LITHUANIAN UNIVERSITY OF HEALTH SCIENCES Medical Academy
Faculty of Public Health
THE PERCEPTIONS OF MEDICAL DOCTORS ON CLINICAL RESEARCH ETHICS IN LITHUANIA AND INDIA
Master Thesis Master of Public Heath
Student:
Ravi Kumar
Supervisor:
Assoc. Prof. dr. Eimantas Peicius
KAUNAS 2019
SUMMARY
The perceptions of medical doctors on clinical research ethics in Lithuania and India Aim. To reveal the attitudes of medical doctors and their awareness on clinical research ethics in India and Lithuania.
Methods: A cross sectional survey was conducted simultaneously major hospitals in India and Lithuania. Overall, 180 medical doctors (97 from India, 83 from Lithuania) were interviewed anonymously (N=180) by using the convenience sampling method. The response rate was 60 %.
The originally elaborated questionnaire was employed. The descriptive and factor staitistical analysis elaborated, the coreelation between variables evaluated by (the correlation between variables measured by χ2, significance evaluated when p<0.05.
Results. It was revealed that almost all of Indian and only a quarter of Lithuanian respondents were critical about the approach that ethics are equally important as scientific research. It was revealed that Indian respondents tend more to disagree that philosophers should not dictate what is ethical and what is not while almost half of the Lithuanians agreed. The significant differences comparing respondents by the country were also determined by comparing their ethical awareness of research:
83.5% Indians and 64% of Lithuanians were aware that research participants do not have to participate in all procedures of clinical trials after they have given consent. More Indians than Lithuanians disagreed to the statement that participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options. While comparing the level of awareness of Lithuanian and Indians in clinical rearch ethics, we found that the mean average awareness score of Indian respondents was 36.53 (SD= 1.52) out of maximum of 45 and it was higher as compared to Lithuanian respondents’ mean average awareness score of 31.86 (SD=3.46). The level of awareness increase with increase in clinical experience of respondents and there was improvement in thinking that science is equally important as ethics. The age was important factor for the enhancement of level of awareness (0.44) and less critical attitudes that science is more important than ethics - 0.50 meaning that the increasing level of awareness depends on the level of increased age and experience.
Conclusions. The attitudes of medical doctors towards ethical research in clinical trials were found to be mostly depended on the country. Lithuanian doctors are more inclined to focus on the scientific research and progress of clinical trials, Indian doctors tend to take more account of ethical research ethics. The comparison of perceptions and awareness of medical doctors about research
ethics in Lithuania and India revealed that Indian medical doctors are more likely to comply to ethical requirements in clinical research compared to Lithuanian medical doctors.
Keywords: research ethics; clinical (drug) trials; medical doctors; India; Lithuania.
LIST OF TABLES
Table 1. Social and demographic characteristics of respondents………. 24 Table 2. Value mean for the correlation between the statements expressing the general perceptions on clinical research ethics and their acceptance with the statement that “Scientific progress is more important than ethics”………33 Table 3. Mean score of statements about awareness of research ethics………...39 Table 4. The correlation relationship between the level of awareness and age in years, and between the perception of science is more important than Ethics and age in years.………...40
LIST OF FIGURES
Figure 3.2.1. Respondents’ opinions on the statement “Philosophers should not dictate what is ethical and what is not”………....………. 25 Figure 3.2.2 Respondents’ opinions on the statement “participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options”……….. 26 Figure 3.2.3. Respondents’ opinions on the statement “research participants must participate in all procedures of clinical trials after they have given consent”………..27 Figure 3.2.4. Respondents’ opinions on the statement “public and Scientific interests prevail individual interests while conducting clinical trials”……… 28 Figure. 3.2.5. Respondents’ opinions on the statement “research participants can leave the study at any time without any explanations”……….. 28 Figure 3.2.6. Respondents’ opinions on the statement “philosophers should not dictate what is ethical and what is not”………. 29 Figure 3.2.7 Respondents’ opinions on the statement “Participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options” ………...30 Figure 3.2.8. Respondents’ opinions on the statement “research participants must participate in all procedures of clinical trials after they have given consent” depending on clinical experience (years)……….31 Figure 3.2.9. Respondents’ opinions on the statement “participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options” depending on age group ……...31 Figure 3.2.10 Respondents’ opinions on the statement “every clinical trial can be started only after the approval of Bioethics Committee in particular country” depending on age group……….32 Figure 3.2.1.1 Respondents’ opinions on the statement “Attitude that science is more important than ethics”………34 Figure 3.3.1 Respondents’ opinions on the statement “Clinical trials are more risky than beneficial to research participants in phase II”………. 34
Figure 3.3.2. Respondents’ opinions on the statement “The application of randomized placebo control in phase iii clinical trials is morally justified” ………..35 Figure 3.3.3 Respondents’ opinions on the statement “research participants can leave the study at any time without any explanation’s Indian respondents” ……….36 Figure 3.3.4 Respondents’ opinions on the statement “the incapable to consent individuals can be involved into clinical trials only if they can freely express their will” ……….36 Figure 3.3.5 Respondents’ opinions on the statement “a trial can only be conducted involving persons with incapacity only if the trial relates directly to a medical condition of the person” ……37 Figure 3.3.6. Respondents’ opinions on the statement “incapable to consent individuals can be involved into clinical trials only if they can freely express their will depending on clinical work experience”……….37 Figure 3.3.7. Respondents’ opinions on the statement “research participants can leave the study at any time without any explanations” ……….38 Figure 3.4.1. Comparison of awareness about clinical research ethics between Indian and Lithuania……….41
TABLE OF CONTENTS
SUMMARY………...1
LIST OF TABLES AND FIGURES………..3
ABBREVATIONS……….6
INTRODUCTION………..7
Relevance of the study………7
Novelty of the study………8
AIM AND OBJECTIVES………...9
1. REVIEW OF THE LITERATURE……….10
1.1 International guidelines on biomedical research ethics……….10
1.2 Ethical aspects of clinical drug trials……….14
1.3 Empirical studies on clinical research ethics……….16
2. METHODOLOGY………..22
2.1 Organization and sampling of the study………22
2.2 Research instrument………...22
2.3 Statistical analysis………..23
2.4 Research ethics………...23
3. RESULTS……….24
3.1 Social and demographic characteristics of respondents……….24
3.2 The attitudes on ethical provisions in clinical research……….……….25
3.3 The level of awareness of respondents towards research ethics in clinical trials……….. 34
3.4 The correlation relationship between respondents’ attitudes and their awareness about research ethics………..39
