Question

locate one article either from the library or the Internet regarding an ethical issue in clinical research. Choose one of the clinical research roles described in the environment and state how this group would interact with others to handle the situation. Remember to provide references.

Answer 1

Clinical research in recent times has become synonymous with drug research with special emphasis on Clinical trials, although it literally refers to all types of research involving human participants related to generation of new knowledge for diagnosis, treatment, and prevention in the field of human health and diseases, scanning molecular genetics on one end and epidemiology and public health research on the other end. Many do not realize that a systematic testing of a hypothesis by analyzing data from patients’ case records or application of new technologies on stored human biological materials also come under the purview of clinical research. As per the current national and international debate on this issue, the present definition of clinical research includes any study conducted on human beings themselves, their biological materials, and human biological data with the potential to improve well being of the human race.

THE ETHICAL ISSUES IN CLINICAL RESEARCH PRIMARILY INVOLVES PROTECTION OF RIGHTS, SAFETY, AND WELL BEING OF THE RESEARCH PARTICIPANTS

All national and international guidelines lay emphasis on the code of conduct to be followed by researchers and the other stakeholders in clinical research to uphold this basic commitment to safeguard the rights and safety of the research participants who play a central role in research without whom-either themselves, their data or their biological samples-no research is possible. However, reviewing and constant monitoring of the research activities to ensure adherence to the principles laid down in these guidelines or policies or legislation are the main concerns of the Ethics Review Committees (ERC/EC), whether institutional or independent, which are entrusted with the responsibility of protecting the rights and safety of the research participants. Although all the guidelines are based on the cardinal principles of autonomy, non-maleficence, beneficence, and justice, the ethical issues to be tackled are increasing day by day with the advancement of new technologies, a wide range of research activities, and globalization of clinical research. While majority of the countries have only guidelines and few have regulations or laws related to clinical research as in the USA, the threat posed to the human participants are similar all over the world and there is a need for wider dissemination of these principles to all stakeholders of clinical research including the public at large and the participants in addition to the researchers, sponsors, institutions, members of ethics committees, regulators, and the policy makers, so that the rights of the research participants and the responsibilities of those involved in research are well understood by all concerned. This will lead to constant updating of guidelines, developing new guidelines, proposing new policies, and enacting appropriate regulations, so that the human research participants and the community rest assured that they are well protected while participating in any research. As of now, the crucial structure to ensure such protection is the well-constituted, well functioning ERC/EC whose capability strengthening is the main focus of the different national and international fora such as FERCI (Forum for Ethics Review Committees in India), FERCAP (Forum for Ethics Review Committees in Asia and Western Pacific region), SIDCER (Strategic Initiatives in Developing Capacity for Ethical Review), etc. to name a few.

THE FUNDAMENTAL ETHICAL CONCERN RAISED BY CLINICAL RESEARCH IS WHETHER AND WHEN IT CAN BE ACCEPTABLE TO EXPOSE SOME INDIVIDUALS TO RISKS AND BURDENS FOR THE BENEFIT OF OTHERS

Risk-benefit analysis is the main responsibility of ethics committees which give final approval for implementation of any research proposal, thereby taking care of the principles of non-maleficence and beneficence. How this is being done is anybody's guess and the capability of the members in doing such an analysis is a debatable issue. Medical research often involves exposure to minor pain, discomfort, or injury from invasive medical procedures, or harm from possible side effects of drugs. All of these should be considered “risks” for purposes of EC review. Some of the adverse effects that result from medical procedures or drugs can be permanent, but most are transient. Procedures commonly used in medical research usually result in no more than minor discomfort (e.g., temporary dizziness, the pain associated with venipuncture, etc). Some medical research is designed only to measure more carefully the effects of therapeutic or diagnostic procedures applied in the course of caring for an illness. Such research may not entail any significant risks beyond those presented by medically indicated interventions. On the other hand, research designed to evaluate new drugs or procedures may present more than minimal risk, and, on occasion, can cause serious or disabling injuries. Participation in research may result in undesired changes in thought processes and emotion (e.g., episodes of depression, confusion, or hallucination resulting from drugs, feelings of stress, guilt, and loss of self-esteem). These changes may be either transitory, recurrent, or permanent. Most psychological risks are minimal or transitory, but ECs should be aware that some research has the potential for causing serious psychological harm. Once the risks have been identified, the EC must assess whether the research presents greater than minimal risk. The regulations allow ECs to provide expedited review of proposals if the research presents no more than minimal risk. Alternatively, when the proposed research presents no more than minimal risk, waiver or modification of consent requirements are also allowed. For research that involves more than minimal risk of harm to the participants, the investigator must assure that the amount of benefit clearly outweighs the amount of risk. Only if there is a favourable risk-benefit ratio, a study may be considered ethical.

