Registration and ethics committee approval for observational studies: Current status and way forward

Namrata Singh and Vasudha Background parency (Figure 1). However, RCTs are Turacoz Healthcare Solutions, Gurugram, India Randomised controlled trials (RCTs) investigate performed under tightly controlled conditions the efficacy of new interventions and are and, thus, their results are limited to the patients considered the gold standard in medical research. in experimental settings. Real-world clinical Correspondence to: They are considered strong evidence in the practice comes up with many different situations Dr Namrata Singh hierarchy of evidence-based medicine (EBM) that might not have been tested in a . Director, Medical Services because of their well-defined study designs, There can be a new adverse event, an off-label Turacoz Healthcare Solutions compliance with strict protocols, and trans - indication, a co-morbid condition, or a co- 505, First Floor, Phase V Udyog Vihar, Sector 19 Gurugram, Haryana, India – 122002 –––– Systematic review/Meta-analysis [email protected] +91-9810036125 –––––– Double-blind RCTs

Abstract –––––– RCTs Randomised controlled trials (RCTs) have always been recognised as the highest level of –––––– Non-randomised trials evidence in medical research. However, they cannot address the questions that one comes –––––– Cohort studies across in real-world clinical practice. Obser- vational studies can answer such questions as they are based upon real data obtained from –––––– Case-control studies patient healthcare records, medical databases, and registries. Literature review has shown –––––– Case series & Cross-sectional studies that observational studies are as important as RCTs and should be considered when making any clinical decisions. However, there is a lack –––––– Case reports of standard guidelines for registering and reporting observational studies, which may –––––– Editorials & reviews contribute to publication and reporting bias. Furthermore, guidelines differ on the ethical –––––– Animal, in vitro & cell considerations for observational studies. models This article discusses these issues, focusing on the current situation and gaps in the registration, ethics approval, and publication of observ ational studies. Figure 1. Level of evidence in medical research.4 The positions of randomised controlled trials and observational studies in the pyramid of evidence for medical research are shown.

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medication that can change the course of the have been based on observational study results, various guidelines have been published by illness. In such situations, an observational study such as the Data Collection on Adverse Events of scientific and regulatory organisations. The guide - can provide answers to many questions and can Anti HIV Drugs (D:A:D) study. The D:A:D lines identified in the literature along with their supplement the clinical trial in applying the study was conducted in 33,347 HIV-1-infected key objectives are summarised in Table 1.11–20 intervention to the general population.1–4 patients and showed that the risk of heart attack Literature review shows that these guidelines In observational studies, the interventions are increased by 49% and 90%, respectively, with the are not all in agreement on standards of not determined by the protocol and are based on use of didanosine and abacavir. On the basis of observational studies: There was no consensus real-world clinical practices. These studies are these study results, the FDA advised healthcare for 12 out of the 23 elements discussed in the based upon data obtained from patient health - providers to evaluate the risks and benefits of guidelines. This may contribute substantially to care records, health care databases, and registries, HIV antiretroviral drugs, including abacavir and disparities in research and, thus, a low quality of and can be prospective or retrospective in nature. didanosine.10 evidence for patient care decisions, leading to Observational studies can be of various types, poor healthcare outcomes. Moreover, there is a including cross-sectional, case-control, and Ensuring the quality of lack of standards for ethical considerations and cohort studies; however, their main strength lies observational studies: dissemination. Only three out of nine guidelines in the fact that they are more proximate to real- What do the guidelines say? addressed these aspects; however, no actions life evidence.1–3 To ensure the quality of observational studies, were suggested regarding implementation.11 Going beyond randomised controlled trials: Where do Table 1: Guidelines for observational studies observational studies stand? Benson et al compared observational studies Guideline Key objective with RCTs across 19 diverse treatments and 1 Agency for Healthcare Research Quality To identify the minimum standards and best found summary estimates of the treatment effects (AHRQ): Developing a Protocol for practices for designing observational to be similar for both types of studies.5 Further, Observational Comparative Effectiveness comparative effectiveness research studies Concato et al identified meta-analyses of RCTs Research12 and observational studies for five clinical topics 2 Comparative Effectiveness Research To assess the relevance and credibility of and found the summary estimates and 95% Collaborative Initiative: Observational Study observational studies for informed health confidence intervals (CIs) to be similar. For Assessment Questionnaire13 care decision making example, the odds ratio (95% CI) was found to 3 European Network of Centres for Pharma - To consider the important principles when be 0.49 (0.34–0.70) and 0.50 (0.39–0.65), coepidemiology and Pharma covigilance designing and writing a pharma coepidemi - respectively, for RCTs and observational studies (ENCePP) Checklist for Study Protocols14 ological or pharmacovigilance study protocol assessing the effectiveness of the Bacillus 4 ENCePP Guide on Methodological To provide methodological guidance for Calmette-Guérin vaccine against active tuber - Standards in Pharmacoepidemiology15 researchers in pharmacoepidemiology and culosis.6 Furthermore, literature shows that pharmacovigilance observational studies are being used by the 5 United States Food and Drug To provide guidance on good American Geriatrics Society, the Endocrine Administration (FDA) Guidance for pharmacovigilance practices and Society, and various other vitamin D expert Industry: Good Pharmacovigilance Practices pharmacoepidemiologic assessment of groups to make recommendations on vitamin D and Pharmacoepidemiologic Assessment16 observational data regarding drugs supplementation.7 6 Good ReseArch for Comparative To provide a checklist for observational RCTs and observational studies need to be Effectiveness (GRACE) Checklist17 comparative effectiveness studies that are viewed together because their different study rigorous in design to help in decision support designs and methods are crucial to provide as 7 GRACE Principles18 To help decision makers evaluate the quality much information as possible in terms of the of observational research studies of safety, efficacy, and effectiveness of an inter - comparative effectiveness vention.8,9 RCTs might not give accurate answers 8 International Society for Pharma co - To provide guidance on framing research in complex situations, for example the presence economics and Outcomes Research questions and reporting findings for of confounding factors, interventions of long (ISPOR) Good Research Practices for retrospective epidemiologic and health duration, larger patient populations, and use of Retrospective Database Analysis Task Force services research studies concomitant medications. Observational studies Report19 can, and should, be used in such complex 9 Patient-Centered Outcomes Research To provide guidance on various topics, domains to explore the best practices in the real Institute (PCORI) Methodology including formulating research questions, world; however, their findings should be Standards20 data integrity and analysis, data registries, considered with due caution.2,4 and systematic reviews There are instances where FDA decisions

