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Abstract
Objectives To analyse the perspective of clinical research stakeholders concerning post-trial access to study medication.
Methods Questionnaires and informed consents were sent through e-mail to 599 ethics committee (EC) members, 290 clinical investigators (HIV/AIDS and Diabetes) and 53 sponsors in Brazil. Investigators were also asked to submit the questionnaire to their research patients. Two reminders were sent to participants.
Results The response rate was 21%, 20% and 45% in EC, investigators and sponsors’ groups, respectively. 54 patients answered the questionnaire through their doctors. The least informative item in the consent form was how to obtain the study medication after trial. If a benefit were demonstrated in the study, 60% of research participants and 35% of EC answered that all patients should continue receiving study medication after trial; 43% of investigators believed the medication should be given to participants, and 40% to subjects who participated and benefited from treatment. For 50% of the sponsors, study medication should be assured to participants who had benefited from treatment. The majority of responders answered that medication should be provided free by sponsors; investigators and sponsors believed the medication should be kept until available in the public health sector; EC members said that the patient should keep the benefit; patients answered that benefits should be assured for life.
Conclusions Due to the study limitations, the results cannot be generalised; however, the data can contribute to discussion of this complex topic through analysing the views of stakeholders in clinical research in Brazil.
- Clinical Ethics
- Informed Consent
- Research Ethics
- Scientific Research
- Public Health Ethics
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Introduction
Many multinational trials, previously conducted only in Europe and North America, now include sites and patients in Latin America as well as Western Europe and Asia.1–4 Several reasons explain why research is expanding to these regions. The decision involves scientific aspects as well as economic and political ones: continued scientific progress in these countries; increasing demand for academic achievement among investigators; unmet medical needs, where patients are likely to look for access to best available treatments within the context of a clinical trial; search for more cost-effective sites around the world.4 ,5 Practical and technical concerns surround the strategies of clinical research and how they affect collective and public health processes.
Guidelines and regulations for ethical biomedical research traditionally focus on protecting the rights of study subjects through a well designed protocol, previous review by ethics committees (EC) and an adequate process of informed consent of participants. The recent trend in the globalisation of clinical trials raised some concerns that had not previously been addressed in guidelines and regulations, such as continuity of treatment after the conclusion of the study.6–9 Inclusion of developing countries in these trials brings these issues to the forefront and links them to the participants’ vulnerability, due to limited availability and access to medical treatment in these countries.
In 2000, the World Medical Association added a new provision to the Declaration of Helsinki stating that at the end of a study, access to interventions proven beneficial by the study should be assured to participants. International controversy ensued over the implications of this new provision and a clarification note was issued in 2004. The most recent version of the Declaration of Helsinki (2008) amended the paragraphs related to post-trial access: ‘the protocol should describe arrangements for post-study access by study subjects to interventions identified as beneficial in the study or access to other appropriate care or benefits’.10
The Council for International Organizations of Medical Sciences (CIOMS), in collaboration with the WHO as early as 2002, wrote that for research conducted in communities with limited resources: ‘the sponsor and the investigator must make every effort to ensure that any intervention or product developed, or knowledge generated, will be made reasonably available for the benefit of that population or community’, and ‘if an investigational drug has been shown to be beneficial, the sponsor should continue to provide it to the subjects after the conclusion of the study, and pending its approval by a drug regulatory authority’.10 CIOMS goes on to note, however, that sponsors may not be in a position to make investigational interventions generally available to the community, at least before a drug regulatory authority has approved it.11
