LITERATURE REVIEW
2.2 THE ETHICS OF RANDOMISATION, PLACEBO USE AND DOUBLE-BLINDING
2.2 THE ETHICS OF RANDOMISATION, PLACEBO USE AND
draft version of the Declaration of Helsinki which restricted the use of placebo. The use of placebos was also widely debated during the revision of the Declaration of Helsinki in year 2000. Some bioethicists expressed concern that the use of placebos may disadvantage participants on the placebo arm and may even lead to a deterioration of their health status (Goodyear, Lemmens, Sprumont & Tangwa, 2009;Kimmelman, Weijer & Meslin, 2009;
Nicholson & Crawley, 1999).
On the other hand, those who justify the use of placebos justify their use as ethical in instances where delaying or omitting available treatment has no permanent adverse consequences for the patient and for as long as patients are fully informed about their alternatives (Ellenberg &
Temple, 2000). There have also been arguments that restricting the use of placebos could discourage the development of new drugs. Subsequent debates on this and other issues finally led to the 2004 and subsequently the 2008 version of the Declaration of Helsinki, which allows for the use of placebo under certain conditions, such as where no proven alternative therapy exists and where delayed treatment does not result in serious harm to the patient (WMA, 2000, 2002, 2004, 2008). Prior to year 2010, (at the time of writing this thesis) there were no
comparators that could be used in HIV prevention research. No gels or vaccines had been proven to be effective by then. In 2010, there were some findings suggesting the effectiveness of tenofovir in preventing HIV transmission (Abdool Karim et al., 2010; Keller, 2010).
UNAIDS (2007) supports the use of placebo together with voluntary counselling and testing (VCT) and condoms. Where no proven alternative exists or where no established active control exists, as in the case with microbicides, the use of placebos is routine and generally less controversial. Regardless of all the arguments against the use of placebos in research, placebos will remain in use in clinical research in future because of their advantages. Placebo controlled trials are regarded as the gold standard by most regulatory agencies and funding agencies because of their advantages, such as the conclusive nature of the results they yield within a
short period of time, thereby saving on costs (Ellenberg & Temple, 2000; Rothman & Michels, 1994).
The answer to understanding the concepts of randomisation and double-blinding lies in understanding how the scientific method is often incompatible with one of the principles of research beneficence – the obligation to do good (Beauchamp & Childress, 2001). According to this principle, the researcher is obligated to do good to the research participant’s well being.
The researcher is bound to maximise the chances of a successful outcome. Failure to adhere to this principle creates a potential disadvantage for the clinical research participant in a
developing country setting who often opts to participate in research for the sake of accessing medical care. Even in trials comparing two treatments, it is very unlikely that the two
treatments will be identically desirable for a particular patient. The physician may have reason to believe, for example, that a given treatment is more likely efficacious for a particular patient based on the physician’s previous experience with a sub group of patients or even the patient’s own past treatment experience or the family history of responsiveness to treatment.
Participants may have had previous unsatisfactory responses to one of the medications in the trial, or may display clinical characteristics that suggest that one class of medication is more likely to benefit them than another (Rothman & Michels, 1994).
Ordinarily, the above factors would guide the therapeutic approach, but in a double blind randomised trial, the physician/researcher usually cannot allow these factors to influence treatment decisions except under exceptional circumstances. While efforts to control for such factors in the selection of research participants are possible, they are often cumbersome, expensive and may bias the sample. The reliance on randomisation and double-blinding represents an inevitable compromise of the principle of beneficence in the service of attaining scientifically valid and generalisable research results (Edwards, Lilford & Hewison, 1998;
Hellman & Hellman, 1991; Schafer, 1982). The need for control groups also produces similar effects. In a therapeutic trial, patients will rarely receive medications that are deliberately designed to be pharmacologically ineffective. Placebos are routinely employed in clinical trials without the intent of benefiting the individual participant. Double-blind procedures, on the other hand, may delay the recognition of side effects or drug interaction, and may have other adverse consequences (Brahams, 1988).