4. DISCUSSION OF RESULTS………..42
CONCLUSIONS………..45
RECOMMENDATIONS……….46
REFERENCES……….47
ANNEX 1. The copy of approval of Bioethics Center at LUHS ...………..51
ANNEX 2. The research questionnaire….………52
ABBREVIATIONS
AEs - adverse Events CDT – clinical drug trial
CTRI - Clinical Trial Registry in India ECs - Ethical Committee
ICD - informed consent document GCP - Good clinical practice PI - Principle investigator SAE- Severe Adverse Events SD. -Standard Deviation
SPSS - Statistical Package for Social Sciences U. S. – United States
USAID - United States Agency for International Development WHO - World Health Organization
WMA – World Medical Association
INTRODUCTION
Fom last few decades, more international pharamceutical companies have increased their studies on clinical research and, clinical trails in particular, to developing countries. The expansion of scientific research in general and inclussion of new developing countries into high level scientific research in medicine were followed by the new concerns about ethical and scientific implications of globalization of clinical trials to developing countries (1, 2). A number of Indian doctors were involved into clinical research activities because of many factors, but mainly because the less cost of clinical trials and one of the biggest number of patients around the world (1,3). These concerns have also been reflected in scientific literature and media stories, which have highlighted issues of vulnerability, consent deviations, compensation for patients, Ethics Committee (EC) training and functioning, placebo, post-trial access and other potential issues related to clinical drug trials in India (4, 5, 6).
The importance of the competences of medical doctors while conducting clinical research in India was addressed by one of the moost important documents - National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, released in 2017. According to it
“rapid advances in the whole field of biomedical sciences have added newer responsibilities and complex dilemmas for medical persons – both practitioner and researchers” (7). This document addressed on responsible conduct of research, informed consent process, vulnerability, public health research, social and behavioural sciences research for health, biological materials, biobanking and datasets, International collaboration and research during Humanitarian Emergencies and Disasters (7). These guidelines also discussed the need for capacity building in the area of research ethics in order to improve the ethical conduct of research in India. The section 7 emphasized that “national ethical guidelines for biomedical and health research involving human participants” should focus on ethical guidelines for clinical drug trials in India. The main requirements include “planning, conducting and reporting clinical trials in a manner that ensures that the dignity, rights, safety and well-being of participants are protected”.
Basically the Natioanl Ethical guidelines entailed the major principles of research ethics and good clinical practice declared in the most important international documents.“Research including studies on basic, applied and operational research designed primarily to increase the scientific awareness about diseases and conditions (physical or socio-behavioural), their detection, cause and evolving strategies for health promotion, prevention, or amelioration of disease and rehabilitation including clinical research” (7).
Relevance of the study. This study was designed to find out how these documents are being appraoached and applied by medical doctors in this context of new ethical requirements in India.
how the adoption of these principles might be approached by Indian medical doctors. In India, it is necessary to. Accordingly, the comparison of perceptions and awareness of medical doctors in two different contexts – context of developing country and context of European country with highest standards of biomedical research was taken as the basis for study design elaboration.
Despite the potentially diverse attitudes, the main areas of interest appear to be informed consent process, safety and protection of research participant’ srights, equality of ECs based on independence and competence, and awareness of security and responsibility of researchers involced in clinical drug trials or other type of clinical research in tertiary level of health care. This survey attempts to understand the overall perceptions of clinical research professionals about ethics of clinical research in India and Lithuania.
Novelty of the study. Despite the importance of research ethics recognized worldwide, there is a little data was available regarding the research ethics in issues in India. This study is aimed to contribute to some previous studies done in India or other neighborhood countries and to discussion, the potential opportunities to control and manage clinical research process in ethical and civilized way and to compare the attitudes and awareness of medical doctors involved in clinical drug trials and other kind of research between one European country Lithuania and India explicitly.
The perceptions and awareness of medical doctors about research ethics is different in different countries but both are very important. Because perception and awareness both having impact on research ethics. We can’t compromise with any of these two things because its directly related to the human life. The big thing is that the participant which participate in the clinical drug research their awareness about research ethics is very less.
AIM AND OBJECTIVES
Aim of the study was to reveal the attitudes of medical doctors and their awareness on clinical research ethics in India and Lithuania.
Objectives:
1. To determine respondents’ attitudes towards general ethical provisions of clinical research.
2. To determine the level of awareness of respondents towards research ethics in clinical trials.
3. To find out the relationship correlations between awareness and attitudes on clinical research ethics among Lithuanian and Indian physicians.
1. LITERATURE REVIEW
1.1 International guidelines on biomedical research ethics
Historically, the growing importance of medical research have reduced the morality of the research, the value of human life and research participant health in the name of scientific progress. The modern ethical principles regarding medical research were established in response to the
“unethical” researches made in the past. The most featuring example is the Nazi Germany doctors’
experimentations on the victims at concentration camps during World War II. During the Nuremberg Trial in 1946 it was constituted the scope of inhuman violations of rights of research participants and it started the adoption of the first international document of research ethics known as Nuremberg Code, 1947. This document declared major principles of research ethics in medical research including clinical drug trials for future medical doctors in essence: the consideration of an appropriate risk-benefit ratio, the voluntary consent of the human subject as absolutely essential and the protection of vulnerable groups (8). It draws the outline of research ethics and raised the most fundamental questions for future researchers: how to protect people against unethical practices; how to reduce the risk and potential of research participant. In clinical drug trials, how to establish drugs safety in testing and how to protect patient volunteerism and preserve the integrity of the science (14).
