MAIN ETHICAL BREACHES IN MULTICENTER CLINICAL TRIALS REGULATIONS OF TURKEY

Abstract

Turkey has been a growing market for multicenter clinical trials for the last ten years and is considered among the top ten countries in terms of potential study subject populations. The objective of increasing the share of Turkey in multicenter clinical trials is strongly supported. This ambitious goal of Turkey raises the need to have regulations in compliance with other leading countries conducting clinical trials. The latest published Turkish regulations on clinical trials are structured in compliance with the International Conference on Harmonization (ICH) Guidelines and in harmony with the regulations of other leading countries in clinical research, such as the US. There are still flaws in Turkish regulation with the risk of violating human subjects’ rights and issues with responsible conduct of research. The aim of this article is to compare Turkish clinical trials regulations with those of the US, to determine if there exists any incompatibility between the countries’ regulations and, if so, how to ameliorate these. The main flaws in Turkish clinical trials regulations are identified as follows: lack of definition of the term “human subject; absence of explicit referral to the unacceptability of Conflict of Interest (COI) and taking measures to avoid it; exiguity of emphasis on plurality of the IRB members; nonexistence of a clear expression that this is research; and clinical equipoise, regarding the treatment of the existing clinical problem and lack of integration with international accreditation systems for Institutional Review Boards.

INTRODUCTION

Since the number and extent of multicenter international clinical trials are increasing, the harmonization of regulations, with internationally accepted documents, such as the Declaration of Helsinki, The Council for International Organizations of Medical Sciences (CIOMS) guidelines and the International Conference on Harmonization guidelines, become more important for the planning, conduct and reporting of research. Harmonizing national regulations with these international documents means that any research, conducted in multiple countries, would be subject to similar regulations. [1, 2, 3]

Apart from administrative concerns, the harmonization of regulations is crucial to assure the responsible conduct of research. Protection of fundamental human rights and respect for the autonomy of human subjects can be secured, at least to a minimal standard, with the presence of national regulations in compliance with internationally accepted ethical principles. [4]

Turkey has been a growing market for multicenter clinical trials for the last ten years. According to data of the Turkish Drug and Medical Devices Institute (TDMDI), Turkey is considered among the top ten countries in terms of potential study subject populations. These consist of the United States, China, India, Brazil, Russia, Japan, Mexico, Germany, Turkey and Thailand. [5] Currently there are seventy eight Institutional Review Boards (IRBs) in 34 provinces, with a total number of 977 IRB members. None of the IRBs is accredited by an international accreditation institute. The objective of increasing the share of Turkey in multicenter clinical trials is strongly supported and expressed by the Turkish Government, with the objective of increasing drug research investments to 3 percent of gross national savings by 2023. [6]

This ambitious goal of Turkey raises the need to have regulations in compliance with other leading countries conducting clinical trials. Turkey’s candidacy to enter the European Union (EU) and the commitments of the Turkish Government to align Turkish legislation with that of the EU, has opened the way for transferring internationally accepted standards and procedures to Turkish national regulations. [7] International Conference on Harmonization (ICH) Guidelines are established, with the cooperation and collaboration of the regulatory bodies of the EU, Japan and the US, to set common grounds required for international multicenter clinical trials. The latest published Turkish regulations on clinical trials are structured in compliance with the ICH Guidelines and in harmony with the US regulations. [6]

There are still some flaws with the risk of violating human subjects’ rights and responsible conduct of research. The aim of this article is to compare the Turkish clinical trials regulations with those of the US, determine any incompatibility and, if they exist, to discuss how to ameliorate them.

Evolution of Regulations on Clinical Research on Human Subjects

In the US, after the exposure of multiple instances of inappropriately conducted research involving human subjects, such as the Tuskegee experiment, the Willowbrook Hepatitis study and human radiation experiments, the Senate Committee on Labor and Human Resources held hearings which ultimately culminated in the 1974 National Research Act. [8] This Act established requirements for Institutional Review Boards (IRBs), as well as the supporting policy and procedures. The regulations addressed several items, such as: how research should be defined; who should be considered as a human subject; which type of research should be reviewed by IRBs; as well as the structure and the responsibilities and authority of IRBs. There are two major bodies for clinical research regulations in the US: The US Food and Drug Administration (FDA) and National Institutes of Health (NIH), the Office for Human Research Protection (OHRP). The FDA has the authority for jurisdiction over research involving primarily drugs, biologies and devices that must be approved by the FDA prior to marketing, while the OHRP has jurisdiction over federally funded research and non-federally-funded research conducted at the institution.

