Building capacity for randomized controlled trials in Pakistan psychia
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《中华医药杂志》英文版
Building capacity for randomized controlled trials in Pakistan psychiatry
Department of Psychiatry，The Aga Khan University
Correspondence to Dr.Haidr A.Naqvi, Clinical Epidemiological Unit (CEU), Department of Community Health Sciences, Aga Khan Univeristy (AKU) and Consultant Psychiatrist at Department of Psychiatry, AKU. P.O. Box 3500，Stadium Road，Karachi 74800, Pakistan
Tel: 493 0051 ext.4692，Fax: 493 4294
E-mail: haider.naqvi@aku.edu
INTRODUCTION
It is astonishing to note that during a period of 10 years (1993~2004) only 108 publication have appeared from Pakistan in Indexed journals (77.8% Medline, 22.2% psychInfo; Figure 1). There were only 43 individuals, actively involved in the research; among these 34 were psychiatrists. There was only one Randomized Control Trial (RCT) from the whole country. The mean country based impact factor (IF) of these studies is 2.75[1].This speaks about the dismal state of mental health research in Pakistan. It is also evident that research in high-income countries is not easily transferable or appropriate for use in low and middle-income countries
Mental health research capacity has been focus of few recent reviews and editorials[2,3].However no attention has been focused on the capacity for RCT in Pakistan psychiatry. There are several reasons for this. First and foremost is lack of awareness pertaining to issues surrounding the conduct of RCT. This is followed by actual capacity, in epidemiological sense, to carry it out.
Figure 1 Publication Year for studies published in Indexed Journals from Pakistan
HEALTH TECHNOLOGY DEVELOPMENT
Good clinical practice guidelines and ethical issues involving human subject research are summarized.Cursory inquiry will tell us that not many psychiatrists in Pakistan are aware of the fact that consortium of leading journals, like Lancet, BMJ, American Journal of Psychiatry, British Journal of Psychiatry are signatory of allegiance to good clinical practice guidelines (GCP). Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects[4].Compliance with GCP assures that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible.
GCP and other regulations on human research in drug development have now been formalized in many international and national guidelines and regulations. One such regulation is International Conference on Harmonization (ICH) of technical requirement for registration of pharmaceuticals for human use[5].This International Conference on Harmonization (ICH) guidance provides a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions. Aim of ICH is to unify registration requirement for various products besides reducing the medicinal product development cost.
The basic principle of ICH，GCP guidelines is that trial should be conducted in accordance with the
ethical principles that have their origin in the Declaration of Helsinki and International Ethical Guidelines for Biomedical Research Involving Human Subjects[6].Before initiation a trial, foreseeable risks and inconveniences should be weighted against anticipated benefits for the individual and the society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety and well being of the trial subjects are the most important considerations and should prevail over the interests of science and society. Clinical trial should be scientifically sound, and described in clear, detailed protocol, which should have received prior institutional review board (IRB)/independent Ethics Committee (IEC) approval[6].These guidelines clearly specify that freely given informed consent should be obtained from every subject prior to clinical trial participation. The confidentiality of record that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with applicable regulatory requirement(s). Investigational products, if any, should be manufactured, handled, and stored in accordance with applicable good manufacturing practices (GMP). They should be used in accordance with the approved protocol. ICH，GCP guidelines are a detailed document in which specific chapters provide elaborate guidelines on these issues.
In Pakistan, Drug Control Organization has been established for facilitating local pharmaceutical units and drug importers in the registration and licensing. Federal Ministry of Health, Pakistan, has devised Drug Regulatory Authority Act, 2006, in order to provide frame work for various activities in this regards. It aim to establish the Drug Regulation System in Pakistan by ensuring production, availability and accessibility of quality, safe, efficacious drugs and medicines to those in need, besides promoting relevant research and development, pharmacovigilance and drug information[7].
Unfortunately for various reasons Government of Pakistan has been slow in establishing its own standards and guidelines. Original ICH,GCP came out in 1996, since than Singapore GCP (1998), Malaysian GCP (1999) and Indonesian GCP (2001) have come out for guidance in regards to local standards of clinical trial practice[8].These principles are not legal requirements but represent a standard of practice that is acceptable by international regulatory bodies like FDA.