These the ethical issues were later addressed in a number of recognized international documents, which formulated the major ethical principles and guidelines of biomedical research. The most important international ethical guidelines in biomedical research are:
• The Universal Declaration of Human Rights, issued by the United Nations, 1948 (9).
• The Declaration of Helsinki, issues by World Medical Association (WMA), 1964- 2002 (10);
• Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research, issued by The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research,1979 (11).
• International ethical guidelines for biomedical research involving human subjects, issued by Council for International Organizations of Medical Sciences (CIOMS), 2002, 2016 (12,13);
• Good clinical practice guidelines E6 (R1), issued by the International Conference on Harmonization, 2000 (15);
• Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine, issued by the Council of Europe, 1997 (16);
• Additional Protocol to the Convention for the Protection of Human Rights and Biomedicine Concerning Biomedical Research, issued by the Council of Europe, 2005 (17);
• Universal Declaration on Bioethics and Human Rights, issued by UNESCO, 2005 (18).
The main purpose of those and other ethical guidelines were to protect patient volunteers that might be at risk. The Declaration of Helsinki was released by World Medical Association (WMA) in 1964 and later was continuously updated. The last version of Helsinki declaration is issued at 2008. In general, this document has represented the global approach (it represents all medical doctors around the world) to medical research ethics on human subjects. The Declaration of Helsinki and Belmont report outlined the fundamental principles to be followed in order to ensure ethical research.
Research Ethics principles
The principle is social and clinical value. It constitutes that every research study should be designed to answer a specific question which have significant value for society or for present or future patients with a particular illness. Answers to the research question should improve our ways of preventing, treating, or caring for people with a given disease (21). (Sharing results, both negative and positive — can exposing human subjects to the risk.
Secondly, was the scientific validity. The study should be designed in a certain way that will get an understandable answer to the valuable research question. Medical research involving human subjects must be justifiable on scientific grounds. This requirement is meant to eliminate projects that are unlikely to succeed. For example, if patients are being asked to participate in a research project, even where risk of harm is minimal, there should be an expectation that important scientific awareness will be the result (21).
Another principle is fair subject selection. The primary basis for recruiting groups and individuals should be the scientific goals (21) of the study — not vulnerability, privilege, or other factors unrelated to the purposes of the study. Particular groups or individuals (i.e. women or children) must not be removed from the opportunity to get involved in research without a solid scientific reason or hazard sensitivity.
The principle of favorable risk-benefit ratio means that the degree of risks and benefits associated with a drug, device, or procedure being tested is inherent in clinical research, science these problems are generated in clinics. In case of drug clinical trials, the risks and benefits should be measured carefully. It is necessary for the researcher to demonstrate that the risks to the research subjects are not unreasonable or disproportionate to the expected benefits of the research, which may not even go to the research subjects. A risk is the potential for an adverse outcome (harm) to occur. It has two components: (1) the likelihood of the occurrence of harm (from highly unlikely to very likely), and (2) the severity of the harm (from trivial to permanent severe disability or death) (23).
Informed consent is one of the most significant principles to conduct clinical research. To be ethical, individuals should make their own decision about whether they want to participate or continue participating in research. Done through a process of informed consent, i.e. research participants should be accurately informed of the purpose, methods, risks, benefits, and alternatives to the research; they should understand the given information and how it relates to their own clinical situation or interests; they should make a voluntary decision about whether to participate(24).
Research subject should have sufficient awareness and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision.
In case of clinical drug trials CIOMS stated that informed consent must be provided for all research studies involving humans. This means that the contract research organization conducting the drug trial is required to provide comprehensive details of the study; the procedures involved and how volunteers will be affected - particularly the risks or related discomforts - before an individual agrees to take part in a study. Informed consent relates to the entire duration of a study, regardless of how long it takes to conclude (12,13). If an individual agrees to take part in a study, they can always withdraw at any stage and for whatever reason (11). This means that candidates should only sign an informed consent if they are totally satisfied with what they have read.
In later versions the independent review is established as the most important guideline for ethical research. To minimize potential conflicts of interest and make sure a study is ethically acceptable before it even starts. Regarding the Ethics Review Committee approval, every proposal for medical research on human subjects must be reviewed and approved by an independent ethics committee before it can proceed (18) In order to obtain approval, researchers must explain the purpose and methodology of the project; demonstrate how research subjects will be recruited. The reason why ethics committee approval of a project is required is that neither researchers nor research subjects are always awarenessable and objective enough to determine whether a project is scientifically and ethically appropriate.The ethics committee may approve the project as presented,
require changes before it can start, or refuse approval altogether. Review and approval is generally required in each country.
In summary, the later versions emphasized the respect for potential and enrolled subjects.
Individuals should be treated with respect from the time they are possible participation, even if they refuse participation in a study & throughout their participation and after their participation ends.(21) he other documents likewise CIOMS has mainly developed, explained and more specified the previously mentioned principles in the context of clinical drug trials. According to these guidelines, research subjects have a right to privacy with regard to their personal health information.
Additionally, medical research involving human subjects must be justifiable on scientific grounds.
The Council for International Organizations of Medical Sciences (CIOMS) was founded under the auspices of WHO and the United Nations Educational, Scientific and Cultural and Organization (UNESCO) in 1949. Among its mandates is “maintaining collaborative relations with the United Nations and its specialized agencies, especially UNESCO and WHO” (12). With strong international approach, “The Working Group decided to broaden the scope of the 2002 Guidelines from “biomedical research” to “health-related research” (13). And, “the Working Group considered biomedical research too narrow since that term would not cover research with health-related data,”
(13). “The term “health-related research” in these Guidelines referred to activities designed to develop or contribute to generalizable health awareness within the more classic realm of research with humans, such as observational research, clinical trials, bio-banking and epidemiological studies. Generalizable health awareness consists of theories, principles or relationships, or the accumulation of information on which they are based related to health, which can be corroborated by accepted scientific methods of observation and inference” (13). These developments of research concepts in biomedicine had an important impact on the elaboration of good clinical practice which will be reviewed in the next chapter.
