Curricular adequacy on basics of clinical trials.

INTRODUCTION: Clinical trials are integral to innovation in the treatment modalities and are conducted to assess the safety and efficacy of novel drugs. Clinical trials of modern era have evolved through stern consequences and tragedies in the past. This study was designed to know knowledge on ethics, adverse drug reactions (ADRs), and tragedies in clinical trials among interns and postgraduates (PGs).
METHODOLOGY: A cross-sectional study was carried out on graduates undergoing internship (interns) and PG residents of a medical college and a dental college from Punjab. This descriptive cross-sectional study was conducted on 151 professionals of medical college and 100 professionals of dental colleges in Punjab with the help of a prevalidated questionnaire. The data were then analyzed using descriptive statistics.
RESULTS: There was no significant difference between dental and medical doctors regarding ethics and ADRs, but a significant difference was observed among interns and PG residents, with interns having higher awareness regarding ethics and ADRs. There was no significant difference (P = 0.941) in knowledge among dental and medical doctors as well as among interns and PG residents, with P = 0.264 about tragedies in clinical trials.
CONCLUSION: From the study, it can be concluded that interns and PGs do not get enough exposure to basics in clinic research such as research ethics, ADRs, and tragedies in clinical trials. It is suggested that there is a requirement for suitable modifications in the teaching curriculum at undergraduate level and regular training must be provided to professionals.

Introduction

Clinical trials are integral to innovation in the treatment modalities and are conducted to assess the safety and efficacy of new drugs. Clinical trials of modern era have evolved through tragedies such as sulfanilamide disaster, clioquinol tragedy, and thalidomide tragedy associated with significant mortality and morbidity.[1] These tragedies happened due to lack of adequate preclinical safety and efficacy data,[2] lack of scientific conduct, safety data misinterpretation, inattentive patient care, inadequately informed consent (IC),[34] lack of pharmacovigilance (PV), and nonapproval of drug by the FDA.[345] Regulatory requirements and authorities have thereafter taken solemn steps to protect the patient's rights, safety, and well-being before their enrolment and during their participation in a clinical trial.[6]

Regulations and guidelines such as Investigational New Drug Application, New Drug Application, International Conference on Harmonization guidelines, Periodic Benefit-Risk Evaluation Report, and Postmarketing Surveillance have been framed with the purpose to reinforce ethics and participants' safety.[7] Physicians play a significant and larger role in any clinical trial and need to be well aware of research ethics, adverse drug reaction (ADR), and tragedies that happened in the past.

Indian Council of Medical Research (ICMR) has issued bioethics guidelines for research. Drug Controller General of India (DCGI) provides authority to the ethics committee (EC) as an important regulator of ethical research. There is no central public authority that is responsible for supervising the proper and competent functioning of ECs. ECs function as self-sufficient isolated bodies which deal with the approval of research conducted in their respective institutes, with no accountability whatsoever as ICMR and DCGI lack autonomy over the research reviewed and approved by the ECs in India.[8]

According to the World Health Organization (WHO),[9] ADR is defined as “any response to a medication which is unintentional and noxious which occurs in humans at doses normally taken for diagnosis, prophylaxis or therapy.” PV is defined as the science and activities which are related to the detection, assessment, understanding, and prevention of adverse effects. The main objectives of PV are to assess and communicate the risks and benefits associated with the drugs and inform and provide education to patients about rational and safe use of medical drugs.[910] Monitoring of ADRs is not only important for clinical trials but also equally important during routine practice to identifying possible ADRs, preventing harm by timely intervention, and bringing to attention of fraternity for further research.

Literature review suggests lower knowledge and awareness about these issues among physicians.[111213] Medical and dental colleges are otherwise meant to be primarily research institutions. Research is a continuous and evolving process bringing insight into more and more processes, technology, and treatment approaches. On the one extreme end are clinical trials on newer treatment strategies and on the other end are routine treatment (including medication) approaches which themselves are a research activity requiring monitoring, observation, and recording deviations from expected outcomes and possible variations. Ethics in medical practice, monitoring ADRs, and sensing impending tragedies need to be a proactive process and must be practiced for each patient and for each treatment approach. It is expected that medical and dental colleges teach and inculcate the above in young medical graduates (to ensure safe treatment) through teaching and educating future doctors. This in turn shall promote active feedback for early intervention.