Several authors have reported some difficulties that participants face regarding the adequate understanding of the concepts of randomisation, placebo use and double-blinding to research participants (Featherstone & Donovan, 1998; Kerr et al., 2006; Pace et al., 2005; Pucci et al., 1999; Stead et al., 2004; Yuval et al., 2000). This problem was also evident during the
researcher’s own training of research teams from various projects in Zimbabwe, including staff from a microbicide trial. Most consent documents do not address adequately the purpose and justification of the trial procedures in use, as well as the implications of those procedures (Bhutta, 2004; Stead, et al., 2004). According to the same authors, consent documents and study materials mainly explain the study procedures involved as a way of promoting adherence.
This may be due to an assumption that lay persons do not understand science and scientific procedures.
The apparent failure of participants to understand the use of randomisation, placebo and double-blinding in research is ethically problematic, particularly if it means that participants do not realise the implications of these procedures on themselves and their health (Dunn, Palmer
& Keehan, 2006). Kilmarx et al. (2001) recommend that in order to ensure true informed consent, researchers need to assess comprehension before they initiate their studies.
Assessments of comprehension are important as they make it possible for researchers to address potential problem areas in participants’ comprehension. The authors further
recommend that research staff need to be well trained in communication and counselling and should not have substantial language or cultural barriers. Consent forms should be readable and easily understood by potential participants. Special media such as videos, flip charts, booklets or role plays should be prepared for participants and these should be reviewed by community representatives, ethics committees and other experienced members. Research staff need to facilitate participants’ understanding of technical concepts and their consequences and the personal and psychosocial implications of trial participation. Research staff also need to emphasise the rights of participants to withdraw at any time and also the right for the
researchers to exclude the participants if they deem it necessary through the exclusion criteria.
The problems and issues highlighted above are very significant when one considers the principles of beneficence and respect for persons. In addressing these issues, there is a need to empirically investigate the research participants’ understanding of the concepts of blinding, randomisation, and placebos as well as the prevalence of false confidence among microbicide trial participants. Of concern are the ways in which researchers convey the information
regarding randomisation, double-blinding and placebos, as well as the kind of information they convey (Lindegger & Richter, 2000). This has a bearing on whether trial participants
understand key elements of research participation as well as the trial procedures, and ultimately on the quality of informed consent.
Several studies have been conducted to assess trial participants’ attitudes towards the concepts and procedures of randomisation, double blinding and placebo use. In a quantitative study conducted by Heitenan, Aro, Holli and Absetz (2000), only 23percent of the respondents believed that their treatment had been chosen randomly. Several studies have reported that despite being aware of the use of procedures such as randomisation, trial participants found the concepts hard to understand and appreciate. This has been attributed to the expectation by
patients that clinicians would assign them to treatment based on their specific symptoms, clinical findings and age (Glogowska, Roulstone, Enderby, Peters & Campbell, 2001). In interviews with parents who had consented for their children to participate in a RCT,
Glogowska et al. (2001) reported that some parents considered it unethical to use a placebo when there was an alternative whose value had been proven. In another study involving focus group discussions with cancer patients and women in the community, randomisation and the uncertainty in randomised controlled trials (RCTs) were considered negative aspects of clinical trials (Ellis & Butow, 1998)
Ellis, Dowsett, Butow and Tattersall (1999) found that 51 percent of their respondents agreed that RCTs were not the best way of testing new treatments. In a study by McQuellon et al.
(1995), 95 percent of breast cancer patients reported that they would not allow the flipping of a coin to determine their treatment allocation. In a study by Snowdon, Garcia and Elborne (1998), the majority of parents in a neonatal trial found it hard to believe that chance had denied their baby better treatment when it was later revealed to them at the end of the study that their child was on placebo.
Similar findings were reported by Slevin et al. (1995). In a study involving cancer outpatients, respondents reported that they found randomisation and double blinding to be less appealing in clinical trials as this meant that treatment was not decided either by the doctor or the patient. In a study assessing the willingness of patients to participate in some hypothetical trials,
Llewellyn-Thomas, McGreal, Theil, Fine and Erlichman (1991) reported that more than half of the respondents indicated that they would not agree to enter into a RCT and 63 percent reported that randomisation was the reason why they would refuse to join the trials. A few studies have demonstrated positive attitudes towards trial procedures. Some studies have also confirmed that provision of adequate information on the trial and its procedures increases positive
attitudes towards the trial (Kruse et al., 2000; Searight & Miller, 1996; Weston, Hannah &
Downes, 1997). Robinson et al., (2005) report evidence that provision of adequate
information may actually lead to greater understanding, which may ultimately lead to lower consent rates.