In summary, ethical guidelines refer researchers to:
• Gain useful awareness.
• Fair subject selection.
• Favorable risk-benefit ratio.
• Independent review.
• Comprehensive and voluntary informed consent.
• Independent review of research
.Respect for potential and enrolled subjects.
1.2 Ethical aspects of clinical drug trials Clinical drug trials: conceptual background
One of the most important achievements in biomedical scientific research is related to clinical drug trials. Clinical drug trials are assumed as a systematic study on pharmaceutical products in human subjects (including patients and other volunteers) in order to discover or verify the effects of and/or identify any adverse reaction to investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the object of ascertaining their efficacy and safety (19). In other words, it is prospective, biomedical research study of human subjects designed to deal with biomedical or behavioral interventions drugs. The goals of clinical research are usually to develop general awareness that improves human health or increases understanding of human biology in general (19, 20). This kind of scientific research is used to determine whether new drugs are safe, efficacious and effective.
In summary, drug trials are one of the concluding stages in an extensive and carefully planned research process, generating safety and efficacy data. It is one kind of clinical trial. During the trial, investigators: recruit patients with the predetermined characteristics, administer the treatment(s) and collect data on the patients' health for a defined time period. in most of the cases, the clinical drug trials involving human subjects are interventional and therefore they require an ethical evaluation by an independent and authoritative body such as the research ethics committee (REC). It is because the clinical research including drug trials impose many ethical requirements and legal regulations on research ethics to be discussed in the following chapters.
Good clinical practice and ethical aspects of clinical research
The regulatory process appeared adequate to the majority of respondents. However, there were suggestions to improve the process e.g. trained GCP experts to inspect/monitor trials, clarity in guidelines, and regulatory bodies meeting the subjects.
Good Clinical Practice (GCP) should be used for designing, conducting, recording, and reporting trials that involve the participation of human subjects.(19) This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. Unlike other types of clinical research, clinical drug studies shouldn't just be conducted in accordance with basic principles of research ethics, but should also be driven by good clinical practice. GCP is an international standard of quality provided by the International Conference on Harmonization (ICH) and endorsed in 2000 as the GCP Guidelines (15). ICH guidelines have been adopted into law in several countries, but used as guidance for the FDA in the form of GC. GCP is
defined as a level for designing, conducting, performing, auditing, documenting, analyzing and investigating clinical trials or studies and takes place upon preparation. Clinical research project offers thorough directives for staff of clinical researchers and procedures for obtaining approval from the Research Ethics Committee. GCP compliance generally provides a public guarantee that the rights, safety, and well-being of research-involved human patients are secured. Besides other objectives, it is aimed at: defending the rights, safety, and welfare of human beings involved in the research ensures the quality, reliability, and integrity of the information collected provide requirements and guidelines for conducting clinical research (15).
Clinical research ethics in India
Ethical concerns and some issues related to clinical research practices in India were repetdely reported by many previous studies. The risk of exploitation of research subjects or host communities was mentioned as one of the most important ethical questions while conducting clinical drug trials in the developing countires (2, 4, 21). As a matter of fact, “society funds research to improve health, researchers and research institutions are part of the larger community, and there is an infrastructure, even if imperfect, that translates research results into health-care practices for the benefit of the larger community” (21). That is why research in developing countries creates a greater risk of exploitation: individuals or communities in developing countries and medical doctors whould be reqady to assume the risks of research with most of the benefits may accure to people in developed countries (21). In india the issue of exploitation and abuse or research subjects is even more vulnerable as “the socio-cultural ethos in India and its varying standards of healthcare pose unique challenges to the application of universal ethical principles to biomedical and health research” (7).
The last decade has seen emerging ethical issues necessitating further revision of the earlier guidelines and preparation of the current National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017. “These guidelines have covered some newer areas like public health research, social and behavioral sciences research for health and responsible conduct of research, and research during humanitarian emergencies and disasters while a few other specialized areas like informed consent process, biological materials, bio-banking and datasets and vulnerability have been expanded into separate sections” (7).
Ethics in clinical research focusing on the finding and executing the best conditions for the subjects who take part in clinical research. All clinical trials must be planned, conducted and reported in a way that protects test subjects ' integrity, freedom, safety, and well-being which is very important aspects for the ethical research (22).
In summary, before starting the clinical trial we should calculated the risk and benefit of clinical trial. We should start the trial if benefit is more than risk. All clinical trials must be conducted in accordance with the Indian GCP guidelines, the Declaration of Helsinki (2013 or later versions as applicable), National Guidelines for Biomedical and Health Research Involving Human Participants (2017), the Drugs and Cosmetics Act (1940), and Rules (1945), and applicable amendments (including Schedule Y), and other relevant regulations and guidelines, wherever applicable. It says that “a subjects decision to participate in research should be the final decision. A respondent's confidentiality should be preserved at all times and any data collected from the participant should be kept confidential (7, 22). National Ethical Guidelines for Biomedical and Health Research Involving Human Participants also require from medical doctors who conduct clinical trials to deal with the problem of the clinical misconception (7). “In the subject on which the trial is scheduled, at least one member of the research team must have the skills , experience and sufficient clinical research experience. EC approval and regulatory approvals is must. All clinical trials must be registered with the Clinical Trial Registry -India (CTRI). Each participant must obtain written informed consent before any research-related procedure is carried out. For vulnerable population extra care should be taken and justification needed. Quality of trial is important part and needed some procedure to ensure that (7, 22).