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Ethical principles for medical increased and observational studies now patient records.29 By contrast, retrospective research represent about 15% of all studies on studies are excluded from the code of ethics As per the , medical ClinicalTrials.gov. Around half of these studies approval in Turkey.30 research involves research on identifiable human are from North America (50%), followed by Ethics committee approval of observational material or data and needs to be continuously Europe (20%) and Asia (13%), and 85% are studies has been a topic of great debate. This is challenged to prove the efficacy, effectiveness, or funded by non-industry sources. However, the well illustrated by the differences in opinion in quality of prophylactic, diagnostic, and ther - number of observational studies registered is still the literature. While Orchard (2008) argued that apeutic procedures. The design and results of all considered low, exposing observational studies most observational studies are not ethically clinical studies should be publicly available and to reporting bias.24,27 sensitive and that ethics requirements are an are subject to ethical standards. Furthermore, all Some of the challenges in the registration of unnecessary barrier, others (Moser and Röggla, experimental procedures involving human beings observational studies include:24 2008) disagreed, stating that ethical require - should be well-defined in a protocol, which needs ● Most of the studies registered are prospective ments are important to prevent bad practices in to be approved by an ethics committee.21 in nature, and there is a need to establish research.31,32 The two most important points to be methods for registering other types of studies, considered are registration of clinical studies and such as retrospective studies Observational studies and ethics committee approval of any study involving ● The timeframe for registering observational publications human beings. In this article, we discuss the studies needs to be defined, along with the Differences in guidelines on observational current status of these two points in reference to attributes that should be mentioned studies may lead to serious confusion when it is observational studies, as well as future ● Whether or how to register sub-studies or time to publish them. This is illustrated by a case implications. secondary studies using the same prospective in which manuscripts based on various French data observational studies were rejected or retracted Registration of observational ● Defining the data elements for reporting by US peer-reviewed journals because the studies: Current situation different types of observational studies protocols had not been approved by an ethics and gaps To ensure complete transparency of obser - committee. As per French law, which comes Registering clinical trials is not only ethical but vational studies, these issues need to be properly under the European regulations, only biomedical also has a scientific rationale. It provides global addressed. This requires discussions among all research involving an intervention and not access to information, reduces duplication, stakeholders, including sponsors, regulatory performed in the normal medical follow-up of enables monitoring for adherence to ethical authorities, and the public.24 patients needs ethics approval. The authors of the principles and regulations, improves the credi - French studies stated that ethics approval was not bility of the information, accelerates knowledge Ethics committee approval sought as the studies were performed using creation, and ensures transparency of research.22 of observational studies: routine techniques. However, this was against US As per Food and Drug Administration Current situation and gaps requirements and, thus, the studies were Amendments Act (FDAAA) 801 requirements, Although it is clear from the rejected. One important point to consider there is no mandatory requirement for Declaration of Helsinki that research here is that even if there is no requirement observational studies to be registered on protocols must be approved by an for ethics approval of such studies in ClinicalTrials.gov, unlike RCTs.23 Thus, ethics committee before the start France, it is compulsory to have an observational studies are quite vulnerable to of any experimental procedure, ethics opinion.33 publication and reporting bias, owing to selective the situation is a little confusing In 2004, an international initiative, reporting, misinterpretation of analyses, and lack for observational studies. Some Strengthening the Reporting of Obser - of regulations related to their registration and countries may waive the requirement vational Studies in Epidemiology reporting. This undermines the overall validity for ethics committee approval of (STROBE), was launched to provide of observational studies and provides a rationale observational studies because there is guidance on the reporting of obser - for registering them.22,24 no experimental intervention.28 v ational studies. The STROBE Currently, ClinicalTrials.gov allows the Currently, ethics committee guidelines include a complete registration of observational studies and provides approval is needed for all checklist of items that need specific data elements to be filled in for research in Canada, to be addressed when registration. In Europe, the European Union including the review of reporting observa - electronic Register of Post-Authorisation Studies tional studies (e.g. (EU PAS Register) is publicly available for study design, par - registration of post-authorisation studies to ticipants, and improve the transparency of observational results), but there research.25,26 is no mention of Over the past few years, the number of ethical require - observational studies registered per year has ments and regis-