Several arguments have been explored as moral obligations to ensure post-trial access to study medication, including benefit to participants, obligations inherent to the researcher–participant relationship, duties of reciprocity and duties of rescue.12–16 However, there is not a consensus. Bioethics commissions and drafters of guidelines have concluded that researchers and sponsors do have some post-trial obligations to participants, but practical issues make them difficult to implement, mainly in the arena of chronic diseases. Few data exist describing what study participants and, in fact, all clinical research players think about the issue of post-trial obligations. The limited published data is concentrated on the field of HIV research, where the issue was raised some years ago.6 ,17 Sofaer et al. report in the only study we found, describing the perceptions of patients with chronic conditions, that many participants in USA agreed that there are obligations to facilitate post-trial access to the trial drug or to a therapeutic equivalent; however, there was disagreement about whether there were more substantial obligations. They note that such views were less demanding than those of non-US subjects reported in other studies.18 This broader concept of post-trial care, including other aspects besides the study medication, has already been mentioned by other authors.5 ,6 ,17–20
Inadequate plans for continuing treatment after a trial have resulted in non-approval of protocols by the ECs in some countries, Brazil included.21–23 The reason for not approving a protocol is that, in some countries, the new medicine may never reach the market and, if it does, it is not always included in the formulary to be furnished (free) to patients. Additionally, most trials in developing settings are funded by developed nations, underscoring the importance of discussing obligations around standard of care and post-trial obligations.24
Previous papers have documented the results from qualitative research performed with clinical investigators, EC members and research participants.12 ,17 ,18 ,20 Since pharmaceutical companies sponsor the majority of clinical investigation related to the development of medicines, their ideas and comments may help to define solutions to this very complex topic. The goal of this research was to identify and analyse the perspectives of all these stakeholders in clinical research regarding the continuity of the investigational medicine after a trial is concluded.
Material and methods
Search strategy and participant selection
A non-probabilistic approach was chosen in this study. The study surveyed four different populations in Brazil: (1) clinical investigators in two therapeutic fields, HIV/AIDS and diabetes mellitus (DM); (2) members (usually chairs) of ECs registered in the National Commission of Ethics in Research in May 2009; (3) sponsors (pharmaceutical companies doing research in Brazil and/or established Clinical Research Organisations (CRO) in the country, represented by their medical directors or heads of clinical research, or any other member they designated); (4) current or recent research participants in HIV/AIDS and DM clinical trials.
The preliminary list of investigators was obtained through the sponsors. An e-mail was sent to all pharmaceutical companies doing clinical research in Brazil, as well as to all CROs identified in the country in September 2009. Additionally, the http://www.clinicaltrials.gov homepage was searched looking for names not identified by the sponsors but who had participated in clinical trials in HIV/AIDS and/or DM field in Brazil (searching for Brazil ‘AND’ HIV or AIDS or diabetes). Investigators without a known electronic address were excluded from the original list, since the survey would be carried out through the internet.
Survey development
The questionnaires were developed after a literature search and customisation to the current study objectives.20 ,25 ,26 The literature on survey methodology was also reviewed with a focus on the guidelines for web-based surveys (Checklist for Reporting Results of Internet e-Surveys, CHERRIES) as well as for observational studies (Strengthening the Reporting of Observational Studies in Epidemiology, STROBE).27 ,28 The survey instruments were pretested for clarity, adequacy of terms, sequence of questions and completion time through a pilot assessment performed with clinical investigators, EC members, lawyers, sponsors and lay people (12 invited, 10 answered with comments). The final instrument consisted of 19–28 questions depending on the group, mostly multiple-choice questions. The questionnaire covered the following domains: (1) demographic and individual characteristics of participants; (2) experiences and satisfaction with the informed consent process; (3) motivation for participating in clinical studies; (4) opinions and impressions about the continuity of treatment after the end of the trial. An e-mail was sent to the identified participants in October 2009, including initial information about the study, the questionnaire to be completed and the informed consent. Return of the self-administered questionnaire indicated consent to participate in the research. A reminder e-mail was sent to all invited participants after 1 month. A second reminder was sent a couple of weeks after the first reminder but only to non-responders. Patients were identified and surveyed through the investigators willing to collaborate in the survey. Together with the original invitation, investigators received a question about the availability of their research patients for a survey. In the case of acceptance, paper-and-pen questionnaires were sent to them, and they conducted the patient interview.
Ethics approval
The study protocol, questionnaires and informed consent were approved by the EC of Faculty of Medicine of Sao Paulo University. An exemption from the EC from other sites participating in the survey was granted because all documents had already been approved by the original institutional EC.