There are problems, in clinical epidemiological sense that makes design and conduct of RCT a challenge. Nevertheless, RCT remains a ‘gold standard’ method for demonstrating safety and efficacy of treatment. Three features that give a RCT its unique superiority also predispose it to unique ethical issues. These are randomization, blinding and control group/setting.
RANDOMIZED CONTROL TRIALS ：ETHICAL AND EPIDEMIOLOGICAL ISSUES
The basic Philosophy of Randomization is that treatment and comparison groups should be comparable in all respects except the one being studied, i.e. drug being tested. Researcher can achieve comparability on factors that are known to have an influence on the outcome, such as age, sex, race, or severity of the disease, by matching for these factors. But one cannot match persons for factors whose influence is not known or cannot be measured. This problem is usually resolved by the random assignment of individuals to the treatment and comparison groups. Randomization helps to ensure that the distribution of all factors-known and unknown, measurable and not measurable-except for therapy being studied is based on chance and not some factor, such as patient preference, that may lead to a bias in assignment. In addition, randomization is the means by which the investigator avoids introducing conscious and subconscious bias into the process of allocating individuals to the treatment or comparison groups.Preventing biased assignment permits definitive interpretation of the trial results. Because of the random assignment of subjects to the treatment and comparison groups, however, certain ethical questions arise. Hill (1977) has aptly stated this dilemma:
“The question at issue then is whether it is proper to withhold from any patients a treatment that might, perhaps, give him benefit. The value of treatment is, clearly, not proven; if it were, their would be no need for a trial. But, on the other hand, their must be some basis for it-whether it be evidence obtained in test tubes, animals or even in a few patients. There must be some basis to justify a trial at all”[10].
This highlights the issue of ‘clinical equipoise’. An honest and bona fide null hypothesis can also be referred to as equipoise. For example, in comparing treatment A and B, the clinical community aggress that there is no convincing evidence that A is better or less toxic than B. Additionally there is no superior therapy C, unless good reason exists to reject C. Hence, a doubt about which treatment is superior justifies giving subjects and equal chance to get either one; no one is being assigned to inferior treatment. However, not knowing which treatment is better for a group of patients does not preclude judgement about what is better for individual patients at a particular time. It may be possible to make recommendation for an individual in favor of one of two unproven treatments based on individual’s unique symptoms, side effects and preferences. Even if new therapy is superior, what if there isn’t enough evidence to support it? Answer, inherent in the design of the RCT, is that randomization will ensure a fairest distribution of limited resources.
Issues like these create a tension for researcher who has a dual role of clinician and investigator. In research role of a physician is systematic investigation of human beings in order to develop generalizable knowledge. While in practice they pursue diagnosis and treatment of an illness in order to meet the health needs. Similarly in research, researcher is motivated to test hypothesis which permits conclusions to be made, while practice is designed to enhance the well being of the patients. Subject may or may not benefit, as the goal of clinical research is to serve common good by generating the knowledge. This may later on benefit other individual and society in general. It is expected that physicians sole obligations is well being of the patient, yet in the context of trial conduct, the physician has a competing obligation to generate high quality data. Physician-patient dependency relationship is also expected to invalidate informed consent. Being aware of tension inherent in dual roles can help researcher-clinician deal effectively with these issues. Physician-Investigator can also rely on other members of the research trial team for delegating certain responsibilities. However patients need to be informed accordingly. In RCT, there are other issues which require careful thought and planning.
CONCLUSION
In conclusion, it is imperative that research capacity for RCT be inculcated in early years of training. Professional bodies like College of Physicians and Surgeons, Pakistan and Pakistan Psychiatric Society should take steps to remedy current situation. Way forward lies in training group of committed young researchers. Institutional support in identifying and training such individuals can go a long way. Identifying and training group of people will have synergistic effect as opposed to training individuals. Providing protected time to these individuals for acquiring essential skills from centers of excellence in Pakistan and abroad can be one of the strategies. Short courses in research methodology, bio-statistics and epidemiology can be helpful to such individuals. Net works and collaboration with international organizations like International Clinical Epidemiological Unit (INCLEN) can be invaluable. Another way forward can be encouraging trainees in mental health professionals to move towards analytical and interventional studies. Mentorship and guidance in this regards also needs to be developed. Trainees can be encouraged to carry out quasi-experiments or pragmatic trials. It is expected that such a start will prime them towards methodologically robust RCT’s.
