• Darren Wogman

Only clinical research that is ethical is acceptable to support the marketing. How do we know [..]

“Only clinical research that is ethical is acceptable to support the marketing of medicines. How do we know that this clinical research is ethical?”


NB: Please review the feedback post for guidance


Introduction

The ethics of clinical research has a complex history, for example research conducted during WW2 and subsequent cases involving vulnerable and marginalised people such as, the Tuskegee syphilis ‘experiments’ in Alabama continuing to 1972 (Park, 2017). The idea that individuals innately know for themselves what is ethical behaviour and they can be trusted to act accordingly is not borne out of the evidence. Fundamental principles and practices like, The Hippocratic Oath have not been sufficient to adequately safeguard human life. Legislation aims to codify fundamental principles that must be adhered to. The Nuremberg Code was the first real attempt and put the concept of informed consent at its heart (Weindling, 2001). The Declaration of Helsinki followed as a collaborative effort by the World Medical Association to balance scientific discovery and participant safeguarding (World Medical Association, 2018). The later Belmont Report in the USA defined core principles of respect, beneficence, and justice (HEW, 1979).


European ethical guidelines for clinical practice are governed by the EU Clinical Trials Regulation which hold paramount the “..safety, dignity and well-being of [participants]” explaining that The protection of the individual participant must be the first and overarching priority for research. In addition, guidelines are also supplemented by individual member states. (EMA, 2014).


International consensus is sought to provide a baseline for ethical practice and determines the minimum acceptable standard of clinical practice as ICH Good Clinical Practice (GCP). However, disparity between guidelines creates ambiguity. The use of placebo, when a standard of care can be provided, is not permitted by recent DoH (WMA, 2018) and GCP (EMA, 2016) updates but, is not proscribed in earlier revisions (Wolinsky, 2006). GCP states the standard of care should be relative to what is ordinarily locally available. If the primary decision of sponsor to run trials in less economically developed countries is not to address specific health needs of that population, there is an ethical dilemma, despite its legislative acceptability under the guidelines (Weigmann, 2015).


It is not always clear what is and isn’t ethical conduct, this essay will continue to discuss the primary question of how we know clinical research is ethical and how we ensure that clinical research is conducted ethically. While the environmental impact of research should not be discarded, it is outside the scope of this assignment.



Ethics Approvals for Clinical Research


Drug sponsors have internal reviews of clinical research protocols. These boards review, at the early stages of development, clinical research plans prior to seeking external independent approval. At this ‘checkpoint’, development and clinical research plans may be altered or withdrawn altogether due to ethical concerns (GSK, n.d.).


The Declaration of Helsinki, EU Clinical Trials Regulation, ICH’s GCP (E6) guidelines and the USA’s National Institute of Health (NIH) require prior independent ethics approval for a trial, to ensure that participants are fully safeguarded and not placed at unnecessary risks of harm. Research Ethics Committees (RECs) aim to determine that trial data collected is proper for the investigation and that the appropriate permissions for the collection and processing of the data are ethically sound, the burden of clinical equipoise is met i.e. that research is not futile and risks to participants are proportional (Garrard, 2005). REC decisions are guided by established Standard Operating Procedures (SOPs) in the case of the UK, these are approved by the regulator through Governance Arrangements for Research Ethics Committees. These SOPs are grounded in GCP principles (HRA, 2019).


Authorisation to conduct clinical trials may be required from the regulator, who will request evidence of REC approval and may have further stipulations such as, the social value of the research and evidence of patient risk have been mitigated, managed and minimised before they will provide approval for the clinical trial to proceed. The role of RECs differs internationally. In the USA and UK, RECs are independent from the FDA. While in Holland, the REC can be a part of the national regulator (CCMO, n.d.). Despite these structural differences, the requirement for ethics approval and review is common amongst jurisdictions.

REC opinions are subjective and can differ from committee to committee, which is not a new complication (Downie, 1963). RECs deliberate and decisions are made by consensus. The specific make-up of each REC can determine what practices are considered acceptable or not. This is beneficial when decisions are made within the context of local considerations, however, it raises an issue that a common ethical standard may not always be maintained (Edwards, Ashcroft and Kirchin, 2004). Further questions are raised when considering the range of expertise and experience within an REC (Sayers, 2007). The volume of ethics legislation means that nuances are not always picked-up and considered. RECs are criticised as stifling innovative methods in research, especially in vulnerable and at-risk patient groups (Edwards, Ashcroft and Kirchin, 2004). However, this is due to their risk-averse nature in wishing to safeguard participants (Fistein and Quilligan, 2011).