Statistical analysis
Data were double entered by two separate individuals and analysed through descriptive and non-inferential statistics. The database was built based on EpiData Program 3.0 (2003). Data were validated by comparing both data entries and resolving discrepancies by referring to the original questionnaire. Descriptive statistics were applied using both absolute and relative frequencies according to the different groups (investigators, EC members, sponsors and patients). For Likert scales (five possible answers), the Kruskal–Wallis test was performed; when significant differences were found, an additional non-parametric multiple-choice test was done in order to complete the analysis. For all other questions with nominal responses (non-Likert), the association among groups was verified with the χ2 test (usually) or the likelihood ratio test. The Friedman test was used to verify, inside the groups, which aspect was considered more important for each one, and completed with the non-parametric multiple-choice comparison for repeated measures.
Results
A total of 260 completed surveys were received from 124 of 599 invited EC members, 58 of 290 investigators and 24 of 53 sponsors, reflecting a response rate of 21%, 20% and 45%, respectively. Around 60% of all responses in the three groups arrived after the first email, justifying the reminder as an important tool to increase the response rates. Fifty-four patients also answered the questionnaire through their doctors.
As shown in table 1, the majority of clinical investigators (64%) and the minority of the sponsor respondents (37%) were male. About half the members of EC as well as research participants were male. The mean age of the researchers was higher than the other groups of participants (53, compared with 49, 47 and 40, respectively, for research participants, EC members and sponsors). Twenty-three percent of research participants initiated a university course, but only 13% had completed it; 28% completed high school (equivalent to 11 years of schooling), and 47% of them had less than 8 years of schooling. In the researcher, sponsor and EC member groups, most respondents had at least a superior course completed (close to 100% for all three groups), and many had a PhD (52%, 25% and 46%, respectively). Respondents in all groups came from all parts of Brazil; however, the majority was from the southeast (43% of researchers and EC members, 79% of sponsors and 81% of research participants) and, inside this region, from Sao Paulo state, where the most part of CROs and pharmaceutical companies are located and, hence, more studies are carried out. Almost 70% of research participants said they usually utilise the public health system (called the Unified Health System, Sistema Unico de Saude, in Brazil). Investigators had a mean of 12 years of clinical research experience, and 31% of them had already previously acted as EC member.
Characteristics of Ethics Committee (EC) members, sponsors, clinical investigators and research participants
When asked how well informed they were about protocol design, adverse events, number of visits and tests required, possibility to withdraw, potential benefits of the new treatment and how to obtain the study drug after trial, the research participants reported feeling equally and well informed about all the above aspects (p=0.249), although, according to all groups put together, research participants are less well informed about how to obtain the drug after trial (p<0.05). The research participants also considered themselves better informed about all topics than the other groups thought they were (p<0.05). For most items, clinical investigators were more likely than EC members to believe that research subjects are well informed (p<0.05).
Another question asked respondents to rate the importance of information, such as study objective, study design, potential benefits and potential risks in the informed consent process. The least important information for all groups of respondents was the study design. For all groups, the potential risks were the most important information in the informed consent, except for the research participants, who answered that potential benefits were more important than potential risks (80% vs 59%, p<0.05).
Concerning motivations for participating in a clinical trial, 96% of patients answered that obtaining better healthcare and attention was ‘very important’, and 94% mentioned also as ‘very important’ the possibility of collaborating with the progress of the science. However, considering all groups together, the major motivation for patients would be access to better healthcare and attention (78%), as well as searching for access to treatment alternatives for their diseases (73%).
The domain of the questionnaire which specifically related to post-trial access had a leading question: ‘who should receive the study medication after trial?” The greater part of the research participants (60%), and of the EC members (35%), answered that all patients (study participants as well as non-participants) should receive it. Of the clinical investigators, 43% responded that the medication should be given to study participants; the other 40% only to those subjects who benefited from the study treatment. Fifty percent of sponsors responded that study medication should be assured only to the participants who benefited from the treatment (table 2). There was consensus among all the respondent groups that post-trial medication should be given free by the sponsors (tables 3 and 4). The majority of clinical investigators (51%) and sponsors (73%) thought medication should be provided by the sponsors until it became available in the public health sector; while EC members thought it should be furnished as long as patients benefit (49%); patients answered that benefit should be assured for life (51%) (table 5).