It is thus pertinent to assess young doctors (medical and dental) knowledge on research related issues such as ethical aspects, ADRs, and tragedies and to identify gaps in their knowledge levels. The cross-sectional study was conducted to assess the knowledge on ethics, ADRs, and tragedies related to research and clinical trials among interns and postgraduates (PGs) of dental and medical colleges.

Methodology

A cross-sectional study was carried out on graduates undergoing internship (interns) and PG residents at a medical college and a dental college from Punjab. Medical and dental streams were chosen to compare and identify differences in knowledge imparted to medical and dental graduates. Approval was taken from respective institution. The study did not involve patient data and/or patients. All the interns and PGs were selected for the study. Lists of eligible participants and their duty rosters were obtained from the respective colleges. Participants were contacted individually and/or in short groups and requested to volunteer for the study. All the professionals were briefed about the purpose of the study and assured about the confidentiality of their responses. Written prior consent was obtained from each participant.

Based on the review of literature and previous research studies, a questionnaire was devised and got validated from the faculty members at selected medical and dental college. A pilot study was conducted on five participants from each college and no changes were required in the questionnaire after the pilot study. Such ten participants were included in the study. Cronbach's alpha for the said questionnaire was 0.824 and was thus found to be reliable. Questionnaire included ten questions on ethics, five questions on ADRs, and eight questions on tragedies. Each question was a multiple-choice question with only one correct answer. Of total 296 enrolled professionals, 256 professionals volunteered and submitted their responses for the study (response rate of 86.4%). Grossly incomplete questionnaires (n = 5) were excluded from the study. The final analysis included 251 respondents. Respondents comprised 58.5% (147) females and 37% (94) males [Table 1]. Ten respondents did not disclose their gender. Medical doctors were 60% (151) and dental doctors were 40% (100).

Table 1

Demographic distribution of respondents

	Dental			Medical			Total
	I	P	NS	I	P	NS
Females	46	32	2	19	48	0	147
Males	5	10	0	27	52	0	94
NS	2	3	0	2	2	1	10
Total	53	45	2	48	102	1	251

I=Interns, P=Postgraduate residents, NS=Not specified

Data were fed in spreadsheet for analysis, and further, each correct response was given 1 mark. Incorrect response and unanswered questions was given 0 mark. Maximum scores ranged from 0 to 10 marks for research ethics, 0 to 5 marks for ADRs, and 0 to 8 marks for tragedies in clinical trials. Knowledge levels were assessed as percentage of correct responses. Data were analyzed for percentage correct responses, mean values, and intergroup comparison by applying t-test using Statistical Package for the Social Sciences version 20 (IBM, Armonk, NY, United States of America).

Results

Data collected were analyzed for knowledge on ethics, ADRs, and tragedies among young graduate doctors divided as dental and medical graduates and interns and PGs.

Ethics in clinical research

Knowledge on ethical aspects among dental doctors was 36.5% and medical doctors was 35.4% [Table 2]. Knowledge on ethics for majority respondents was < 60% [Table 3] including when divided into subcategories such as interns and PGs. Knowledge on aspects in clinical trials for pregnant women, children, and vulnerable people was 22.3% [Table 4]. Knowledge about institutional ethics committee (IEC) responsibilities and the role of the institution review board (IRB)/IEC in clinical trials was observed in only 34.3% and 35.1% respondents, respectively. Awareness for abbreviation ICF (Informed Consent Form) used in clinical trials was found in 39.0% [Table 4]. There was observed no significant difference (P = 0.716) of knowledge among dental and medical doctors [Table 5]. Significant difference (P = 0.00004) in knowledge was observed among interns and PG resident with interns having higher awareness [Table 6].