Monitoring ethics during clinical trials

Depending on the study, a Data and Safety Monitoring Board (DSMB) may be convened. America’s NIH, requires a DSMB for all and early-phase trials that involve vulnerable populations, including children (NIH, 2000) and any multicentre Phase III trials (NIH, 1998).

The primary role of the DSMB is to monitor any potential harm to patients and results may be unblinded, such is the importance of their oversight in the safeguarding of clinical research participants. The DSMB reviews trial data and interim analyses of safety and efficacy, which may raise questions regarding the scientific validity of the trial and whether it is ethical to continue or, proceed with does escalations (EUPATI, 2016). A DSMB may recommend the early ending of a trial due to: a beneficial effect so strong it would be unethical to withhold from all participants, study futility if a statistically significant finding in unlikely to be found, if conditional powering cannot be maintained or if there is an unacceptable change in the perceived benefit:risk ratio (EMA, 2018).


A DSMB is advisory and can only suggest changes, the EMA explains that as the sponsor is the ultimately responsible entity, they are not mandated to comply with DSMB recommendations however, any digressions from the DSMB must be justified and documented. The sponsor is also strongly advised to inform both the REC and the regulator if the DSMB recommends the early end of a trial. Any changes made are done through ‘Protocol Amendments’ and will require ethics committee and regulatory approval (CHMP, 2004).


Ethics Approvals for Marketing Authorisation

The regulators ensure that a drug sponsor and any of their 3rd parties involved in the clinical research have complied with REC decisions and at least met international and local standards of practice and they must demonstrate that clinical trials have met with minimum ethics standards. In doing so, they can ensure data integrity and determine whether the proposed drug is fit-for-purpose and for the market (MHRA, 2019).

The role of regulators is therefore to ensure that the licences are only provided to drugs when it would be ethical to do so. However, they are often only provided with clinical trial data from the drug sponsor and so, if these trials fail to highlight a safety concern, it may be the case that potentially dangerous drugs are approved for sale.


Compassionate Use

Compassionate use is permitted in many countries from USA & Canada, to the EU, Brazil and China. It allows an unauthorised medicine to be used by patients who cannot enter clinical trials and do not have efficacious treatment options. The EMA suggests that compassionate use initiatives only be considered for patients in the most serious cases (EMA, 2004).

As these drugs are not licenced, their use in these circumstances is necessarily considered some form of clinical research. Clearly there is a complex issue with the use of unlicensed medicines with unproven or unknown safety profiles and uncertain efficacy. Furthermore, gaining informed consent from some of these patients can be challenging (Borysowski, Ehni and Górski, 2017).


However, this example further highlights that ethics are not fixed and are subject to have nuance. In this case, the use of the drug for the wider population is considered unethical but, that same drug’s use in this context is acceptable ethical practice.


Conclusion

Despite the legislation, ethics do not only determine legality, they concern the evaluation of research and its consequences for participants and wider society.

We can’t know that research is ethical, but a number of pieces of legislation are in place to ensure that conduct is ethical. Marketing approval is predicated on ethical principles being met namely, that the drug being marketed is both safe and efficacious and that these claims have been proven in clinical trials that themselves have been planned and proven to be conducted ethically.


This declaration of ethical practice is made both from the sponsor and from an independent REC and with inputs from DSMBs. Ultimately RECs determine if the proposed research is socially, and in the case of expert members professionally, acceptable and that the risk of harm to patients is proportional. These are clearly not the only ethical considerations for clinical research. The role of the RECs highlights that ethics are subjective. What is considered acceptable and ethical by one REC may not be acceptable nor, ethical by another. The relaxation of safeguarding procedures in compassionate use cases as well as the involvement of severely ill patients into clinical trials shows that there is nuance to these guidelines and that ethics must be tested, debated, and amended when it is appropriate to do so.


Ethics are also temporal and localised. What was once considered ethical practice in the past, is by today’s standards not considered to be ethical and further, what might be deemed as unacceptable in one authority may well be approved in another. As such, we can only be certain that clinical research is ethical, with the caveats that this ethical declaration is true only for its time and the geopolitics of where the research is conducted. Global ethical guidelines provide a baseline of minimally acceptable practice and to this end, we can be fairly certain that at the very least, this is adhered to.