The concept of risk is generally understood to refer to the combination of the probability and magnitude of some future harm. According to this understanding, risks are considered “high” or “low” depending on whether they are more (or less) likely to occur, and whether the harm is more (or less) serious. In research involving human participants, risk is the central organizing principle, a filter through which protocols must pass; research evaluated by ECs that presents greater risks to potential research subjects will be expected to include greater or more comprehensive protections designed to reduce the possibility of harm occurring. The ethical basis for this position was usefully summarized in the US National Commission's Belmont Report: “The requirement that research be justified on the basis of a favourable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons.” However, relatively little progress has been made in describing the criteria for assessing risk by ECs. In large part, this is due to the multiple difficulties inherent in classifying risk judgments, including the difficulty associated with risk perception in general, and other aspect of objectively quantifying risk. A study presents a minimal risk if “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests". Risk assessment is a technique used to determine the nature, likelihood, and acceptability of the risks of harm. In actual practice, there is always a great deal of controversy about how such assessments should occur. Moreover, few ECs conduct formal risk assessments. Reliable information about risks or potential benefits associated with the relevant alternative interventions is often lacking. Hence, highly accurate risk assessment is difficult and in many cases impossible. Research involving human subjects can yield the following three types of potential benefit: (1) Direct medical benefit to subjects; (2) Indirect benefit to subjects; and (3) Benefit to others. Thus, although crucial, the Risk-benefit analysis appears to be a difficult task in clinical research. Furthermore, given its necessity for decision-making and its complexity in execution, a utilitarian interpretation of risk-benefit analysis is done. First, pain and pleasure from classical utilitarianism are replaced by Quality-Adjusted-Life-Years (QALYs). Second, a constraint on the maximum allowable risks is introduced in order to avoid participants from being sacrificed in experimentation. With this utilitarian interpretation, risk-benefit analysis may support the balancing of potential harms and opportunities to some degree. However, many still feel that it is undesirable to trust risk-benefit analysis as an indisputable calculation model commanding a decision in clinical research.

In the initial review process, ECs evaluate a research proposal's risks and expected benefits based both on study design and on predictions of subject response, and it is widely acknowledged that part of that overall evaluation will include plans for safety and data monitoring. It is necessary to distinguish the process of monitoring data and safety for the study as a whole from monitoring an individual subject's safety. Data and Safety Monitoring Boards (DSMBs) are well-established devices, particularly for multi-site studies, and may even recommend early termination of a study because of evidence that one arm of the study is safer or more efficacious than the other. ECs should expect investigators to describe in their research proposals (particularly in proposing research that involves greater than minimal risk) how potential harms to subjects will be monitored. Guidelines and regulations require the investigator to weigh risks and benefits, but the EC will make a judgment of its own. The EC should discuss the relevant risks and benefits, provides arguments for weighing and then come to a conclusion. This process of weighing and reasoning should be reported in minutes of the meeting and may be accompanied by critical remarks that are to be considered by the investigator, to provide for additional measures, scientific data, and/or other information as a revised version which can be considered in the following session of the EC and this cycle may be repeated a few times until the Committee either approves or disapproves the research protocol for execution. Recognition of potential harm by the investigators and suggesting appropriate methods of tackling such harm while submitting the proposal for review itself will be a major step in protecting the participants. All ECs should include this aspect in the Submission form. In one of the most influential papers in the history of research ethics, Hans Jonas (1969) argues that the progress clinical research offers is normatively optional, whereas the need to protect individuals from the harms to which clinical research exposes them is mandatory. That is the reason ECs are being entrusted with additional responsibility of continuous monitoring of research, which is still not adopted unfortunately by many ECs in the country. The general perception is-once the initial review is done and the research appears to have a favorable risk-benefit ratio, no more evaluation is required by the EC. The researchers may go ahead with the implementation of the project. In reality, risk assessment is a continuous process from the initial submission of proposal to EC till submission of final report including publications arising out of the research.

REFERENCES

1. Ethical Guidelines for Biomedical Research on Human Participants. New Delhi: 2006. Indian Council of Medical Research.