Participants’ opinions about who should receive the study medication after trial
Participants’ opinions about the cost of post-trial medication
Participants’ opinions regarding the primary responsibility for furnishing the drug after trial
Participants’ opinions on how long should the medication be kept after trial
Weighing the pros and cons of keeping the patient on an investigational drug, we asked which would be the best approach after the end of trial. Clinical investigators (57%) answered that patients should be kept on the investigational drug in contrast with EC members and sponsors, who responded that patients should return to the previous standard treatment (56% and 82%, respectively, p<0.001, when compared with the investigators).
We also found a discrepancy in what ‘post-trial access’ means. Clinical researchers and EC members tend to understand ‘access’ as free supply by the sponsors (67% and 78%, respectively), and the sponsors as available in the country by regulatory approval (54%), meaning not supplied directly to the recipients by the sponsor.
Discussion
This study represents one of the first attempts to assess the views of major stakeholders in clinical research, including investigators, members of ECs and research participants as well as sponsors, regarding post-trial access to investigational medicine. It is also one of the first studies to include DM, as an example of a chronic disease other than HIV/AIDS.
Clinical trial stakeholders in Brazil share the view that provision of drugs post-trial is the responsibility of the sponsor, and that drugs should be provided to participants free of charge, but the same stakeholders have mixed views on who should receive the drugs post-trial and for how long. Our data show that clinical investigators and sponsors share the opinion that post-trial medication should be given to study participants who benefited from the study treatment, while the majority of research participants and EC members answered that all patients with the disease should receive the medication after trial if a benefit had been demonstrated in the study. Indeed, some research ethics guidelines suggest that not only the research subjects but also the community where the trial was conducted should receive the benefits of the new treatment.
Data published in 2006, by Pace et al., reported that 83% of research participants in an HIV trial and 42% of the clinical investigators thought that every HIV-infected person in the world should receive the study drug if shown to be beneficial; EC chairs’ responses were split: 34% said all HIV-infected persons in the country who need it; 29% said all HIV-infected persons in the world; and 26% said that only study participants should receive it.20 Pace's data differed from ours regarding how the drug should be provided: only 11% of EC chairs and 18% of investigators replied that the drug should be free of charge. The majority of responses were ‘at a price the average person in the country can afford’ (65% and 64%, respectively). A sub-group analysis of their research participants may help us to make a correlation with our results: participants from Europe and Latin America were more likely to answer ‘free of charge’ than respondents from the USA and Australia. The authors commented that these differences may reflect the underlying values in each region, and what respondents are used to20; they could also be explained by the ‘Americans’ emphasis on personal responsibility for health, lack of socialised or nationalised healthcare system or even greater awareness of the distinction between therapy and research’, as suggested by Sofaer et al.18 Finally, their data on views about who is responsible for making a drug ‘reasonably available’ differed from ours: in Pace's study, most indicated that the primary responsibility for making the drug ‘reasonably available’ should be shared between host country governments and sponsors, whereas in our study, the sponsor is undoubtedly recognised as responsible for the supply.
When asked about how long the treatment should be assured after the trial, the majority of clinical investigators and sponsors in our study replied that the medication should be provided until available in the public health sector; the EC members thought it should be furnished as long as a benefit is present, and the patients answered that the benefit should be assured for life. By comparison, Shaffer et al., in a study with HIV patients, researchers and administrators in Kenya found that if therapy could not be continued for any reason, the patients felt drug therapy should be subsidised or made available through alternative means; all groups unanimously answered it would be unfair to the patients to be withdrawn from the medication following a clinical trial.12
According to our results, the group as a whole thinks that research participants are less informed about how to obtain the study drug after the trial than about other topics in the informed consent. Interestingly, in our study, the investigators thought that research subjects are better informed than EC members think they are. All respondents replied that the least important information to provide during consent would be the study design. This can be a useful insight for reducing the size of informed consents, which are usually difficult to explain and very time consuming. For our respondents, potential risks were the most important information in informed consent except for patients who reported that potential benefits are more important than potential risks.