1.3 Empirical studies on clinical research ethics
The perceptions of the medical doctors about clinical research have been reported by many previous empirical studies conducted in both: developed and well regulated countries as well as in developing countries such as India.
Growing clinical research following product patents for the pharmaceutical industries as per market-related facets of the Intellectual Property Rights Contract and adverse events monitoring of the marketed drugs has raised several ethical and regulatory issues following the promotion of new drugs in Indian markets. Many drugs which is banned in other countries are available in india due to not having strong regulatory bodies .It becomes vital to understand the history, growth and evolution of the regulatory aspects of drugs which are handled by multiple Ministries and Departments of the Government of India. Although amendment to Schedule Y, registration of Contract Research Organisations, registration of Clinical Trials, Speeding up review process, Pharmacovigilance (PhV) programme for India and Inspection of clinical trial sites have been started by the various regulatory agencies. However, due to the relaxed approach to promotional permission for the sale of the drugs, the unethical steps taken by some pharmaceutical companies and medical practitioners reiterated the need to gain an adequate understanding of the current
regulation of drugs and clinical research, particularly with regard to practical rules and regulations.
(27).
All members of Institutional Ethics Committee (IECs) should be aware of the different safety terminologies and pharmacovigilance activities conducted during clinical trials to safeguard the subjects. However, in our study the level of awareness was found to be low among both medical and nonmedical members.
Members of EC (both government and private institution) felt that there was a need for some training regarding EC functioning and responsibility and also safety reporting guidelines in clinical trials and there was a significant difference between medical and nonmedical EC members who felt that patients suffering from disease should be included in EC meeting for its better functioning.
Majority of the EC members (both from medical background and nonmedical background) felt that in case of SAE, EC should decide the compensation to the trial subject, though most of them (nonmedical members) did not know the exact SAE reporting timelines to EC by the principle investigator PI. ECs can be an important medium to aid research workers, particularly the less experienced, in amending an ethically unsound and risky clinical trial protocol, thus benefiting both research professionals and the general population.(29)
The EC member can suggest changes to the ICD to make the language more simple, non technical and layman friendly. The challenges faced by the EC member will be in reviewing the vernacular consents. Often the EC relies on documentary evidence as translation certificates and back translation ICD to ensure that information stated in vernacular consents is matching with English informed consent document ICD. Monitoring the implementation of the consent process will be a crucial task for an EC member. Is it feasible for the EC member to monitor independently the recruitment process, the 'informed consent' process, and debriefing of research participants about the risks and benefits at the trial site for all the projects approved by them? This may be still be feasible for an institutional EC member to monitor the consent process and interview the research participants but for a NEC member to conduct monitoring the feasibility may be low as taking administrative approvals for monitoring the site, logistics may pose problems.(30)
The top three issues which surfaced maximum number of times from the responses were:
Informed consent process and documentation,Empowerment of ECs to be independent and competent,Patient awareness about safety and compensation rights.Some of the other issues highlighted were: a) economically/educationally vulnerable population's participation in trials; b) patient eligibility; c) EC functioning and training; d) awareness across the society about clinical research; and e) patients being tested for drugs which would never be affordable or made available
in India. The researcher found that barrier to independence were conflict of interst and pressure for revenue from trials.(26)
In the contrary to EU the a survey of opinion of medical doctors regarding their point of view for ethical issues in clinical trials in India showed other results. The authors included issues related to ethical issues in conducting clinical trials, how much ethical committee is capable, Independence of ECs, adequacy of regulations, informed consent, etc. (23)
The authors revealed that some patients were not aware of the safety and their compensation rights, ECs was needed to more competent (23). They have also revealed that responder’s response regarding training to ECs was agreed. A responder was agreed that GCP training should be mandatory for the ECs members. Laypersons contribution was low due to lack of awareness most of the responded agree for this. Currently, informed consent is given the opportunity to ask questions and he can leave the study any time. There is a need to improve the consent process a few steps suggested also. Need to follow the regulation for the safety of research participants and response to this question was good. But got some suggestions for more improvement. Safety review from ECs was moderate some changes suggested by the responders. Compensation if injuries happened during the trial most of the respondent was in favor of compensation. Respondents don’t have any problem with the use of placebo during trial. Low education of patients a case of vulnerability, respondents suggested that patient education is important, In India patient believe on doctor as they believe on god we don’t have to take it a good opportunity for clinical trials. (26)
This has been also discussed by other authors, awareness about Clinical trials and perception about clinical trials. They don’t have much clarity about the fact of clinical trials due to the lack of specific training. They used a questionnaire-based study in three Indian hospitals. They try to find factors which were related to their study (23, 24) They revealed that the perception of the doctors for the clinical trial was mixed. From their study analysis, they didn’t get a direct alliance between perception and awareness. The authors revealed a certain area of lack of awareness and technical points where, if they will get the training they can improve awareness. And they got negative perceptions about the CTs which were sponsored by pharmaceutical companies as compared to trials started by the academic settings (23). This survey revealed that doctors having basic awareness about the CTs. Technical awareness about CTs in these hospitals doctors was inadequate.
Their response to the questions regarding good clinical practice was low. Very few doctors from those govt hospitals were familiar to the word adverse event which is a very basic word (23).
The important survey on physicians’ attitudes towards ethical issues in clinical trials was performed in Japan. The Japanese scholars reveled the problems due to the lack of standards for clinical research in Japan. The author did a survey in a hospital in Japan to find out the interest of
doctors to do clinical trials and try to find a method to promote clinical research (27). They revealed that most of the doctors currently taking part in the clinical trials and most of them believe that taking part in doing clinical research is important. They found that very fewer respondents were getting training for clinical research skills and statistics. Respondent shared the problems they faced like more paperwork they, less good patients, and busy schedule and having very less time for conducting clinical research. Most of the respondents want to attend lectures on clinical research topics (27).