In Turkey, the first legislation on clinical research was issued about 20 years after the establishment of the US regulations. In 1993, The Regulation on Drug Research was published, the first legislation to create IRBs in Turkey. In 1995, good clinical practice (GCP) guidelines were issued that explained the rights of human subjects, as well as the measures to be taken to protect the honor, confidentiality and privacy of human subjects and to conduct research in compliance with international standards. In 2004, the Turkish Penalty Law passed the Parliament. Article 90 of this Law determined the basic legal boundaries of clinical research on human subjects. The regulation on human subjects was revised several times due to Turkish commitments to the EU and the final version was issued in 2013. [9] In Turkey there is a very similar structure regarding the institutions regulating clinical research on human subjects. The Turkish Drug and Medical Devices Institute (TDMDI) is the authority that has similar responsibilities and duties as the US FDA, and the General Directory for Health Services (GDHS) of Ministry of Health carries out the work analogous to the OHRP.

Definition of Research

45 Code of Federal Regulations (CFR) 46.102(d) defines research as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for the purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.” [10]

21 CFR 56.102(c) defines clinical investigation instead of research. The definition of clinical investigation is as follows: “Experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of part 58 of this chapter, regarding nonclinical laboratory studies.” [11]

The Turkish regulation on clinical trials (TRCT) defines clinical research as: “research conducted on human subjects to determine or verify pharmacologic, clinic or pharmacodynamics effects, adverse events or reactions, absorption, metabolism and discard, safety and efficacy of one or more research products.” [12]

The wording and scope of these definitions differ from each other, since 45 CFR 46.102(d) definition is general to all research, while 21 CFR 56.102(c) is focused on drugs and medical devices, subject to the approval of the FDA at some point, and the TRCT definition is only concerned with clinical dials on human subjects, without considering any necessary approval from TDMDI. This variation gives important hints regarding the aim and coverage of these regulations.

Definition of Human Subjects

45 CFR 46.102(f) defines a human subject as “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information.” [10]

21 CFR 56.102(e) has a different definition: “human subject means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient.” [11]

TRCT does not define human subject, but describes a volunteer instead. “a volunteer is a healthy person or a patient, who declares written consent by herself or by a legally authorized representative (LAR) to be involved in a clinical trial.” [12]

The definition of human subjects in 45 CFR 46.102(f) is more comprehensive than the definition in the other two regulations, since it not only refers to the involvement of human subjects but also the identifiable data. Emphasis is on the precondition of “being alive” and offers clarification about the use of left over specimens of human subjects after they pass away. 21 CFR 56.102(e) and TRCT have a more simplistic approach with no referral to identifiable data. [10, 11]

IRB Membership

According to 45 CFR 46.107 and 21 CFR 56.107 each IRB shall have/be [10, 11]

At least 5 members of varying backgrounds;

• Sufficiently qualified through the member’s expertise, experience and diversity (race, gender, and cultural backgrounds)

• Able to ascertain the acceptability of the research (i.e. laws, standards, institutional responsibilities)

• At least 1 scientific member

• At least 1 non-scientific member

• At least 1 member who is unaffiliated with the institution/not an immediate family member of someone affiliated with the institution

IRB members

• Cannot comprised members of a single-profession

• Cannot participate in initial or continuing review of any project in which the member has a conflict of interest (COI) except to provide information

TRCT determines two types of IRBs: IRB for clinical trials and IRB for trials on bioequivalence and bioavailability of drugs. Both IRBs are responsible for scientific and ethical evaluation of research protocols and they should be/have: [12]

• Minimum 7, maximum 15 members with a PhD or residential degrees in various medical areas

• Medical specialists, preferably those who have experience in international research designed in compliance with good clinical practice

• A member who has a PhD in pharmacology

• A member with a PhD in biostatistics or a public health specialist

• A pharmacist who has PhD in biopharmaceutics, pharmacokinetics, or pharmaceutics technology.

• A lawyer

• A non-medical person

• A member who has a PhD in ethics or deontology -if available-

IRB members

• Cannot be a member of more than one ethic committee

• Cannot include managers of the institution in which the trial is going to be conducted

The composition of IRBs, in Turkish regulations, seems to be more strictly defined than that of the US IRBs. Some issues, with possible unethical consequences, are left out of the TRCT. The lack of an expression to avoid conflict of interest (COI) is one of them. Although it may be argued that excluding people in managerial positions of research institutes is a covert way to avoid COI, it is dubious as to its effectiveness with a lack of a clear deliniation. Another such issue that has been left out with potential for unethical conduct is the lack of a requirement for the existence of gender, race and cultural diversity among IRB members. Turkey is a country with cultural and ethnic plurality so assuring the representation of all groups would enhance the soundness of the decisions to be taken in the IRB meetings.