Cohen et al. published a review of clinical trials conducted between 2004 and 2007 in HIV/AIDS, malaria and tuberculosis, and observed that only 1.3% (4 in 312 studies) mentioned post-trial provisions.24 Shah et al. (2009) assessed NIH-funded studies with antiretroviral drugs conducted in developing countries between July 2005 and June 2007. Each of the 18 identified studies had post-trial access plans for participants. More than 70% had specific mechanisms described for this access, however, none of them assured long-term sponsor funding after the trial.29
Obtaining access to better healthcare, and collaborating with the progress of science appeared as the main drivers for patient's participation in our study. These results were similar to a recent study, which also demonstrated altruism-related motivations as major reasons for Brazilian patients to participate in clinical research.30 However, among the other groups, the major reason for patients would be access to better healthcare as well as access to treatment alternatives for their diseases, reflecting personal benefits as motivation, which are also described in the literature.
A clinical trial is a very controlled setting making possible a close follow-up of participants. Therefore, a good option for continuing patients on investigational drugs would be an open-label extension of the protocol, ensuring the patients give their informed consent again and continue to be monitored, mainly regarding adverse events and drug accountability.31 However, study extensions are not always possible. An international collaboration including all stakeholders from many countries should be established in order to bring different perspectives and possible solutions to the table. It is absolutely essential to enhance these collaborations by creating an atmosphere based on more than partnership, but also in trust.
Issues related to post-trial access should be addressed early in the setting of clinical trials; prospective agreement between trial sponsors, investigators, regulatory national bodies, patient advocacy groups and participants may be the most appropriate way to follow. Investigators should be encouraged to formulate plans in advance and to work with other stakeholders to provide access to healthcare, not necessarily limited to the investigational medicine.4 ,6 ,19 In any case, the participation of patients from non-developed countries in clinical trials should not be discouraged just because of this issue.4
Our study had some limitations: the response rate and internet survey methodology may limit the representativeness of our data; non-respondents could have different opinions than the actual responders. Since the questionnaire only looked at what the respondents think but not how they act, it is possible that reported practice differs from actual practice. This is a Brazilian survey; therefore, the results may differ from other countries and also from other diseases or therapeutic fields. Even inside Brazil, the majority of respondents were from the southeast, where indeed the most clinical trials in our country are conducted.
Conclusion
The majority of clinical trial stakeholders in Brazil (investigators, members of ethics review boards, sponsors and research participants) share the opinion that investigational medicine should be given free by the sponsor after trial. However, there is not a common view on who should receive the drug post-trial and for how long. Sponsors consider that the drug should be provided until it becomes available in the public health system; members of ECs argue that it should continue as long as patients can have the benefit; for research participants, the drug should be provided for life. The inherent limitations of this study prevent their results to be generalised. Nonetheless, these data add to the limited data on post-trial access, mainly in chronic diseases and in a developing country. Further studies and open discussions on the topic are welcome.
Acknowledgments
We thank Dr Christine Grady (NIH/USA) for the careful review of the manuscript; Rogerio Prado and Miriam Souza (Faculdade de Medicina da Universidade de Sao Paulo) for the statistical analysis and database entries, respectively, as well as the responders (EC members, investigators, sponsors and patients), who made this research possible.
References
Footnotes
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Competing interests SD works nowadays in the Boehringer Ingelheim Brazil and had previously worked in other pharmaceutical companies as well as in clinical research center in the university. She was also president of the Brazilian Association of Pharmaceutical Medicine (SBMF).
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Ethics approval Hospital das Clinicas da Faculdade de Medicina da USP (Sao Paulo).
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Provenance and peer review Not commissioned; externally peer reviewed
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Data sharing statement We submitted other papers related to this one to other magazines (Revista da Associação Medica Brasileira and Braz J Epidemiology), but with different focus. None of them contain the same information and data we are now submitting to JME.
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