Selected and reviewed qualitative studies that evaluated the factors influencing participation of Indian subjects in clinical trials. The meta synthesis of factors cited by Indian subjects provides a better picture of their mindset by revealing what favors or hampers their decision to participate in clinical trials. India needs to take steps to ensure adequate participation in the cliniical trial in order to sustain its status as a centre for clinical trials. Insights into Indian subjects ' attitudes regarding trial involvement can guide investigators and sponsors when planning trials throughout the future.
The latter category, but at the other hand, includes : mistrust of trial organizations, concerns about the effectiveness and safety of trials, psychological reasons, trial burden, loss of confidentiality, problems of dependency and language.Though these figures may not be precise and accurate they do represent the broad percentages and would certainly needs attention as to which of the theme might need more focus in terms of any rectification that might have to be implemented either to eliminate barriers or to encourage participation. Indian subjects expressed 'privacy and the negative impact of loss of confidentiality' as an important concern. In order to maintain its status as a hub for clinical trials, India needs to take steps to ensure adequate trial participation. Insights into the mindsets of Indian subjects in relation to trial participation can guide investigators and sponsors when they plan trials in the future. Non consideration of these factors during the planning stage may lead to delays in the trial enrolment and subsequent implications on trial completion and costs.
There are several other reasons and factors associated with the decision to participate in a trial that have been expressed by other subjects belonging to different ethnic groups from various parts of the world. However, they remain specific to the region, ethnicity, the disease under study like HIV, cancer, type of intervention-invasive/non invasive, type of study design-use of placebo or any other.(31)
The ethical justification for clinical research involving human subjects is the hope of finding new ways to benefit the health of individuals. Such research can only be morally justifiable if it is conducted in a manner that respects and protects and is fair to the subjects of that research and is morally permissible within the groups in which the research is conducted. Furthermore, since scientifically incorrect research is unethical in that it reveals research subjects to risks without any
potential benefit, researchers and corporate partners should make sure that suggested studies involving human subjects conform to generally accepted scientific principles and are based on adequate awareness of the relevant scientific literature.All research proposals involving human subjects must be submitted to one or more scientific review and ethical review committees for review of their scientific merit and ethical acceptability. The review committees must be independent of the research team and the outcome of their review should not be contingent on any direct financial benefit they may obtain from the study. Before conducting the research, the researcher must obtain their approval. In the course of the research, the ethical review committee should carry out further reviews as necessary, along with monitoring of the study progress.The investigator must obtain voluntary informed consent from the prospective subject for all biomedical research involving humans or, in the case of an individual who is unable to give informed consent, consent from a legally authorized representative in accordance with applicable law (32). Public Health Ontario has avoided this distinction between research and other evaluation activities, choosing to adopt a common framework and process to guide ethical reflection throughout their lifecycle – from initial planning to awareness exchange – on all public health evaluation projects.
The goal is to move towards a culture of ethical integrity among researchers. Public Health Ontario has developed an ethical framework for any evidence-generating activity, regardless of whether research is labeled. (33). The Clinical Trials Registry- India (CTRI) is a free and online public record system for registration of clinical trials being conducted in India that was launched on 20th July 2007. Only registered trials is consider for publication. In the CTRI, details of Indian investigators, trial sites, Indian target sample size and date of enrollment are captured. After a trial is registered, trialists are expected to regularly update the trial status or other aspects as the case may be. After a trial is registered, all updates and changes will be recorded and available for public display (34).
Clinical equipoise is widely accepted as the basis of ethics in clinical research and requires investigators to be uncertain of the relative therapeutic merits of trial comparators. When clinical equipoise is in question, innovative trial designs are needed to reduce ethical tension while satisfying regulators’ requirements. We report a novel response-conditional crossover study design used in a Phase 3, randomized, double-blind, placebo-controlled clinical trial of intravenous 10%
caprylate-chromatography purified immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. During the initial 24-week period, patients crossed over to the alternative treatment at the first sign of deterioration or if they failed to improve or were unable to maintain improvement at any time after 6 weeks (35).
The general problem with the ethics of clinical trials stems from the fact that those who stand to gain from the trial results are not the same that bear the risk and burden of trial participation. Participation in a clinical trial entails an increased level of risk with respect to ordinary clinical care, particularly due to the potential for exposure to unexpected effects of a new treatment. These risks are actually not offset by a prospective clinical benefit, since the primary end of the trial is not that of treating trial participants but rather that of producing generalisable medical awareness. One of the most important ethical constructs of modern biomedical ethics, informed consent is nowadays an essential condition both for therapy and research. Written authorisation forms were occasionally submitted to participants also in the early times of medical experimentation. However, this was, in most of the cases, a device aimed at ensuring the subject’s compliance rather than an expression of concern for their welfare. Modern informed consent is very different from these early instances in that it stems from a basic principle, expressed in the Nuremberg Code, of the respect due to persons and the value of a person’s autonomy (36).
In summary, clinical trials and the research and health care that accompany them can directly benefit patients, in particular those who would otherwise have no or only little access to health care services. Nonetheless, taking advantage of people's deprivation to impose on them the risk of health research can be exploitive if it is not carefully planned and regulated. At the moment, there is such a variety of legislation that the conduct of trials differs widely, often depending on why a company decided to use a developing country in the first place. Trials that address locally relevant diseases and that will deliver affordable drugs and care for the local population are certainly to be lauded. Ones that do not provide immediate or obvious benefits locally are less laudable and must be assessed on a case-by-case basis (37).
Change in the way new drugs are developed, including the privatization of clinical trials, has altered the arrangement and roles of health care professions. Coordinators see this type of interaction as what is necessary for individuals to feel comfortable about participating in research studies, and they highlight the importance of establishing strong ties of trust with patient-subjects.
This tone is often established from the first interaction coordinators have with prospective patient- subjects. Moreover, the relationships that coordinators build with patient-subjects must be maintained and built upon during the course of the entire study (38).
