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Regulatory considerations for real-world research studies in Europe

Posted 28 July 2021 | By Stuart McCully, PhD  | PDF Link PDF | ©

Regulatory considerations for real-world research studies in Europe

Real-world research studies are a valuable source of real-world evidence (RWE). In Europe, successful deployment of these studies is dependent on identifying, understanding, and demonstrating which regulations are not applicable, as well as identifying (and complying with) the regional (Europe Union) and national requirements that are applicable.
 
Introduction
The European Medicines Agency (EMA) recently called for high-quality observational research of real-world data (RWD) collected during the pandemic, as this could be an important complement to the results of randomized clinical trials in providing evidence on the safety and effectiveness of vaccines and treatments for COVID-19. Such research is also critical to understand how exposure to certain medicines can affect the risk or the severity of infection with the virus.1-3
 
This is just one example of the value of real-world research studies that collect RWD and generate RWE, which can be leveraged to bring new products to market, evaluate the safety and effectiveness of existing products for new uses, and assess the continued performance and safety of products once on the market.4
 
Real-world evidence is defined as the clinical evidence regarding the use and potential benefits or risks of a medical product derived from analysis of RWD. RWE can be generated by different study designs or analyses including, but not limited to, randomized trials, which can include large simple trials, pragmatic trials, and observational studies.5
 
This article focuses on regulatory issues or “pain points,” considerations, and requirements that should be addressed when conducting noninterventional studies (NIS), a type of observational study that has a standardized regulatory definition at the European level (Table 1).
 
McCully_Table-1.png
 
‘Pain points’ in regulatory considerations
In Europe, the legal definition for NIS can be found in the clinical trial legislation.6,7 However, the defining clinical trial legislation is not applicable to NIS.10,11 Regulatory compliance is usually approached from the perspective of “what do I need to comply with?” For NIS in Europe, when initially determining the requirements for study start-up and conduct, the opposite approach is true. The first question becomes “what do I not need to comply with?” In the author’s experience, a significant proportion of regulatory compliance and intelligence effort is routinely required to demonstrate why certain laws and guidelines are not applicable to NIS, as demonstrated by the pain points below:
 
  • Pain point 1 – NIS are not clinical trials. Therefore, clinical trial regulations are not applicable. However, this cannot be assumed, it must be proven and documented. Noninterventional studies are clinical studies, but not clinical trials. Clinical trials intervene (as per protocol) in the diagnosis and/or treatment of patients, whereas noninterventional studies do not intervene in the diagnosis or treatment of the patient. Hence, the regulatory definition under the EU Clinical Trials Regulation, which states “Non-interventional study means a clinical study other than a clinical trial”.12
  • Pain point 2 – The standards routinely applied to clinical trials, such as those of the International Council for Harmonisation for good clinical practice, are not applicable to NIS, or more correctly, are not legally enforceable in the context of NIS.13
  • Pain point 3 – The regulatory requirements for the classification, approval, and conduct of NIS are not standardized. Each country within Europe has its own regulatory framework, meaning you cannot assume that the requirements, for example, in France, are the same as those in Germany, Italy, and Spain.14
  • Pain point 4 – The terminology for NIS is not standardized. Methodological descriptions are often confused with legal definitions (Figure 1), resulting in confusing terminology that must be discounted to allow the relevant regulatory definitions and associated framework(s) to be identified.
  • Pain point 5 – NIS guidelines, such as GVP Module VIII, if read in isolation, can be unintentionally misleading. A common misconception is that research ethics committee (REC) approval is not required for postauthorization safety studies (PASS). This is actually true for only one EU country, Lithuania.15,16 According to Section VIII.C.2.1. of GVP Module VIII: “The [noninterventional post authorization safety study] may commence only when the written endorsement from the national competent authority or the Pandemic Response Accountability Committee, as appropriate, has been issued.”17 A sentence that is repeated twice in GVP Module VIII, and which is easy to overlook, but very important, states: “National and Union requirements for ensuring the well-being and rights of participants in noninterventional PASS shall also apply [DIR Art 107m(2)].”18-20 Figure 2 illustrates the impact of this sentence on the regulatory requirements.
 