There is no single solution to ethical dilemmas and ethical decisions cannot really be standardised. The debate that is being constantly held is critical to ensuring that clinical research is always ethical and represents the evolving understanding and societal changes that it is predicated on.

References

Borysowski, J., Ehni, H. and Górski, A. (2017). Ethics review in compassionate use. BMC Medicine, 15(1).


CCMO (n.d.). Guide to the review procedure. [online] English.ccmo.nl. Available at: https://english.ccmo.nl/investigators/guide-to-the-review-procedure [Accessed 14 Feb. 2020].


CHMP (2004). Guideline on data monitoring committees. [online] Ema.europa.eu. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-data-monitoring-committees_en.pdf [Accessed 14 Feb. 2020].


HEW (1979). The Belmont Report. [online] Department of Health, Education, and Welfare. Available at: https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html [Accessed 13 Feb. 2020].


Downie, R. (1963). Human Conduct: An Introduction to the Problems of Ethics. By Hospers John. (Harcourt, Brace and Company, New York. 1961. Pp. 600. Price $6.50; £3 16s. 6d.). Philosophy, 38(144), pp.192-193.


Edwards, S., Ashcroft, R. and Kirchin, S. (2004). Research Ethics Committees: Differences and Moral Judgement. Bioethics, 18(5), pp.408-427.


EMA (2004). Regulation (EC) No 726/2004 Of The European Parliament And Of The Council. [online] Ec.europa.eu. Available at: https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf [Accessed 14 Feb. 2020].


EMA (2014). Regulation (EU) No 536/2014 of the European Parliament and of the Council. [online] ema.europa.eu. Available at: https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf [Accessed 13 Feb. 2020].


EMA (2016). Guideline for good clinical practice E6(R2). [online] Ema.europa.eu. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf [Accessed 14 Feb. 2020].


EMA (2018). Questions and answers on Data Monitoring Committees issues. [online] Ema.europa.eu. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-questions-answers-data-monitoring-committees-issues_en.pdf [Accessed 14 Feb. 2020].


EUPATI (2016). Clinical Trial Data Safety Monitoring Board (DSMB) - EUPATI. [online] EUPATI. Available at: https://www.eupati.eu/clinical-development-and-trials/clinical-trial-data-safety-monitoring-board-dsmb/ [Accessed 14 Feb. 2020].


Fistein, E. and Quilligan, S. (2011). In the lion's den? Experiences of interaction with research ethics committees. Journal of Medical Ethics, 38(4), pp.224-227.


Garrard, E. (2005). What is the role of the research ethics committee? Paternalism, inducements, and harm in research ethics. Journal of Medical Ethics, 31(7), pp.419-423.


GSK (n.d.). Global Ethics and Compliance. [online] Gsk.com. Available at: https://www.gsk.com/en-gb/about-us/governance/global-compliance/ [Accessed 14 Feb. 2020].


HRA (2019). Standard Operating Procedures for Research Ethics Committees. [online] hra.nhs.uk. Available at: https://www.hra.nhs.uk/documents/1775/RES_Standard_Operating_Procedures_Version_7.4_June_2019_lHKuibH.pdf [Accessed 14 Feb. 2020].


MHRA (2019). Clinical trials for medicines: apply for authorisation in the UK. [online] Gov.UK. Available at: https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk [Accessed 14 Feb. 2020].


NIH (1998). Nih Policy For Data And Safety Monitoring. [online] Grants.nih.gov. Available at: https://grants.nih.gov/grants/guide/notice-files/not98-084.html [Accessed 14 Feb. 2020].


NIH (2000). Further Guidance On A Data And Safety Monitoring For Phase I And Phase Ii Trials. [online] Grants.nih.gov. Available at: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html [Accessed 14 Feb. 2020].


Park, J. (2017). Historical Origins of the Tuskegee Experiment: The Dilemma of Public Health in the United States. Korean Journal of Medical History, 26(3), pp.545-578.


Sayers, G. (2007). Should research ethics committees be told how to think?. Journal of Medical Ethics, 33(1), pp.39-42.


Weigmann, K. (2015). The ethics of global clinical trials. EMBO reports, 16(5), pp.566-570.


Weindling, P. (2001). The Origins of Informed Consent: The International Scientific Commission on Medical War Crimes, and the Nuremburg Code. Bulletin of the History of Medicine, 75(1), pp.37-71.


WMA (2018). WMA - The World Medical Association-WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. [online] WMA.net. Available at: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ [Accessed 14 Feb. 2020].



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