Research Exempt From IRB Review

Exemptions from IRB requirement in 21 CFR 56.104 are: [11]

• Any investigation which started before July 27, 1981 and was subject to requirements for IRB review under FDA regulations before that date, provided that the investigation remains subject to review of an IRB which meets the FDA requirements in effect before July 27, 1981.

• Any investigation started before July 27, 1981 and was not otherwise subject to requirements for IRB review under Food and Drug Administration regulations before that date.

• Emergency use of a test article, the use of which must be reported to the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review.

• Taste and food quality evaluations and consumer acceptance studies.

Exemptions from IRB requirement in 45 CFR 46.101 are:[10]

• Research conducted in established or commonly accepted educational settings, involving normal educational practices.

• Research involving the use of educational tests.

• Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available.

• Research and demonstration projects which are designed to study, evaluate, or otherwise examine public benefit or service programs.

• Taste and food quality evaluations and consumer acceptance studies.

21 CFR 56.104 and 45 CFR 46.101 have quite different criteria for research that is exempt from IRB review. According to the TRCT, all clinical trials should go to full IRB review. There is no qualification defined to exempt research from full IRB review.

Informed Consent

45 CFR 46.116, 46.117 and 21CFR 50 cover informed consent in the US regulations. These regulations mandate all researchers to obtain legally effective informed consent of the subject or the subject’s legally authorized representative (LAR) under circumstances that provide the prospective subject, or the representative, sufficient opportunity to consider whether or not to participate aimed to minimize the possibility of coercion or undue influence, before enrolling a human subject in the clinical trial. [10, 11]

The information that is given, to the subject or the representative, shall be in language understandable to the subject or the representative and shall exclude any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. [10, 11]

According to 45 CFR 46.116(a) and 21 CFR 50.25, informed consent shall be comprised of eight components: [10, 11]

1. Research

2. Risks

3. Benefits

4. Alternatives

5. Confidentiality

6. Compensation for injury

7. Contact Information

8. Voluntary Participation and Withdrawal.

45 CFR 46.116(b) and 21 CFR 50.25(b) defines additional elements of informed consent that should be provided to subjects when appropriate. [10, 11]

1. Unforeseeable risks

2. Termination

3. Costs

4. Consequences of withdrawal

5. New findings

6. Number of subjects.

According to the TRCT, during informed consent procedure, a satisfactory amount of information shall be delivered in an understandable language by a medical doctor or a dentist or a trained member of the research team. The informed consent shall include: [12]

1. The aim and methodology of the research

2. Expected benefits

3. Foreseeable risks

4. Unconformity between the subject’s health status and her personal qualifications

5. The conditions under which the clinical trial will be conducted

6. The right to withdraw at any time without facing any inconveniences.

The part, dedicated to informed consent in the TRCT, is significantly brief when compared to 45 CFR 46.116 and 21 CFR 50.25. There exists no concrete requirement to provide information about the duration of the clinical trial and identification of the procedures that are experimental. The TRCT does not mandate investigators to deliver information regarding any appropriate alternative procedures or courses of treatment that may be advantageous to the subject or the measures for securing the privacy and confidentiality of the subjects. The most significant flaw of the informed consent procedure, defined in the TRCT, is neglecting to clearly state that enrollment in the clinical trial is voluntary. Although the term “volunteer” is used throughout the TRCT, instead of the term “human subject”, there is no explicit expression that the prospective human subjects should be informed that participation in the trial is voluntary. On the contrary, article I of the TRCT says that “the consent of the volunteer means that she is enrolled in the study by her free will without any expectation of interest.” The emphasis is on free will and lack of expectation of interest not on voluntariness. According to the mandate of the TRCT, a human subject might consent to enroll in a clinical trial by her free will, but without being told that she has other appropriate alternatives other than getting involved in the trial and that it is up to her voluntariness to take part in the trial or not. [12]

The TRCT says that there shall be measures to compensate for injury and a person from the investigation team shall be appointed to answer questions of the subjects about their health status and the course of the trial. There is no requirement to include this information in the informed consent form. This means that human subjects may be totally ignorant about how to ask for compensation for injuries emerging from clinical trials or who to call if they have to contact the trial team. The questions that can be asked of the designated contact person are limited very strictly by the TRCT. The human subjects may only contact the designated person to ask about their health status or how the trial is proceeding. Human subjects are not entitled to ask about their rights nor are they expected to contact that person in case of research related injury or incompliance with the research protocol.

