The doctrine of informed consent can be little understood and followed in international clinical trials, therefore necessitating an examination of ethical and other dimensions. Arguably, informed consent provides the foundational basis for all clinical research, and also represents the right of every individual to have control and make a personal decision to accept being a volunteer in a research study, and also have to domain over personal choices in medical treatment. To exercise this right in a clinical research study, the patient or clinical research subject must receive adequate and unambiguous information to make an informed decision that will be conducive to consenting, refusing treatment, or partaking in a study (Thornton, 2000). With this right, now also codified in statute, it is therefore incumbent upon physicians and researchers to provide disclosures about the risks associated with the proposed treatment, vital in all clinical research studies involving human subjects. Palmeirim et. al, (2001) expressed a universal dilemma in a Tanzanian context, that although study participants must sign an informed consent form (ICF), the optimal methods to convey trial-relevant information in the ICF, in low-income countries remains a challenge and an inadequacy. The process of creating awareness by clinical investigators by providing to research subjects, full information the deep level of knowledge and insight to human participants and volunteers represents the fundamentals of informed consent, with full disclosure.
Informed Consent and Challenges
The goal of clinical research is to aid discovery in drug development, however, it is mired in many difficulties, even with the best interests in mind of researchers and study participants. The process of informed consent entails patient autonomy to voluntarily participate in a trial with full awareness, knowledge, and ability to make an informed decision. However, with the copious amounts of documentation to be maintained in a study, extensive patient and other records, the overall bureaucratic process, regulations, documentation, and oversight, this process represent a complex and burdensome enterprise with many details and protocols for participants and investigators, and short timelines do not alleviate the situation as well. Nevertheless, informed consent must never be taken lightly and a sponsor and CRO must err on the side of informed decision-making by participants. In Sub-Saharan Africa, De Pretto-Lazarova et al., (2021) suggested specifying the minimum maternal age for transparency in the recruitment of children with minor mothers, the proxy decision-makers in international clinical trial guidelines would facilitate correct and transparent informed consent for children and children with minor parents.
The responsibility of IRB’s, clinical researchers, and investigators, therefore, cannot display any laxity in respect of the informed consent process in the era of complexity in clinical research, with the expeditious intent and the emerging focus on biotechnology, gene, and other therapies. Laws and amendments must be fully cognizant of and complied with to the letter and spirit. For instance, the difference between consent in clinical trials of investigational medicinal products (CTIMPs) and other kinds of clinical research that are non-CTIMPs is of significance, as the Mental Capacity Act 2005 does not apply to CTIMPs (Craig, 2013). Perin et al., (2021) have called informed consent rightly, “a defining moment” where researchers must facilitate patients’ comprehension of their condition and outcomes, to build trust and confidence.
With the intense scrutiny and copious FDA and regulatory stipulations, some may contend they would arguably limit discovery and business growth, however, the informed consent process cannot be less stringent in any way merely due to voluminous reporting or comprehensive processes. Meeting standards in regulatory compliant written informed consent is difficult when besieged with communicable and infectious diseases (Woods et al., 2016). Knowledge from clinical research benefits humankind where vigilance is required to ensure the choices made by patients, physicians, administrators, policymakers, and others in the clinical research enterprise is compliant with the responsible informed consent process. The inculcation of good recruitment practices and standards during the initial study startup is essential. Observance of regulatory compliance must not be construed as obstacles and impediments; rather they denote the oversight and advance planning which may help in observance of compliance, and informed consent reflects the voluntary and personal choices participants may make in participating in a clinical research study or considering otherwise. When patents, investors, decades of research, and— most importantly—patients’ lives are at stake, a one-size-fits-all approach simply will not work (Goldman, 2004), and this can be said of the informed consent process, as well. Research subjects must be furnished with extraordinary detail so that they can comprehend the risks and benefits and make an informed decision in willfully partaking in a study, or abstaining.
The recommendation of this author is that the FDA Code and guidelines are a good starting point to examine the elements of Informed Consent since all research must display conformance to the regulatory agency guidelines and dictates. Critically, research studies falling under the purviews of the requirements of the FDA regulations, the informed consent documents should meet the requirements of 21 CFR 50.20 and contain the information required by each of the eight basic elements of 21 CFR 50.25(a), and each of the six elements of 21 CFR 50.25(b) that is appropriate to the study (FDA, 2016). IRBs however are the final arbiters to determine the adequacy of the information in the informed consent document.
