resource-limited areas, where there are often high levels of illiteracy and lack of experience with clinical research. Such an area, a remote field site in the northeastern part of the state of Minas Gerais, Brazil, is currently being prepared for clinical trials of experimental hookworm vaccines. This study was conducted to assess whether special educational tools can be developed to increase the knowledge and comprehension of potential clinical trial participants and thereby enable them to make truly informed decisions to participate in such research.Methodology/Principal FindingsAn informational video was produced to explain the work of the research team and the first planned hookworm vaccine trial, using a pedagogical method based on analogies. Seventy-two adults living in a rural community of Minas Gerais were administered a structured questionnaire that assessed their knowledge of hookworm, of research and of the planned hookworm vaccine trial, as well as their attitudes and perceptions about the researchers and participation in future vaccine trials. The questionnaire was administered before being shown the educational video and two months after and the results compared. After viewing the video, significant improvements in knowledge related to hookworm infection and its health impact were observed: using a composite score combining related questions for which correct answers were assigned a value of 1 and incorrect answers a value of 0, participants had a mean score of 0.76 post-video compared to 0.68 pre-video (p = 0.0001). Similar improvements were seen in understanding the purpose of vaccination and the possible adverse effects of an experimental vaccine. Although 100% of participants expressed a positive opinion of the researchers even before viewing the film and over 90% said that they would participate in a hookworm vaccine trial, an increase in the number who expressed fear of being vaccinated with a novel vaccine was seen after viewing the video (51.4% post-video versus 29.2% pre-video). Increases were also seen in the proportion who thought that participation in a vaccine trial would be inconvenient or disrupt their daily activities.Conclusions/SignificanceEven in rural, resource-limited populations, educational tools can be specially designed that significantly improve understanding and therefore the likelihood of obtaining truly informed consent for participation in clinical research. The observed changes in the knowledge and perceptions of the research participants about hookworm infection and the experimental hookworm vaccine demonstrate that the video intervention was successful in increasing understanding and that the subjects acquired knowledge pertinent to the planned research.

Transparency as a Means to Increase Clinical Trial Enrollment

In this age of mandated clinical trial registries and results databases, pharmaceutical, biotechnology, and medical device companies struggle to disseminate information about protocol and trial results in ways that patients can easily understand. Patient advocacy groups are seldom consulted when clinical trial protocols are developed or when trial results are released, yet these groups represent tens of thousands of patients with diseases and disorders. In fact, patient advocacy groups were key drivers in the passage of the Food and Drug Administration Amendments Act (Section 113), which fostered in the era of transparency. This article highlights how advocacy organizations function as a direct conduit to specialized patient populations and how these groups can provide a communication channel to reach thousands of potential clinical trial participants.

The Health Informatics Trial Enhancement Project (HITE): Using routinely collected primary care data to identify potential participants for a depression trial

BackgroundRecruitment to clinical trials can be challenging. We identified anonymous potential participants to an existing pragmatic randomised controlled depression trial to assess the feasibility of using routinely collected data to identify potential trial participants. We discuss the strengths and limitations of this approach, assess its potential value, report challenges and ethical issues encountered.MethodsSwansea University's Health Information Research Unit's Secure Anonymised Information Linkage (SAIL) database of routinely collected health records was interrogated, using Structured Query Language (SQL). Read codes were used to create an algorithm of inclusion/exclusion criteria with which to identify suitable anonymous participants. Two independent clinicians rated the eligibility of the potential participants' identified. Inter-rater reliability was assessed using the kappa statistic and inter-class correlation.ResultsThe study population (N = 37263) comprised all adults registered at five general practices in Swansea UK. Using the algorithm 867 anonymous potential participants were identified. The sensitivity and specificity results > 0.9 suggested a high degree of accuracy from the algorithm. The inter-rater reliability results indicated strong agreement between the confirming raters. The Intra Class Correlation Coefficient (Cronbach's Alpha) > 0.9, suggested excellent agreement and Kappa coefficient > 0.8; almost perfect agreement.ConclusionsThis proof of concept study showed that routinely collected primary care data can be used to identify potential participants for a pragmatic randomised controlled trial of folate augmentation of antidepressant therapy for the treatment of depression. Further work will be needed to assess generalisability to other conditions and settings and the inclusion of this approach to support Electronic Enhanced Recruitment (EER).