Table 2

Percentage correct responses

	Dental doctors (%)			Medical doctors (%)
	I	P	Total	I	P	Total
Ethics	38.5	34.4	36.5	48.8	29.4	35.4
ADR	38.1	29.8	34.0	45.0	33.1	36.8
Tragedies	36.8	47.5	41.4	52.3	37.0	41.6

I=Interns, P=Postgraduate residents, ADR=Adverse drug reactions

Table 3

Count of respondents with specified intervals of correct responses

	Interns (dental + medical)*			Postgraduates (dental + medical)*
	<60%	60%-80%	>80%	<60%	60%-80%	>80%
Ethics	75	22	4	133	12	2
ADRs	96	3	2	139	7	1
Tragedies	80	15	6	122	16	9
	Dental doctors			Medical doctors
	<60%	60%-80%	>80%	<60%	60%-80%	>80%
Ethics	89	10	1	122	24	5
ADRs	98	1	1	140	9	2
Tragedies	84	13	4	121	19	12

*Few of the participants did not specify to be interns/postgraduates and thus not counted above. ADRs=Adverse drug reactions

Table 4

Percentage correct responses on ethics in clinical trials

Aspects related to ethics in clinical trials	AL (%)
Knowledge about importance of ethics in clinical research	44.0
Knowledge about ethical issues in clinical trials for pregnant women, children, vulnerable people	22.3
Conception about unethical experiments	49.4
Knowledge about “World Medical Association Declaration of Helsinki” Ethical Principles for Medical Research	37.1
Knowledge about full form of abbreviation IEC used in clinical trials	26.1
Knowledge about key responsibilities of IEC	34.3
Role of IRB/IEC for permission for testing drugs on human beings	35.1
Knowledge about full form of abbreviation ICF used in clinical trials	39.0
Knowledge about definition of informed consent	35.5
Knowledge about protocol of informed consent	36.0

IEC=Institutional ethics committee, IRB=Institution review board, ICF=Informed consent form, AL=Awareness level

Table 5

Difference in knowledge between dental and medical doctors (t-test)

	Levene’s test for equality of variances		t-test for equality of means
	F	Significant	t	df	Significant (two-tailed)
Ethics
Equal variances assumed	6.399	0.012	0.350	249	0.727
Equal variances not assumed			0.364	238.178	0.716
ADR
Equal variances assumed	3.452	0.064	−0.935	249	0.351
Equal variances not assumed			−0.965	233.300	0.336
Tragedy
Equal variances assumed	1.219	0.271	−0.074	249	0.941
Equal variances not assumed			−0.076	225.579	0.940

ADR=Adverse drug reaction

Table 6

Difference in knowledge between interns and postgraduate residents (t-test)

	Levene’s test for equality of variances		t-test for equality of means
	F	Significant	t	df	Significant (two-tailed)
Ethics
Equal variances assumed	2.823	0.094	4.186	246	0.00004
Equal variances not assumed			4.118	202.349	0.00005
ADR
Equal variances assumed	4.864	0.028	3.110	246	0.002
Equal variances not assumed			3.165	227.556	0.002
Tragedy
Equal variances assumed	0.015	0.902	1.118	246	0.265
Equal variances not assumed			1.119	216.117	0.264

ADR=Adverse drug reaction

Adverse drug reactions

Knowledge on ADR was 34.0% among dental doctors and 36.8% among medical doctors [Table 2]. Knowledge of majority of the respondents was < 60% [Table 3] including when spilt into various categories. Only 66.5% of professionals had knowledge on ADR terminology. Awareness about Uppsala Monitoring Centre (UMC-ADR data storage center), a WHO center for ADRs monitoring,[14] was 87% among young doctors [Table 7]. There was no significant difference (P = 0.351) of knowledge among dental and medical doctors [Table 5]. Significant difference (P = 0.002) in knowledge was found between interns and PGs, with interns having higher knowledge [Table 6].