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Table 2: Statements to be included in manuscripts based on observational studies, as per the ICMJE recommendations and journals’ author instructions 35-40

Organisation/ Statement Journal ICMJE “The Methods section should include a statement indicating that the research was approved or exempted from the need for review by the responsible review committee (institutional or national). If no formal ethics committee is available, a statement indicating that the research was conducted according to the principles of the Declaration of Helsinki should be included.” BMJ “Every research article submitted should include a statement that the study obtained ethics approval (or a statement that it was not required), including the name of the ethics committee(s) or institutional review board(s), and the number/ID of the approval(s).” JAMA “For all manuscripts reporting data from studies involving human participants or animals, formal review and approval, or formal review and waiver, by an appropriate institutional review board or ethics committee is required and should be described in the Methods section. For those investigators who do not have formal ethics review committees, the principles outlined in the Declaration of Helsinki should be followed.” PLOS ONE “Methods sections for submissions reporting on any type of observational and field study must include ethics statements that specify: permits and approvals obtained for the work, including the full name of the authority that approved the study; if none were required, authors should explain why.” Lancet “Studies on patients or volunteers need approval from an ethics committee and from participants. These should be documented in your paper.” Springer “The following statements should be included in the text before the References section: Ethical approval “Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.” For retrospective studies “Ethical approval: For this type of study formal consent is not required.”

Abbreviations: BMJ, British Medical Journal; ICMJE, International Committee of Medical Journal Editors; JAMA, Journal of the American Medical Association tration.34 However, the International Committee Key messages of observational studies. This would help to of Medical Journal Editors (ICMJE) along with ● Observational studies are as important as avoid the duplication of data and mis - specific international journals clearly mention RCTs and play an important role in real-world interpretation of results, and would the ethical requirements and considerations evidence. contribute to the worldwide spread of when submitting observational studies for ● Currently, there are no standard guidelines on knowledge. publication (Table 2).35–40 registration and ethics committee approval of ● It is advantageous for researchers/sponsors Ultimately, the Committee on Publication observational studies. to register their studies and consider ethical Ethics recommend ethics approval for all ● It is not mandatory to register observational requirements because the ultimate aim is to observational studies or suggests that a studies and obtain ethics committee approval improve patient healthcare and thereby supporting letter be requested from the ethics before study start. benefit society. committee in cases of exemption (where ethics ● There are no standards on dissemination of ● The ideal process for conducting and approval is not required).41,42 It should be data from observational studies, and this publishing an observational study is understood that regulatory authorities and legal creates confusion in the publication process. illustrated in Figure 2. bodies are not enemies of research but are ● Creating standardised guidelines for all these working towards improving research practices to aspects would help to improve the trans - the ultimate benefit of patients and society.28 parency of research and validate the findings

Identify Prepare Get Ethics Register Conduct Analyse Prepare Publish data Protocol Approval Observational Data Study Manuscript Study Report

Figure 2. The ideal process for designing, conducting, and publishing an observational study.