REFERENCES
1. Naqvi HA. JPPS and research in Pakistan. J Pak Psychiatric Soc 2006,3(1): 52-53.
2. Farooq S. Mental Health Research agenda for the 2005 Earth Quake in Pakistan. (Ed) JCPSP, 2006,16 (2):85-86.
3. Gadit A. Mental Health Research in Pakistan and the developing world (Ed). JCPSP,2006, 16(3): 169-170.
4. World Health Organization (WHO). Guidelines for Good Clinical practice (GCP) for trials on Pharmaceutical Products. Annex 3 of The Use of Essential drugs. Report of the WHO Expert Committee. Geneva: World Health Organization, 1995:97-137.
5. International Conference on harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). Note for the guidance on Good Clinical practice (CPMP/ICH/135/95),May 1996.
6. World Medical Association, Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical research Involving Human Subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964. Last Amendment in 48th General Assembly, Somerset West, Republic of South Africa, October, 1996.
7. Drug Regulation Authority Act, [on line], 2006 [cited 2006 September 29]. Available from: URL: http://www.dcomoh.gov.pk.
8. The Malaysian Medical and Health Directory (MMHD), [on line], 2006 [cited 2006 September 29]. Available from: URL: http://www.acrm.org.my/mmhd.
9. Lilienfeld ED, Stolley PD. Experimental Epidemiology: Randomized Clinical Trials. In: Foundations of Epidemiology, Third Edition. Oxford University press, 1994: 155-178.
10. Hill AB. A Short Textbook of Medical statistics, 10th ed. Philadelphia: J.B. Lippincott Co, 1977.
(Editor Jaque)(Haider A. Naqvi)
Department of Psychiatry，The Aga Khan University
Correspondence to Dr.Haidr A.Naqvi, Clinical Epidemiological Unit (CEU), Department of Community Health Sciences, Aga Khan Univeristy (AKU) and Consultant Psychiatrist at Department of Psychiatry, AKU. P.O. Box 3500，Stadium Road，Karachi 74800, Pakistan
Tel: 493 0051 ext.4692，Fax: 493 4294
E-mail: haider.naqvi@aku.edu
INTRODUCTION
It is astonishing to note that during a period of 10 years (1993~2004) only 108 publication have appeared from Pakistan in Indexed journals (77.8% Medline, 22.2% psychInfo; Figure 1). There were only 43 individuals, actively involved in the research; among these 34 were psychiatrists. There was only one Randomized Control Trial (RCT) from the whole country. The mean country based impact factor (IF) of these studies is 2.75[1].This speaks about the dismal state of mental health research in Pakistan. It is also evident that research in high-income countries is not easily transferable or appropriate for use in low and middle-income countries
Mental health research capacity has been focus of few recent reviews and editorials[2,3].However no attention has been focused on the capacity for RCT in Pakistan psychiatry. There are several reasons for this. First and foremost is lack of awareness pertaining to issues surrounding the conduct of RCT. This is followed by actual capacity, in epidemiological sense, to carry it out.
Figure 1 Publication Year for studies published in Indexed Journals from Pakistan
HEALTH TECHNOLOGY DEVELOPMENT
Good clinical practice guidelines and ethical issues involving human subject research are summarized.Cursory inquiry will tell us that not many psychiatrists in Pakistan are aware of the fact that consortium of leading journals, like Lancet, BMJ, American Journal of Psychiatry, British Journal of Psychiatry are signatory of allegiance to good clinical practice guidelines (GCP). Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects[4].Compliance with GCP assures that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible.