Additional elements of informed consent should be provided to subjects when appropriate but do not exist in the TRCT. There is no obligation to tell the subjects under which circumstances the trial would be ended by the investigators or any other costs that may result from participation in the research. Lack of a requirement to tell the subjects about new findings, developed during the course of the research which may relate to the subject’s willingness to continue participation, may be considered as one of the most important flaws of the TRCT, since it may be considered as a violation of respect for autonomy of the human subject.

21 CFR 50.20 and 45 CFR 46.116 prohibit the usage of exculpatory language in informed consent that would lead the subject or LAR to waive or appear to waive any of the subject’s legal rights or releases the PI, sponsor or agents from liability, such as compensation for injury. [10, 11] The TRCT does not include the prohibition of exculpatory language. Article 23 subparagraph 3 states that “having informed consent of the human subjects does not call off their right to compensation for injury arising from the clinical trial”. [12] Although this statement does not cover all violations of rights that may stem from exculpatory language, it secures the violation of a right to compensation to some extent.

A new element is added to the US law mandating registration of clinical trials to www.ClinicalTrials.gov, for the trials of drugs, biologies, and devices that include interventional studies with one or more arms and meet one of the following criteria:

• The trial has one or more sites in the United States

• The trial is conducted under an FDA investigational new drug application or investigational device exemption

• The trial involves a drug, biologic, or device that is manufactured in the United States or its territories and is exported for research

• If the trial meets FDAAA 801 definition and if it is either initiated after September 27, 2007, or initiated on or before that date and was still ongoing as of December 26, 2007.

This new step is to increase the transparency of clinical trials, to enhance the public accessibility of knowledge and to avoid outcome reporting and publication bias. [13] The amendment, in 2014, to the TRCT involved the same mandate to register clinical trials to a public accessible data base before initiating the trial. The TRCT requires the investigators to ensure the confidentiality of human subjects while registering in the data base. [14] No further specifications are made in the TRCT, such as those in the US regulation.

Documentation of Consent

According to the US regulations, the consent form may be either of the following:

• A written consent document that embodies the elements of informed consent required by 45 CFR 46.116 and 21 CFR 50.25. This form may be read to the subject or the subject’s legally authorized representative, The investigator shall give either the subject or the representative adequate opportunity to read it before it is signed. [10, 11]

• A short form written consent document stating that the elements of informed consent required by 45 CFR 46.116 and 21 CFR 50.25 have been presented orally to the subject or the subject’s legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. The subject or the representative and the witness shall sign the short form and the witness and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short form. [10, 11]

45CFR 46.117 identifies some instances in which an IRB may waive the requirement for the investigator to obtain a signed consent form. These exceptional situations are:

• The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern. [10]

• The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context. [10]

The TRCT is brief about the documentation of informed consent. There is only one phrase in article 5 subparagraph I, stating that “a signed written document is obtained from the volunteer acknowledging that she has been provided the information that is specified in the regulation.” Article 6 is dedicated to the informed consent of children. In subparagraph b of this article, it is stated that signatures of both parents or the legally authorised representative (LAR) in addition to the assent of the child - when possible- is required. Article 8 talks about an incompetent subject’s informed consent procedure and states that the signature of the LAR and assent of the subject -when possible- should be obtained for a proper informed consent. No further specifications or exceptions take place regarding the documentation of informed consent in the TRCT. [12]

The insusceptibility of the TRCT, towards breaches of confidentiality, especially in cases in which the only link between the subject and the data would be the consent document, is a major risk for vulnerable people participating in research. Minimal risk and waiver of consent are not described in the TRCT. This may cause unnecessary paper work and waste of time, both for the research team and the subjects.

Vulnerable Populations and Informed Consent

Vulnerable populations refer to classes of individuals who have reduced autonomy. They are more susceptible to coercion or undue influence. Vulnerable populations have historically been classes of individuals exploited for their ease of manipulation or convenience. In general, foetuses, prisoners, children, mentally disabled individuals, the economically disadvantaged, the educationally disadvantaged, students, employees and those with a life threatening disease are considered to be vulnerable. [1] Inclusion on this list does not imply vulnerability. Assessing vulnerability requires an assessment of the research and the recruitment methods of the researchers as well as the power differential between the human subjects and the investigators, difficulties of communication and decision making.