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27. Boccia S, Rothman KJ, Panic N et al. 37. The JAMA Network. Instructions for Acknowledgements Registration practices for observational Authors. 2017 [cited 2017 June 07]. The authors would like to acknowledge the studies on ClinicalTrials.gov indicated low Available from: clients who gave them the opportunity to work adherence. J Clin Epidemiol 2016;70: http://jamanetwork.com/journals/jama/ on different projects on observational studies and 176-82. pages/instructions-for-authors. gain immense insight on the subject. The authors 28. Rasmussen LS, Gisvold SE, Wisborg T. 38. PLOS ONE. Submission Guidelines. 2017 would like to thank Ritika Paul, Medical Writer Ethics Committee approval for [cited 2017 June 07]. Available from: at Turacoz Healthcare Solutions, for proof - observational studies. Acta Anaesthesiol http://journals.plos.org/plosone/s/ reading this article and formatting it according to Scand 2014;58:1047-8. submission-guidelines#loc-observational- the Medical Writing Instructions for Authors. 29. Perlman M. Ethical issues in ‘observational and-field-studies. research’. Paediatr Child Health 2000;5:89- 39. The Lancet. Instructions for Authors. 2017 Conflicts of Interest and 90. [cited 2017 June 07]. Available from: Disclaimers 30. Kıraç FS. Is Ethics Approval Necessary for http://www.thelancet.com/pb/assets/raw The authors disclose no conflict of interest. all Trials? A Clear But Not Certain Process. /Lancet/authors/lancet-information-for- Mol Imaging Radionucl Ther. authors.pdf. 2013;22(3):73-5. 40. Springer. Publishing ethics. 2017 [cited 31. Orchard J. For debate: should 2017 June 07]. Available from: observational clinical studies require ethics https://www.springer.com/gp/authors- committee approval? J Sci Med Sport editors/journal-author/journal-author- 2008;11:239-42. helpdesk/publishing-ethics/14214. 32. Moser B, Röggla G. Should observational 41. Committee on Publication Ethics (COPE). clinical studies require ethics committee Ethics committee approval. 2015 [cited approval? J Sci Med Sport 2008;11:518. 2017 June 07]. Available from: 33 Claudot F, Alla F, Fresson J, Calvez T, https://publicationethics.org/case/ethics- Coudane H, Bonaïti-Pellié C. Ethics and committee-approval. observational studies in medical research: 42. Committee on Publication Ethics (COPE). Author information various rules in a common framework. Int J Seeking retrospective ethics approval. 2011 Dr Namrata Singh is the Director and Epidemiol 2009;38:1104-8. [cited 2017 June 07]. Available from: founder of Turacoz Healthcare Solutions. She 34. von Elm E, Altman DG, Egger M, Pocock https://publicationethics.org/case/seeking is a paediatrician with more than 10 years of SJ, Gøtzsche PC, Vandenbroucke JP; -retrospective-ethics-approval. experience in medical writing. Her experience STROBE Initiative. The Strengthening the spans all types of medical writing documents Reporting of Observational Studies in and the major therapeutic areas. Epidemiology (STROBE) statement: guidelines for reporting observational Vasudha is a Lead Medical Writer at Turacoz studies. Ann Intern Med 2007;147:573-7. Healthcare Solutions. She has been associated 35. International Committee of Medical with Turacoz since 2015 and is responsible Journal Editors (ICMJE). Preparing for for writing and reviewing documents and Submission. 2016 [cited 2017 June 07]. leading various medical writing projects. Available from: http://www.icmje.org/ recommendations/browse/ manuscript- preparation/preparing-for-submission. html#d. 36. The BMJ. Ethics approval of research. 2017 [cited 2017 June 07]. Available from: http://www.bmj. com/about- bmj/resources-authors/forms- policies-and- checklists/ethics-approval- research.

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