Table 7

Percentage correct responses on adverse drug reactions

Topics on ADR	AL (%)
ADR	66.5
AE/adverse event	18.0
SAE	40.0
Pharmacovigilance	41.4
Knowledge of central database in UMC for ADR reporting	13.1

SAE=Serious adverse event, UMC=Uppsala Monitoring Centre, ADR=Adverse drug reaction, AE=Adverse event, AL=Awareness level

Tragedies in clinical trials

Knowledge on tragedies in clinical trials among dental doctors was 41.4% and among medical doctors was 41.6% [Table 2]. It was found that medical interns (52%) had higher awareness than medical PG residents (37%), while dental PG residents (47.5%) had higher awareness than that of dental (36.8%) interns [Table 2]. Knowledge of majority of respondents was < 60% [Table 3]; however, it was better than on ethics and ADRs. Sources of knowledge on tragedies in clinical trials [Table 8] among respondents were books and internet (59.7%), college lectures (59.3%), and published journals and magazines (56.5%). It was found that 59.8% of participants were unaware of clioquinol tragedy (which occurred in Japan due to drug clioquinol) that resulted in subacute myelooptic neuropathy (a complication involving gastrointestinal system and brain).[1] There was no significant difference (P = 0.941) of knowledge among dental and medical doctors [Table 5] and between interns and PG residents [Table 6] with P = 0.264.

Table 8

Percentage correct responses on tragedies in clinical trials

Topics about tragedies in clinical trials	AL (%)
Source of knowledge about tragedies in clinical trials
Books and internet	59.7
From college lectures	59.3
Published journals and magazines	56.5
Reasons of tragedies were
Lack of preclinical studies
Absence of rules and regulations	45.0
Lack of ethical considerations
Thalidomide tragedy is also known as “Canadian tragedy”	17.1
Thalidomide taken for morning sickness by pregnant women resulted in phocomelia/flipper-like limbs	52.2
Nazi experiments were conducted in the early 1940s during the World War II and holocaust	37.1
Nazi Experiments were experiments conducted in Germany	51.0
Nazi experiments were unethical experiments which were conducted on prisoners and disabled subjects	48.0
Clioquinol tragedy occurred in Japan	40.2

AL=Awareness level

Discussion

Death of participants enrolled for clinical trials and monitoring deficiencies had raised serious issues regarding the monitoring processes and systems applied for patient safety.[15] Poverty and illiteracy leading to easy and faster enrolment rate and lower cost make India the most attractive destination for global clinical trials. This has raised concerns on ethical and scientific issues such as consent requirements, vulnerability, and compensation for patients, EC functioning, and researchers training on ethical aspects.[16] IC is considered as the basic essential standard in the conduct of clinical trials. IC provides essential and detailed information regarding proposed trial to the prospective participants and empowers them to make a balanced and informed decision about enrolment in the trial.[1718] Importance, awareness, and application of medical ethics have been found to be decreasing day by day among professionals.[19] In a study conducted among medical students,[20] as much as 96% of professionals felt that medical ethics were important, whereas in the study conducted among interns and PGs,[21] only 89% of professionals agreed to same and declining to 44.0% in the present study depicting the widening gap in felt importance and actual awareness created by the current education system. It requires high motivational levels among faculty, delivering due education, and building competent professionals.[22] In India, clinical trials are being conducted for a variety of drugs and newer treatment modalities, enrolling vast population with different diseases types where multinational companies conduct trials at the cost and exploitation of ignorant population reducing financial costs, thus generating large profit.[23] IEC) or EC is meant to regulate clinical research and to safeguard the rights of those enrolled and their safety. However, the hospitals and institutions targeting on enhancing their research output have a propensity to ignore the recommendations of IEC and/or bypass it.[8]

In the present study, professionals provided 34.3% correct responses on key responsibilities of IEC. Notably, in the present study, both the medical and dental professionals had lower knowledge on role of IEC and similar results were found in studies conducted earlier.[2425] IECs in India have been found to have limited resources and members are still not trained as there is no formal training on bioethics and there are no training requirements for being IEC members.[26] IEC members are usually senior most faculty members rather than being qualified, trained, and skilled experts.