Figure 1 Confusion of terminology of real-world research studies
 
McCully_Figure-1.png
 
Figure 2 National regulatory requirements for noninterventional, postauthorization safety studies in Europe
 
McCully_Figure-2.png
 
Although simply stated, the impact of these pain points is far reaching. The rest of this article maps out the scientific and ethical foundation for NIS in Europe, as well as where to look for the applicable Europe-wide and national laws and guidelines applicable to prospective NIS. Emphasis is intentionally placed on the primary data collection (prospective) study design because national requirements for NIS can differ between retrospective and prospective NIS.
 
Regional vs. national legislation and guidelines
Having determined which legislation, standards, and guidelines are not applicable to NIS, the next step is to determine what is applicable. This is a two-step process requiring identification of the applicable legislation and standards at the European Union level and national levels.
 
European Union NIS considerations
Consideration 1. The ethical foundation for all NIS in Europe is the Declaration of Helsinki21 (Figure 3). It provides the basic framework of requirements embodied in national regulations in Europe, namely:
  • Participation of patients must be voluntary.
  • Benefits of the research should outweigh the risks and burdens to the research participants.
  • The study design must be clearly described and justified in a research protocol.
  • The research protocol must be submitted for consideration, comment, guidance, and approval to the concerned REC before the study begins.
  • Each potential research participant must be adequately informed … and participant consent must be given freely.
  • Every precaution must be taken to protect the privacy of research participants and the confidentiality of their personal information.
  • Every research study involving human participants must be registered in a publicly accessible database before recruitment of the first subject.
  • Researchers, authors, sponsors, editors, and publishers all have ethical obligations with regard to the publication and dissemination of the results of research.
  • Reports of research not in accordance with the principles of the declaration should not be accepted for publication.
 
The last two points are clearly emulated by the International Committee of Medical Journal Editors in its policy on protection of research participants, which states:
 
All investigators should ensure that the planning conduct and reporting of human research are in accordance with the Helsinki Declaration as revised in 2013. All authors should seek approval to conduct research from an independent local, regional, or national review body (e.g., ethics committee, institutional review board). If doubt exists whether the research was conducted in accordance with the Helsinki Declaration, the authors must explain the rationale for their approach and demonstrate that the local, regional, or national review body explicitly approved the doubtful aspects of the study. Approval by a responsible review body does not preclude editors from forming their own judgment whether the conduct of the research was appropriate.22
 
 
Figure 3 Overview of regulatory foundation and framework for noninterventional studies
 
McCully_Figure-3.png
 
Consideration 2. Scientific guidelines applicable to NIS (Figure 3). The EMA states that these “scientific guidelines should be considered by marketing authorization holders and investigators for the development of study protocols, the conduct of studies, and the writing of study reports”.23 Note the emphasis on the phrase “should be considered,” meaning this is a recommendation rather than a legal mandate.
 
These scientific guidelines include:
  • European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological Standards in Pharmacoepidemiology24
  • ENCePP Checklist for Study Protocols25
  • Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population,26 and
  • Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP)27
 
Consideration 3. The European Federation of Pharmaceutical Industries and Associations (EFPIA) Code of Practice is a form of self-regulation by pharmaceutical companies that defines the expectations for the ethical conduct of employees when interacting with healthcare professionals (HCPs) throughout Europe. The EFPIA Code of Practice is implemented through the regional country-specific codes of practice, which member companies must comply with.28 Examples of European national codes of practice include:
  • France – LEEM Guidance29
  • Germany – FSA HCP Code of Conduct30
  • Italy – Farmindustria Code of Conduct31
  • Spain – Farmaindustria Code of Good Practice32
  • UK – ABPI Code of Practice33
 