While many IRBs have developed uniformity in documents, the customization to local cultures, languages, and dialects remains a challenge. Nevertheless, the standardization serves to provide an acceptable source of reference, that facilitates adherence and compliance with confidentiality, compensation, recording of queries to questions, and to record the voluntary nature of participation. Each investigator should comply with the local IRB requirements before submitting a study for initial review (FDA, 2016). On the surface, it appears that the different regulatory agencies are working seamlessly to advance the cause for research. In looking at the complexities involved, there seems to be a different story of fragmentation and a lack of cohesion. A common thread of lament is failure to achieve harmonization, with reasons including complacency, a maze of bureaucracy, excessive paperwork, comprising of the major reasons which run against the grain of streamlining the responsible conduct of research (Mastroianni, 2008), with informed consent signifying the vital first step in the conduct of a clinical trial.
Facilitators and Barriers in informed consent: Complexities in Clinical Research
A facilitator of informed consent is comprehensive information offered to study participants to make informed decisions. Bolcato, et a., (2014) noted that there is a responsibility in enrolling subjects in a clinical trial, for subjects to be thoroughly informed about the nature of the study, and every possible benefit and risk, so that a voluntary decision to participate is consciously made. The inadequacy of information is a barrier. The authors cite the great emphasis the Ethics Committee (EC) of the Verona University Hospital assigns to ensure the adequacy and completeness of the written information to the subjects, presenting statistics on over 101 the changes the institution saw necessary in recent IC (Informed Consent) processes. Descriptions of major differences between the interventions studied and commonly practiced usual care, as well as potential risks associated with these differences, are essential elements of adequate informed consent (Cortés-Puch, et al., 2016). The willful, or inadvertent failure to provide adequate and comprehensive information on risks and benefits to study participants, represent the major barriers to informed consent and are the facilitators and barriers that would fall under these good practices and lapses.
Some Informed Situations that have Impacted Consenting
Clinical trials are increasingly global and geographically dispersed, for good reasons of economics, a more readily available and suitable pool of research participants, however, that only exacerbates the ethical complexities and increases the potential for informed consent breaches and lapses. The focus of this component of the article is on clinical research studies, with an Indian perspective. The justification is that this is a country of over 1.3 billion people, and an ever-increasing number of clinical trials are conducted there. A country also with the highest number of pharmaceutical companies in the world. Every clinical trial must be customized to the operating environment, for we know that clinical trials will vary by country and geography. Recruitment obstacles to be overcome will include ethical, social, cultural factors, in addition to clinical strengths of researchers, and the inadequacies, relative to the geography of a study, which may pose difficulties in recruitment. The implicit trust by research subjects of their physicians and caretakers, as noted by Kaye (2021) in Uganda, featured as the motivators for participation, with laudable intent in contributing to science and discovery.
While the emphasis globally, and generally is ethically oriented, insofar as providing complete information and ensuring voluntary participation, with the efforts on harmonization of ethical tenets of informed consent, the lapses and breeches prevail. The dilemma seems more prevalent in developing countries, noting “when intentional lapses in conduct of trial hamper the ability of socially and economically disadvantaged communities in developing countries to make a free and informed decision (Agrawal, Joshi, & Shah, 2014). To counter these lapses, regulators have made compulsory the audio-video (AV) recording of informed consent, to supplement the mandatory written consent from participating subjects. The documentation and recording must also be safeguarded and securely stored, to abide by the principles of conﬁdentiality.
Citing the record of accomplishment and current lapses, the authors point to numerous instances globally, and in India, where humans appear often subjected to undue risks and abuses, requiring increased oversight and regulations for their safety (Agrawal et al., 2014). India and the awareness of informed consent and the Hippocratic Oath principles of ‘…never do harm to anyone and physician-directed care of patients is a welcome sign, as well as the Nuremberg code and the declaration of Helsinki. It would be remiss not to mention that some researchers have found redesign of the IC as a limited psychological capacity even in stable patients to fully comply with the informed consent, as set in the Declaration of Helsinki.
Voluntary participation and the ethical tenets to ensure that patient consent is obtained in a fair and just manner, however undesirable lapses in the conduct of clinical trials have not entirely disappeared. Intentional lapses seem to stem from the exploitation of socially and economically disadvantaged communities in developing countries in the conduct of trials. The dangers in developing countries studies for interventions may pose potential to cause serious risk to patients, or those involving minors, and failure to enact ethical recruitment of participants will stymie the speed of drug development and the goal of affordable medicines, an important consideration in India (Agrawal et al., 2014). Video recording may be a step to prevent breaches and lapses in ethical conduct, while ingraining best practices represent those which aid patients in making well-considered and informed decisions, by evaluating the pros and cons.