GCP and other regulations on human research in drug development have now been formalized in many international and national guidelines and regulations. One such regulation is International Conference on Harmonization (ICH) of technical requirement for registration of pharmaceuticals for human use[5].This International Conference on Harmonization (ICH) guidance provides a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions. Aim of ICH is to unify registration requirement for various products besides reducing the medicinal product development cost.
The basic principle of ICH，GCP guidelines is that trial should be conducted in accordance with the
ethical principles that have their origin in the Declaration of Helsinki and International Ethical Guidelines for Biomedical Research Involving Human Subjects[6].Before initiation a trial, foreseeable risks and inconveniences should be weighted against anticipated benefits for the individual and the society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety and well being of the trial subjects are the most important considerations and should prevail over the interests of science and society. Clinical trial should be scientifically sound, and described in clear, detailed protocol, which should have received prior institutional review board (IRB)/independent Ethics Committee (IEC) approval[6].These guidelines clearly specify that freely given informed consent should be obtained from every subject prior to clinical trial participation. The confidentiality of record that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with applicable regulatory requirement(s). Investigational products, if any, should be manufactured, handled, and stored in accordance with applicable good manufacturing practices (GMP). They should be used in accordance with the approved protocol. ICH，GCP guidelines are a detailed document in which specific chapters provide elaborate guidelines on these issues.
In Pakistan, Drug Control Organization has been established for facilitating local pharmaceutical units and drug importers in the registration and licensing. Federal Ministry of Health, Pakistan, has devised Drug Regulatory Authority Act, 2006, in order to provide frame work for various activities in this regards. It aim to establish the Drug Regulation System in Pakistan by ensuring production, availability and accessibility of quality, safe, efficacious drugs and medicines to those in need, besides promoting relevant research and development, pharmacovigilance and drug information[7].
Unfortunately for various reasons Government of Pakistan has been slow in establishing its own standards and guidelines. Original ICH,GCP came out in 1996, since than Singapore GCP (1998), Malaysian GCP (1999) and Indonesian GCP (2001) have come out for guidance in regards to local standards of clinical trial practice[8].These principles are not legal requirements but represent a standard of practice that is acceptable by international regulatory bodies like FDA.
There are problems, in clinical epidemiological sense that makes design and conduct of RCT a challenge. Nevertheless, RCT remains a ‘gold standard’ method for demonstrating safety and efficacy of treatment. Three features that give a RCT its unique superiority also predispose it to unique ethical issues. These are randomization, blinding and control group/setting.
RANDOMIZED CONTROL TRIALS ：ETHICAL AND EPIDEMIOLOGICAL ISSUES
The basic Philosophy of Randomization is that treatment and comparison groups should be comparable in all respects except the one being studied, i.e. drug being tested. Researcher can achieve comparability on factors that are known to have an influence on the outcome, such as age, sex, race, or severity of the disease, by matching for these factors. But one cannot match persons for factors whose influence is not known or cannot be measured. This problem is usually resolved by the random assignment of individuals to the treatment and comparison groups. Randomization helps to ensure that the distribution of all factors-known and unknown, measurable and not measurable-except for therapy being studied is based on chance and not some factor, such as patient preference, that may lead to a bias in assignment. In addition, randomization is the means by which the investigator avoids introducing conscious and subconscious bias into the process of allocating individuals to the treatment or comparison groups.Preventing biased assignment permits definitive interpretation of the trial results. Because of the random assignment of subjects to the treatment and comparison groups, however, certain ethical questions arise. Hill (1977) has aptly stated this dilemma:
“The question at issue then is whether it is proper to withhold from any patients a treatment that might, perhaps, give him benefit. The value of treatment is, clearly, not proven; if it were, their would be no need for a trial. But, on the other hand, their must be some basis for it-whether it be evidence obtained in test tubes, animals or even in a few patients. There must be some basis to justify a trial at all”[10].