2. MATERIAL AND METHODS
2.1 Organization and sampling of the study
The cross-sectional study was conducted in June, 2018 in India, and October to December, 2018 in Lithuania. The survey population incuded medical doctors working at tertiary level health care service hospitals, namely Apex clinic and Metro healthcare hospital, Kerala, India and Lithuanian University of Health Sciences Kaunas Clinics in Lithuania.
Convenience sampling method (41, 42) was used to draw the sample of institutions and respondents for this survey. A sample size of 300 was calculated within 95% confidence interval and a sample error of 5%. Overall, 180 respondents were interviewed anonymously (N=180). The response rate was 60 %.
The survey sample included medical doctors from Cardiology, Pediatrics, Neurology, Oncology, Gynecology, Dermatology and other clinics. Respondents, who did not comply to participate in the study, were excluded. All consenting individuals falling in the age between 18 to 65 years were interviewed. The study was performed after getting the local authority permission in each institution. Information was collected using face-to-face interviews.
2.2 Research instrument
An originally elaborated, semi-structured questionnaire was employed as a research instrument The construction of questionnaire was based on previous studies (1, 10), however it was elaborated initially by co-authors to revels the potential differences of respondents in India and Lithuania. The questionnaire was divided into three sections: (1) socio-demographic characteristic of respondents, and (2) the perception of the individuals’ towards drug promotion, their awareness about existing regulations regarding drug promotion and ethical issues of drug promotion, and (3) attitudes to clinical research ethics including the respondents perceptions of safety of research participants, the protection of their rights in clinical trials as well as ethical and scientific controversies in clinical research. Socio-demographic data from the respondents including their gender, age, occupation, specialization, work experience and involvement in the professional training were collected.
The quality variables were presented in the statements and evaluated by employing the five level Likert’s scale (from absolutely disagree (1) to absolutely agree (5). Attitudes of the respondents regarding drug promotion and research ethics in their actual practice was determined through categories.
2.3 Methods of statistical analysis
The obtained data were coded and analysed with a statistical program „IBM SPSS 23“. Data was analysed by using descriptive statistics methods (Chi-square, two-samples t-test). Also, in order to determine the structure of the attitudes towards the ethics of drug marketing, the principal component analysis was applied, also, regression factor scores were computed in order to detect differences in attitudes between Lithuanian and Indian physicians. In order to assess the relationships between attitudes towards drug promotion ethics and exposure to accepting gifts, Spearman correlations were calculated. P-value of 0.05 was used to determine significance.
We have used bar plot to show the graphical presentation of our data. Tables and figures were used for an all-inclusive viewing of results. In order to assess the relationship between level of awareness, age in years and attitude that science is more impotant than ethics, Spearmans correlations (0.00-0.19-very week, 0.20-0.39-weak, 0.40-0.59-moderate, 0.06-0.79- strong and 0.80-1.0- very strong)(43) were calculated. P-value was used to find significance.
2.4 Research ethics
The survey aims to reveal the perceptions of health care professionals on ethical provisions on clinical research ethics. All respondents of this study were under oral informed consent and received written information about the purpose of the study as well as the guarantee of confidentiality in the preamble of the questionnaire. All gathered information was kept in confidentiality and generalized so to prevent any identification of research participants.
The study project was presented to The Bioethics Centre of Lithuanian University o Health Sciences and the approval was received in 2018-11-16. The copy of approval is attached at the Appendix no. 1.
3. RESULTS
3.1 Social and demographic characteristics of respondents
To analyze social and demographic characteristics of our respondents it was used Descriptive Statistics data analysis tool. The most important characteristic of all respondents and their distribution according to the country are represented n Table 1. It was determined that 61.9%
males participated from India and 66.3% females participated from Lithuania. It shows that male respondents were dominating in India, while more female respondents from Lithuania. The number of respondents with reported training in research ethics significantly differ: 28.9% in Lithuania and only 2.1% in India. Experience of Good clinical Practice was more for both countries it was 95.9%, 69.9% in India and Lithuania respectively.
Table 1. Social and demographic characteristics of respondents.
Social and demographic characteristics of respondents
Country, N (%) Total
N (%) India, N (%) Lithuania, N
(%)
Gender
Male 60(61.9%) 28(33.7%) 88(48.9%)
Female 37(38.1%) 55(66.3%) 92(51.1%)
Have you ever received any training about?
Research Ethics 2(2.1%) 24(28.9%) 26(14.4%)
Good clinical
practice 93(95.9%) 58(69.9%) 151(83.9%)
Years of clinical work experience
1-5 1(1.0%) 56(67.5%) 57(31.7%)
5-10 5(5.2%) 7(8.4%) 12(6.7%)
10-20 59(60.8%) 11(13.3%) 70(38.9%)
>20 32(33.0%) 9(10.8%) 41(22.8%)
Occupation
Head of the
clinics 7(7.2%) 1(1.2%) 8(4.4%)
Professor 1(1.0%) 5(6.0%) 6(3.3%)
Medical doctor 82(84.5%) 17(20.5%) 99(55%)
Medical
resident 7(7.2%) 60(72.3%) 67(37.2%)
Have you involved in any sort of
biomedical research
Yes 48(49.5%) 56(67.5%) 104(57.8%)
No 38(39.2%) 26(31.3%) 64(35.6%)
Not sure 11(11.3%) 1(1.2%) 12(6.7%)
In table 1 it was determined that years of clinical work experience 1-5 years 67% from Lithuania, 10-20 years’ work experience were 60.8% participated more in the study.It may be due to that more busy schedule of experienced doctors in Lithuania compared to the Indians. Most of respondents from India were medical doctors (84.5 %), while medical residents dominates among Lithuanian respondents (72.3 %). The doctors on higher position such as head of clinics and professor were less participated in the studty due to their busy schedule. Regarding the involvement in biomedical research during the last 5 years 49.5% Indians were involved as compare to 67.5%
Lithuanians. The respondents from India 39.2% and 31.3% from Lithunia were not involved in any kind of biomedical research.