According to Article 18 of the EFPIA Code of Practice,28 noninterventional studies that are prospective and involve the collection of patient data from or on behalf of individual, or groups of, HCPs specifically for the study must comply with all of the following criteria:
  • They must be conducted with a primarily scientific purpose and must not be disguised promotion.
  • There is a written study plan (observational plan/protocol).
  • In countries where ethics committees are prepared to review such studies, the study plan must be submitted to the ethics committee for review.
  • The study plan must be approved by the member company’s scientific service and the conduct of the study must be supervised by the member company’s scientific service.
  • The study results must be analyzed by or on behalf of the contracting member company and summaries thereof must be made available within a reasonable period of time to the member company’s scientific service, which service must maintain records of such reports for a reasonable period of time.
  • The member company must send the summary report to all HCPs that participated in the study and must make the summary report available to industry self-regulatory bodies and/or committees in charge of supervising or enforcing applicable codes upon their request.
  • If the study shows results that are important for the assessment of benefit-risk, the summary report must be immediately forwarded to the relevant competent authority.
  • Member companies are encouraged to publicly disclose the summary details and results of NIS in a manner that is consistent with the parallel obligations with respect to clinical trials.
  • Medical sales representatives may be involved only in an administrative capacity and such involvement must be under the supervision of the member company’s scientific service that will also ensure the medical sales representatives are adequately trained. Such involvement must not be linked to the promotion of any medicinal product.
 
Consideration 4. EU regulations, directives, and guidelines are applicable to NIS in all 27 member states (Table 2).
 
Consideration 5. There are different regulatory requirements for voluntary NIS versus imposed noninterventional PASS (Table 2).
 
Table 2 Nonexhaustive summary of EU regulations, directives, and guidelines for noninterventional studies
[Click for Table 2]

National NIS consideration
Consideration 1. Each country within Europe has its own regulatory framework, meaning successful study conduct is directly dependent on a knowledge of the applicable national legislation, standards, and guidelines (Table 3).
 
Table 3 Overview of the national regulatory requirements for prospective noninterventional studies in Europe
 [Click for Table 3]

Consideration 2. National requirements must be considered in the context of the applicable European Union legislation and standards. Just because an activity is not captured in the national legislation, does not mean it is not already covered in the European Union requirements (e.g., EU PAS registration,46-48 safety reporting requirements36 and timelines35). This is where the regional and national NIS frameworks come full circle and the science of regulatory affairs, also becomes an art.
 
Consideration 3. Do not assume there is a single regulatory requirement for NIS in the country of interest. For example, prospective NIS require REC approval in Italy, whereas retrospective NIS only require notification to the REC(s).49
 
Consideration 4. Websites, regulations, and guidelines will be in the local language. When English is not the native language, an English alternative website may be available, but this should not be relied on as it may be out of date or inaccurate.
 
Conclusions and considerations
Real-world research studies, such as prospective NIS, are a valuable source of RWD and RWE. Successful and efficient deployment of these studies is dependent on identifying and understanding the issues or pain points (what isn’t applicable); identifying the regional (European Union) and national requirements (what is applicable); and connecting them all together into a regulatory roadmap that covers study approval, conduct, and close-out. This is where the science of regulatory affairs also becomes an art.
 
Abbreviations
EMA, European Medicines Agency; ENCePP, European Network of Centres for Pharmacoepidemiology and Pharmacovigilance; HCP, healthcare provider; NIS, noninterventional study/studies; REC, research ethics committee; PASS, postauthorization safety study; RWD, real-world data; RWE, real-world evidence.
 
About the author
Stuart McCully, PhD, is the founder and CEO of Phoenix-RWR, which specializes in regulatory compliance for real-world research (RWR). He has specialized in RWR regulatory affairs since 2009. McCully recently helped create a trial master file for noninterventional studies and was the founder of a globally recognized NIS regulatory intelligence brand. McCully has bachelor of science and doctorate degrees in pharmacology. He can be contacted at stuart.mccully@phoenix-rwr.co.uk
 
Citation McCully S. Regulatory considerations for real-world research studies in Europe. https://www.raps.org/news-and-articles/news-articles/2021/7/regulatory-considerations-for-real-world-research. Regulatory Focus. Published online 28 July 2021.

References
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