Multiculturalism is another potential barrier in India, arising from logistical, linguistic, cultural, and other challenges. The difficulties in efforts at harmonization notwithstanding, national and international guidelines, codes, and regulations do serve to guide the ethical conduct of research involving human participants in India. The problem is compounded when applying ethical principles in obtaining informed consent in a multicultural society in India. Kulkarni (2014), expressed the challenge eloquently: “While, on the one hand, they are not to violate universally applicable ethical standards, the local culture of research participants must also be considered”, citing a strong role of Ethics Committees (ECs, over 850 registered in India) for researchers to document the informed consent process and all the relevant information in the protocol before initiation of the study, including waivers. In a multi-center study, it takes Regional Ethics Committees (RECs) to examine the informed consent (Kulkarni, 2014), which may be the solution to overcome the potential exploitation and the barriers due to cultural and other factors.
In summary, Kulkarni (2014) has listed the important issues and challenges of Informed Consent as participant-related factors, involving comprehension and translation to regional languages for the understanding of participants, where there are many vulnerable participants. Storage period of biological samples and obtaining audio-visual and online informed consent, providing post-trial access and benefits to the participants, and monitoring the process of informed consent in studies, and where applicable, a waiver of informed consent. Awareness of these challenges appears a step in the right direction to forging a path to drug development and affordable health for all in India.
The Road Ahead
Is informed consent going to be redundant in the future will be anybody’s guess? Genetic mapping, molecular genetics, and developments in biomedical research and healthcare can in the future cause a revisiting of the concept of informed consent, as we know it, and possibly challenge existing perceptions and imperatives in informed consent. The informed consent concept hinges on informed decision-making based on a careful evaluation of risks and benefits, and forms as well, the underlying principles for the protection of study participants, safeguarding their privacy, and the responsible conduct of research. However, advances in genetics and biomedical research as well as new forms of decision-making in healthcare may well require a rethinking of this traditional idea (Kegley, 2004).
The author of this article calls for the preparation of IC models to be adaptable, customizable, and ready to reference with checklists to different situations. For instance, Pal et al, (2021) found value in using a validated questionnaire in testing for clinical trial comprehension and cautioned that with the increased ethical, level of detail and contentiousness in the early phase and terminally ill cancer patient clinical trials, and patient selection and participant information sheets (PIS.
The Clinical Trials Directive (CTD), adopted in 2001, aimed to change this by harmonizing all legal regulations on clinical trials applicable in the EU but nevertheless allowing national deviations in implementation into national laws through opening clauses and aspects that were left unregulated. In view of the Clinical Trials Regulation (CTR) which, according to the current status, will with high probability be applied from 2022 on, and which in future will be the legal basis for clinical trials with medicinal products in humans, applied directly in all EU member states, the necessity to take stock of the effects of the CTD was evident.
It is hoped that increased oversight and awareness may remedy the problem cited in the past, in the selection of countries for conducting clinical trials, for financial and other considerations, and legal requirements, secondarily (Schweim, et. al., 2021). Adequate information is the cornerstone of informed consent, which may not reflect future trends. To promote thought in this direction, there are recent advances in genetic science and medicine, and particularly the development of population genetics databases, and perhaps it may be not long before the notion of informed consent is laid to rest as new forms of consent emerge, such as the application of artificial intelligence in data scrutiny, with patients therefore not in the forefront of direct risk. Kegley, (2004) vociferously has the crystal ball prediction: “Old rules often cannot fit new situations, and the changing needs, knowledge, and globalization in biomedical and genetic research may demand a new ethical and legal framework for consent”.
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Lionel de Souza, LL.B., MBA, MACPR, PhD
Dr. de Souza is a well-published and award-winning Professor, Philanthropist, and leads US, International University, and School education initiatives. In the sphere of global higher education development, he is actively involved in advancing the educational needs of aspiring and deserving populations worldwide. Extensive global engagements are in clinical research, management healthcare, and pharmaceutical marketing and he is the CEO of a global law firm. The current projects of Dr. de Souza are in the USA, India, the Middle East, and Africa. Dr. de Souza is currently heading up projects on healthcare, involving Artificial Intelligence and customized IT Solutions to advance and optimize organizational effectiveness. As a professor, he graduates many doctoral graduates and is the recipient of awards and nominations for Excellence in Doctoral and Masters’ advisement in the disciplines of management, business, healthcare, and marketing in leading US/UK institutions. Dr. de Souza is the Executive Director of UniversitiGoGlobal, an organization that creates Worlds of Opportunities for students and Universities, towards one goal of expanding the frontiers and boundaries of knowledge and innovation globally!