3.2 The attitides on ethical provisions when conducting a clinical drug trials
Clinical trials are important to find new treatment options or tests for the management or prevention of diseases. And the main responsibility in this whole process is on medical doctors. To know about the attitude of respondents.
We provide them some questions to show their attitude on ethical provisions when conducting clinical drug trials. Almost all of Indian respondesnts were disagree that philosophers should not dictate what is ethical and what is not (Fig. 3.2.1.) as compared to Lithuanians.
Figure 3.2.1. Respondents’ opinions on the statement “Philosophers should not dictate what is ethical and what is not”
*-p<0.05, compared to Indians.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Disagree Neither agree, nor disagree Agree
99.0%
1.0%
27.7%* 31.3%* 41.0%*
India Lithuania
Almost half of the Lithuanians were agreed for this statement, it shows that Indians think ethics are equally important as scientific research.We can see that quater of the lithuanian respondent were neutral for the statement as compared to Indian respondents. (p < 0.05)
We can see in (Fig. 3.2.2) below, almost all Indian respondent were disagreed to the statement that participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options as compared to Lithuanians. Near to the half of the Lithuanian respondents were neutral for the statement. If we see the agree response then, Lithuanian respondents were approximately twenty times more agreed for the statement as compared to the Indians.
Figure 3.2.2 Respondents’ opinions on the statement “participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options”(*-p<0.05, compared to Indians).
As the result of survey from India and Lithuania, 83.5% Indians were disagreed for this statement research participants must participate in all procedures of clinical trials after they have given consent (Fig. 3.2.3) as compared to the the Lithuanian respondents. As you can notice in (Fig.
3.2.3) the trend for the disagreement to agreement to the statement in case of India going from high to low as compared to Lithuanian respondents it is going low to high. Indians think more about the rights of the subjects.as compared Lithuanians.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Disagree Neither agree, nor disagree Agree
96.9%
1.0% 2.1%
25.3%*
38.6%*
36.1%*
India Lithuania
Figure 3.2.3. Respondents’ opinions on the statement “research participants must participate in all procedures of clinical trials after they have given consent” (*-p<0.05, compared to Indians).
If you look at this chart (Fig. 3.2.4.) Below, you will notice that, both Indian and Lithuanian respondents agreed that public and scientific interest’s superior on individual interests while conducting clinical trials. We can see that 84.5% Indian as compared to 56.6% Lithuanian respondents agreed to the statement, and the neutral response was 14.4% Indian and 32.5%
Lithuanian respondents. In last almost times Lithuanian respondents were disagreed as compared to Indians.
In summarizing this statement, that Lithuanian respondents response was better than Indians means they think that ethics and clinical research is equally important. We have to consider the individual interest as we consider public and scientific interests.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Disagree Neither agree, nor disagree Agree 83.5%
16.5%
21.7%*
36.1%*
42.2%*
India Lithuania
Figure 3.2.4. Respondents’ opinions on the statement “public and Scientific interests prevail individual interests while conducting clinical trials” (*-p<0.05, compared to Indians)
This chart below shows the attitude about the statement that research participants can leave the study at any time without any explanations (Fig. 3.2.5.).
For leaving the study at any time 84.5% Indians, 60.5% of Lithuanians agreed for the statement . This (Fig. 3.2.5.) shown a trend from agree, neither agree and then disagree in case of Lithuanian respondents.and in case of India it stops at Neither agree, nor disagree. This revealed that Indians think more about the rights of the subjects. They think that clinical research and ethics both are equally important.
Figure. 3.2.5. Respondents’ opinions on the statement “research participants can leave the study at any time without any explanations” (*-p<0.05, compared to Indians)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Disagree Neither agree, nor disagree
Agree 1.0%
14.4%
84.5%
10.8%*
32.5%*
56.6%*
India Lithuania
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Disagree Neither agree, nor disagree Agree 15.5%
84.5%
18.5%* 21.0%
60.5%*
India Lithuania
From the result we analyzed gender wise the attitude of respondents that philosophers should not dictate what is ethical and what is not (Figure 3.2.6.).You will understand that almost all male respondents views was negative as compared to more than half female respondents. it shows that they were considering that both Scientific progress and ethics are equally important. According to the statement 22.8% females and 6.8% males were neutral were neutaral about the statement.
Figure 3.2.6. Respondents’ opinions on the statement “philosophers should not dictate what is ethical and what is not”
(*-p<0.05, compared to male respondents)
If you look chart (Fig. 3.2.7) below, we found the views of male and female respondents, in which almost all male and approximately half of the female respondents were disagreed. Their attitude regarding the participants is that, we don’t have to take disadvantaged people participation as good opportunity. In this anylsis we revealed that females were more agree than male respondents and they think that its an good opportunity to do reseach on disadvantagesd people.
0%
10%
20%
30%
40%
50%
60%
70%
80%
Disagree Neither agree, nor disagree Agree
79.5%
6.8%
13.6%
53.3%*
22.8%* 23.9%
male female
Figure 3.2.7 Respondents’ opinions on the statement “Participation of disadvantaged people in clinical trials is a good opportunity to get new treatment options” (* - p<0.05, compared to male respondents)
As you can see the chart (Fig. 3.2.8.) It revealed Opinion that research participants must participate in all procedures of clinical trials after they have given consent depending on clinical experience (years). It shows that with increase in clinical experience, respondents emphasize that science is equally important as ethics. In last >20 years 65.9% were disagree which was more disagreed than 1-5,5-10 years which again prove that with experience perception of respondents is more toward the view that science and ethics are equally important.
The difference between 10-20 years and >20 years was very less that might be due to some other reasons. But overall information from the below (Fig. 3.2.8.). It was revealed that, with increase in age respondent think equally about science and ethics. And there level of awareness increase with increase in experience.
0%
10%
20%
30%
40%
50%
60%
70%
80%
Disagree Neither agree, nor disagree Agree
79.5%
9.1% 11.4%
48.9%*
27.2%* 23.9%*
male female