This highlights the issue of ‘clinical equipoise’. An honest and bona fide null hypothesis can also be referred to as equipoise. For example, in comparing treatment A and B, the clinical community aggress that there is no convincing evidence that A is better or less toxic than B. Additionally there is no superior therapy C, unless good reason exists to reject C. Hence, a doubt about which treatment is superior justifies giving subjects and equal chance to get either one; no one is being assigned to inferior treatment. However, not knowing which treatment is better for a group of patients does not preclude judgement about what is better for individual patients at a particular time. It may be possible to make recommendation for an individual in favor of one of two unproven treatments based on individual’s unique symptoms, side effects and preferences. Even if new therapy is superior, what if there isn’t enough evidence to support it? Answer, inherent in the design of the RCT, is that randomization will ensure a fairest distribution of limited resources.
Issues like these create a tension for researcher who has a dual role of clinician and investigator. In research role of a physician is systematic investigation of human beings in order to develop generalizable knowledge. While in practice they pursue diagnosis and treatment of an illness in order to meet the health needs. Similarly in research, researcher is motivated to test hypothesis which permits conclusions to be made, while practice is designed to enhance the well being of the patients. Subject may or may not benefit, as the goal of clinical research is to serve common good by generating the knowledge. This may later on benefit other individual and society in general. It is expected that physicians sole obligations is well being of the patient, yet in the context of trial conduct, the physician has a competing obligation to generate high quality data. Physician-patient dependency relationship is also expected to invalidate informed consent. Being aware of tension inherent in dual roles can help researcher-clinician deal effectively with these issues. Physician-Investigator can also rely on other members of the research trial team for delegating certain responsibilities. However patients need to be informed accordingly. In RCT, there are other issues which require careful thought and planning.
CONCLUSION
In conclusion, it is imperative that research capacity for RCT be inculcated in early years of training. Professional bodies like College of Physicians and Surgeons, Pakistan and Pakistan Psychiatric Society should take steps to remedy current situation. Way forward lies in training group of committed young researchers. Institutional support in identifying and training such individuals can go a long way. Identifying and training group of people will have synergistic effect as opposed to training individuals. Providing protected time to these individuals for acquiring essential skills from centers of excellence in Pakistan and abroad can be one of the strategies. Short courses in research methodology, bio-statistics and epidemiology can be helpful to such individuals. Net works and collaboration with international organizations like International Clinical Epidemiological Unit (INCLEN) can be invaluable. Another way forward can be encouraging trainees in mental health professionals to move towards analytical and interventional studies. Mentorship and guidance in this regards also needs to be developed. Trainees can be encouraged to carry out quasi-experiments or pragmatic trials. It is expected that such a start will prime them towards methodologically robust RCT’s.
REFERENCES
1. Naqvi HA. JPPS and research in Pakistan. J Pak Psychiatric Soc 2006,3(1): 52-53.
2. Farooq S. Mental Health Research agenda for the 2005 Earth Quake in Pakistan. (Ed) JCPSP, 2006,16 (2):85-86.
3. Gadit A. Mental Health Research in Pakistan and the developing world (Ed). JCPSP,2006, 16(3): 169-170.
4. World Health Organization (WHO). Guidelines for Good Clinical practice (GCP) for trials on Pharmaceutical Products. Annex 3 of The Use of Essential drugs. Report of the WHO Expert Committee. Geneva: World Health Organization, 1995:97-137.
5. International Conference on harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). Note for the guidance on Good Clinical practice (CPMP/ICH/135/95),May 1996.
6. World Medical Association, Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical research Involving Human Subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964. Last Amendment in 48th General Assembly, Somerset West, Republic of South Africa, October, 1996.
7. Drug Regulation Authority Act, [on line], 2006 [cited 2006 September 29]. Available from: URL: http://www.dcomoh.gov.pk.
8. The Malaysian Medical and Health Directory (MMHD), [on line], 2006 [cited 2006 September 29]. Available from: URL: http://www.acrm.org.my/mmhd.
9. Lilienfeld ED, Stolley PD. Experimental Epidemiology: Randomized Clinical Trials. In: Foundations of Epidemiology, Third Edition. Oxford University press, 1994: 155-178.
10. Hill AB. A Short Textbook of Medical statistics, 10th ed. Philadelphia: J.B. Lippincott Co, 1977.
(Editor Jaque)(Haider A. Naqvi)