The World Medical Association in 1964 at Helsinki articulated specific guidelines and general principles for conduct of biomedical research known as the Declaration of Helsinki.[6] In our study, it was observed that participants knowledge was only 37.1% for the World Medical Association's Helsinki Declaration. Similar findings were observed among medical and dental PG students in South India[24] and among doctors and nurses regarding healthcare ethics in the West Indies.[27] This may mean that these principles are not routinely and adequately practiced and used by medical and dental professionals. The study highlights that practice of ethics and its teaching declines as doctors proceed from internship phase to PG resident stage with lesser knowledge among PGs as compared with interns. This difference was found to be statistically significant with P = 0.00004 [Table 6].

For ADRs, 66.5% of questions were correctly answered similar to the findings (65.6%) in a study conducted in Malaysia among medical and pharmacy students.[9] Further awareness for terminology adverse event was 18%, and similar findings were reported among doctors of government medical college at West Bengal, India.[27] In our study, only 41.4% of professionals knew correctly about PV and similar findings were observed in studies done at Malaysia.[928] This lower knowledge may be attributed to the fact that medical/dental students are inadequately exposed to aspects of PV in their academic curriculum. Appropriate interventional strategies require educational focus, managerial observation to practice evidence-based prescribing, and close monitoring of patients consuming drugs with potential drug–drug interaction and ADRs.[29]

Young doctors as professionals and resident doctors play a key role in detecting, recording, and reporting ADRs with an objective of strengthening PV program. They are responsible and must counsel patients, take IC, and make patients aware on possible ADRs which may occur during the phase of treatment. Knowledge on ADRs was found to be 13.1% on UMC, thus depicting inadequate knowledge about the international center for ADR reporting. Similar findings were obtained among medical and pharmacy students in Malaysia, among medical students in Puducherry and Nigeria,[92829] and among dental students in South India.[30] In the present study interns possessed higher knowledge than PGs and statistically significant difference was found between the mean knowledge score of interns and PGs. This may essentially mean that knowledge imparted during graduation is not actively practiced as one starts clinical practice. Higher knowledge among interns can also be attributed to their internal motivation aimed at acquiring more and more knowledge and gaining more scores in examinations. Lower score in PG residents can also be attributed to busy schedule of residents with heavy workload in multispecialty hospitals[3132] giving them inadequate time for quality work. While PG curriculum mandates research activity with thesis submission as a part of their final assessment, the study found that the knowledge on ADR and ethics is lesser than that at graduation levels. This may again imply that theoretical knowledge gained during graduate studies is not routinely applied at clinical practice.

Knowledge on the past tragedies is like learning from the past and understanding how things can go wrong. It was observed that college lectures, books, and internet play a vital role in providing knowledge among participants; however, educational curriculum should be strengthened to promote further improvement on a large scale. On literature review, no similar study was found assessing awareness on the past tragedies in clinical trials. Our study identified that awareness of medical and dental graduates about the past tragedies in clinical trials was low. Regulatory authorities and universities need to take necessary steps to improve the knowledge of the professionals by inculcating changes in the curriculum.

Conclusion

From the study, it can be concluded that though being educational institutes, medical and dental curriculum does not provide adequate knowledge on basics aspects of clinical research such as research ethics, ADRs, and tragedies in clinical trials. On the other hand, though being research oriented, these institutes are lacking adequacy on providing practical training in clinical research and exposure to ethics and ADRs. Education during graduation and training during residency (PG) period can make them more knowledgeable and enthusiastic for exploring career in research and active participation in clinical research during active professional clinical practice. Clinical research not only means clinical trials but also includes research activities which can be conducted during routine clinical practice.

This implies a need for modifications in the undergraduate teaching curriculum. PGs need to be additionally evaluated for understanding of clinical research. The aim of the thesis, being mandatory requirement for other professional PG courses, is to impart training in research methodology and to cultivate logical and original thinking so that students communicate their findings as a scientific report. Similarly, PG medical and dental courses must impart them with additional and rigorous training on all aspects of clinical research. Regulatory bodies such as Medical Council of India and Dental Council of India should make it mandatory for all academic programs to include training on all aspects of clinical research in coordination with DGCI and ICMR. It is suggested the dental and medical college must have dedicated departments for clinical research and clinical research must be taught as a separate subject.

Limitations of the study

As the data were collected from one medical and one dental college of Punjab, the findings of the study may not be representative of other colleges of the state.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.