21CFR 56.111 requires the IRBs to take extra safeguards to protect the rights and welfare of the subjects “when some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study.” [11]

45CFR 46 has particular subparts dedicated to three vulnerable groups: pregnant women; human fetuses; neonates; prisoners; and children. 21CFR 50 has specific requirements for children as a vulnerable population only. [10, 11]

The TRCT include subparts for research on children, pregnant or breastfeeding women and those incompetent. There is also a specific guideline dedicated to ethical conduct of research on children. The subparts of the TRCT, on these three vulnerable groups, include basic ethical requirements, such as getting the assent -when possible- from the incompetent and children, in addition to the informed consent of the parents or LAR, including a pediatrician or a psychiatrist, to the IRB when children or incompetents are involved as human subjects, and assuring that the research has the potential to provide a benefit to the target population. These subparts are relatively short, consisting of five to six articles. No referrals to prisoners, economically disadvantaged, educationally disadvantaged, students, employees and those with a life threatening disease are present in the TRCT. [12]

Discussion

One of the major differences stems from the events that provoked the evolution of regulations. The US regulations originated from tragic events reported in the media about the unethical clinical research on human subjects and the devastating effects both on the people involved in these studies and society in general. [15, 16, 17, 18] The evolution of the regulations paralleled the ethical and administrative requirements to protect human subjects’ rights arising from the innovative methods of clinical research, such as the rise of social media, or new areas of research that became possible by improvements in science and technology, such as gene therapy. [19]

The Turkish regulations on clinical trials were structured with the aim of attracting more international multicenter trials to the country or to meet the criteria of the candidacy into the EU. [5] The main motive behind publishing regulations is widely different in both countries. This difference has concrete implications in practice, starting with the definition of research. The TRCT defines research in a more limited scope than does the 45 CFR 46.102(d), omitting universal elements of research, such as a requirement for systematic investigation and the aim of contributing to general knowledge and degrades research to activities carried out to determine or verify pharmacologic, clinic or pharmacodynamics effects, adverse events or reactions, absorption, metabolism and discard, safety and efficacy of one or more research products. [10] The lack of definition of the term “human subject” and substituting the term “volunteer”, in place of “human subject”, is another indication of a simplistic approach, making way for conflicts regarding the use of specimens of dead people or ‘left over’ specimens from human subjects. The absence of the definition of minimal risk and qualifications of research exempted from full IRB review suggest an unreconstructed approach. It is plausible to say that the definition section of the TRCT needs improvement to embrace current pertinent standards.

Another section, in need of improvement, is the structure and implementing procedures of IRBs. The lack of explicit referral to the unacceptability of COI, and taking measures to avoid it, is a major flaw that may lead to serious ethical breaches. [20, 21, 22] Lack of emphasis on plurality of the IRB members constitutes the risk of monologism in the IRB decisions, leaving out the visions and sensitivities of different cultures, religions, vulnerable groups and even genders. [23] The main flaws, in the informed consent section, with a risk of violating the rights of human subjects are the lack of a requirement for a clear expression that this is research and there is clinical equipoise regarding the treatment of the existing clinical problem. [24, 25] A stronger and clearer statement is needed to urge the investigators to tell human subjects that participation is voluntary. [1, 2, 3] The TRCT should define what information a proper informed consent document shall cover and include the requirement to provide a contact person whom participants can reach in case of emergency or unexpected events or with their complaints and questions about their rights. [1, 2, 3] Additional elements of informed consent are subsumable to the TRCT, such as particular circumstances that would lead to the termination of the trial, any other costs that may result from participation in the research or new findings developed during the course of the research and a compensation mechanism. [1, 2, 3] In developing countries, like Turkey, access to a research drug, after the termination of the research study, is a big issue since there may be a time lag between the end of the trial and admission of the drug to a local market. It is possible that the drug may never be admitted to market in the country where the trial was conducted. [26] The rights of participants to access the drug or medical intervention, after the research, is an important issue that is absent in the Turkish regulations. [1]

In Turkey, there is no organization or IRB accredited by Associations for the Accreditation of Human Research Protection Programs (AAHRPP). The lack of accreditation of IRBs raises concerns regarding: the compliance of organizations, IRBs or the researchers and the research staff with a human research protection program; accountability of quality assurance and quality improvement measures; availability of adequate resources; presence of ethics education programs; and transparency through communication and interaction with the community, research participants, investigators and other stakeholders. [26] Encouraging IRBs to apply for accreditation would highlight any flaws in structure or operating procedures and help Turkey to achieve its goal to increase its share in drug research investments.