2. CFR Part 46 (Office for Human Research Protections, US Department of Health & Human Services) [Last accessed on 2012 Oct 1]

3. Wendler D. The Ethics of Clinical Research, First published Fri Jan 30, 2009; substantive revision Thu Sep 20, 2012, Stanford Encyclopedia of Philosophy

4. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000[PubMed]

5. The Belmont Report - Ethical Principles and Guidelines for the protection of human subjects of research. 1979 [PubMed]

One way to ensure that clinical trials are conducted ethically is to join an accreditation programme to make sure the organisation follows modern concepts of clinical research. An example highlighted here is the Association for the Accreditation of Human Research Protection Programs in the US (AAHRPP, http://www.AAHRPP.org). AAHRPP was established in 2001 to advance accreditation as a means of ensuring excellent and ethically sound research. The AAHRPP is a voluntary, peer-driven and educationally based model of accreditation. It seeks to recognise high-quality HRPPs of research organisations. The accreditation standards meet or exceed international and local regulatory requirements for protection, and are also reasonable, attainable and representative of current best practices. The organisation/institution/company/EC seeking accreditation, referred to as the “organisation,” must have a “human research protection program,” as defined by the accreditation standards (see text box). As of December 2009, a total of 200 organisations had obtained the accreditation; 176 of them are research or health care organisations, along with 12 ECs, one clinical trial services provider and one pharmaceutical company. Of the top 26 medical schools in the US, 14 are accredited. The initial step in the accreditation process is for an organisation to engage in a thorough self-assessment. This enables it to identify and remedy programme weaknesses. Prior to seeking accreditation, the organisation should develop a clear concept of the programmatic unit that will seek accreditation. The results of the internal review are submitted to AAHRPP in the form of an application. The key elements of the AAHRPP selfassessment recommendations are the three domains of assessment: (I) Organisation, (II) EC and (III) Researchers. This exercise enables two important aspects of human research protection assurances to be addressed.

In summary, the AAHRPP accreditation standards spell out that the ORGANISATION is responsible for developing a number of written procedures addressing very crucial and essential aspects of an HRPP. The most important issues addressed here are that the organisation must develop written procedures for an independent EC, as well as written procedures addressing the review of the scientific value of a research protocol. The organisation should also establish procedures ensuring that the research complies with applicable laws and regulations, by developing written procedures for educational activities, internal audits and conflict of interest policies. Other topics to be addressed in written procedures are safe storage and accountability of test articles as well as HRPP issues built into sponsor agreements.

In summary, the AAHRPP accreditation standards clearly spell out that ETHICS COMMITTEES should operate according to written procedures addressing very crucial and essential aspects of an HRPP.

Investigator and Staff: The environment in which investigators and staff conduct research and the type of research they perform influence their roles and responsibilities. Competent, informed, conscientious, compassionate and responsible investigators and staff provide the best possible protection for human participants. This domain of standards sets forth requirements for investigators and staff involved in research involving human participants (see text boxes). As part of its HRPP, an organisation can improve its protection of participants if it has arrangements ascertaining and enhancing the competence of investigators and staff.

Quality Assurance and Quality Control: Over the past few decades, we have seen a welcome development of guidance and regulations surrounding human research projects as a result of our improved understanding of the strong need to protect human research participants – no longer tolerating poor science and research ethics. Non-institutional guidance by the Declaration of Helsinki and the ICH GCP Guideline represents general ideas regarding human research. These internationally recognised documents have been developed by a core group of international professionals representing investigators, industry and regulatory authorities. As they stand, they have no legal power. However, many countries, sponsors and/or organisations have adopted those internationally valid, ethical documents as deemed mandatory. In addition, each jurisdiction has developed its own legal framework for the protection of human research participants. Such noninstitutional HRPPs provide the international and national framework of human research operation, but they do not enforce quality control to keep an individual organisation, EC or investigator and staff in full compliance. Similarly, regulatory authorities are never or seldom responsible for quality control at an institutional level, even though they establish legally valid quality assurance structures. Once in a while, regulatory authorities may perform an inspection at a study site for a specific clinical trial. But these are not full “audits” of an organisation, EC or investigators and staff, ensuring overall compliance with either national and organisational regulations, or applicable written SOPs. There has been an increase in demand – though not yet legally enforced – that the organisations must take steps to make sure that trial participants’ well-being, privacy and confidentiality are handled appropriately. The operation of an EC is now well defined and generally accepted. However, in the end, it is the investigator and the site staff that have control over the participants’ well-being during the course of a clinical trial.

REFERENCE

Clinical Trials Center at The University of Hong Kong​