Non-Interventional Study (EU): ‘Non-interventional study’ means a clinical study other than a clinical trial (as per Article 2.2(4) of Regulation EU/536/2014) [ref 1].
Ref1: Article 2.2(4) of Regulation EU/536/2014 [https://eur-lex.europa.eu/eli/reg/2014/536]
Non-Interventional Study (USA): A non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of non-interventional study designs include [ref 1]:
(1) observational cohort studies, in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified, and
(2) case-control studies, in which patients are identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are identified.
According to recent FDA guidance, non-interventional studies are not clinical investigations (clinical trials) as defined under § 312.3 and do not require an IND [ref 2].
Also, according to the FDA…Although many non-interventional studies involve only the analysis of data reflecting the use of a marketed drug in routine medical practice, certain non-interventional studies include ancillary protocol-specified activities or procedures (e.g., questionnaires, laboratory tests, imaging studies) that collect additional data to help address questions of interest in these studies. FDA does not consider these types of studies to be clinical investigations under part 312, and an IND is not required [ref 3].
Ref1: Section II of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021)) [https://www.fda.gov/media/154714/download]
Ref2: Section III.A of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Ref3: Section III.B.1 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Non-interventional studies are not clinical trials
This seems like an obvious statement, but international standards, such as ICH GCP (ICH E6) would have us believe that terms ‘clinical study’ and ‘clinical trial’ or synonymous (as per Section 1.12 of ICH E6). The key here is context. In the context of a clinical trial (i.e., the ICH (E) Efficacy Series), the terms ‘clinical trial’ and ‘clinical study’ are synonymous. In the context of a non-interventional study, these two terms are not synonymous [ref 1] [ref 2].
NIS are not clinical trials. Therefore, clinical trial regulations are not applicable. However, this cannot be assumed, it must be proven and documented. Non-interventional studies are clinical studies, but not clinical trials. Clinical trials intervene (as per protocol) in the diagnosis and/or treatment of patients, whereas non-interventional studies do not intervene in the diagnosis or treatment of the patient. Hence, the regulatory definition under the EU Clinical Trials Regulation (Regulation EU/536/2014), which states “non-interventional study means a clinical study other than a clinical trial” [ref 3] [ref 4].
Ref1: ICH Guideline for Good Clinical Practice E6(R2) [https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf]
Ref2: ICH (E) Efficacy Series [https://www.ich.org/page/efficacy-guidelines]
Ref3: Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC [https://eur-lex.europa.eu/eli/reg/2014/536]
Ref4: McCully S. Regulatory considerations for real-world research studies in Europe. Regulatory Focus. Published online 28 July 2021.
The ethical foundation for all NIS in is the Declaration of Helsinki. It provides the basic framework of requirements embodied in national regulations, namely [ref 1]:
- 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.
Ref1: Declaration of Helsinki (2013) [https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/]
Short answer = No.
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting TRIALS that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of TRIAL subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the CLINICAL TRIAL data are credible [ref 1].
- ICH GCP (ICH E6) is a scientific and ethical quality standard for designing, conducting, recording and reporting CLINICAL TRIALS
- Clinical trials need to comply with ICH GCP because it has been ‘embedded’ into clinical trial law, for example:
- The sponsor of a clinical trial and the investigator shall ensure that the clinical trial is conducted in accordance with the protocol and with the principles of good clinical practice (as per Article 47 of Regulation EU/536/2014) [ref 2]
- The sponsor and the investigator, when drawing up the protocol and when applying this Regulation and the protocol, shall also take appropriate account of the quality standards and the ICH guidelines on good clinical practice (as per Article 47 of Regulation EU/536/2014) (as per Article 47 of Regulation EU/536/2014) [ref 2]
- Non-interventional studies are not clinical trials
- Clinical trial legislation is not applicable to non-interventional studies
- GCP is not legally enforceable in the context of NIS
Ref1: Introduction to Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) [https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf]
Ref2: Article 47 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC [https://eur-lex.europa.eu/eli/reg/2014/536]
Short answer = No.
GPP or the ‘International Society of Pharmacoepidemiology – Guidelines for good pharmacoepidemiology practices’ are a set of scientific guidelines that regulators recommend we should CONSIDER – note the emphasis on ‘consideration’ rather than imposing a legal mandate, which would be a ‘must comply with’ [ref 1]:
- Relevant scientific guidance should be considered by marketing authorisation holders and investigators for the development of study protocols, the conduct of studies and the writing of study reports…These scientific guidelines include – Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP) (as per Section B.1. of GVP Module VIII) [ref 2]
- The observation plan is to be drawn up according to recognized recommendations of scientific or regulatory guidelines…for example “Guidelines for Good Pharmacoepidemiology Practices” (GPP) of the “International Society for Pharmacoepidemiology (ISPE) and the Guidelines for Good Epidemiological Practice (GEP) of the German Society for Epidemiology (DGEpi) (as per Section 2.7.1 of the BfArM/PEI Recommendations – December 2022) [ref 3]
- …fifteen key elements that should be considered for each protocol, and are reflective of…“The Guidelines for Good Pharmacoepidemiology Practices (GPP)” (Health Canada – March 2019) [ref 4]
- The FDA 2005 guidance, the ISPE guidelines [GPP], the STROBE reporting framework, and the ENCePP methods checklist and guide provide general guidance applicable to all pharmacoepidemiologic safety studies. (FDA – May 2013) [Ref 5]
ISPE Guidelines for Good Pharmacoepidemiology Practices (GPP)
- ISPE GPP was initially issued in 1996 (the same year as ICH GCP) and last revised in 2015 [ref 1]
- ISPE GPP is made up of seven (7) sections
- Two (2) sections of ISPE GPP worth noting are those to do with the protocol format (Section 2) and archiving (Section 7):
- Why? Other than the EMA PASS protocol template, there is no national guidance on the protocol format for non-interventional studies.
- Also, very few countries provide guidance on the archiving requirements for NIS.
- ISPE GPP does cover ‘reporting of adverse drug events’ (Section 6), but this should be read with caution as national pharmacovigilance requirements should always be complied with
- A limitation of ISPE GPP as NIS best practice is that the document is not very detailed compared to the clinical trial equivalent (ICH GCP).
Ref1: International Society of Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (Rev 3) [https://www.pharmacoepi.org/resources/policies/guidelines-08027/]
Ref2: Section VIII.B.1. of GVP Module VIII – Post-authorisation safety Studies [https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-post-authorisation-safety-studies-rev-3_en.pdf]
Ref3:
Joint recommendations of the Federal Institute for
Medicinal products and medical devices and the Paul-Ehrlich-
Institute for the notification of observational studies according to § 67 paragraph 6 of the German Medicines Act and for the notification of non-interventional safety studies according to § 63f of the German Medicines Act – December 15, 2022 [https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Zulassung/klin-pr/nichtInterventPruef/Gemeinsame%20Empfehlungen%20zu%20AWB%20und%20PASS.pdf?__blob=publicationFile&v=1]
Ref4: Health Canada – Elements of Real World Data/Evidence Quality throughout the Prescription Drug Product Life Cycle, 5 March 2019 [https://www.canada.ca/en/services/health/publications/drugs-health-products/real-world-data-evidence-drug-lifecycle-report.html]
Ref5: FDA Guidance for Industry – Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data (May 2013) [https://www.fda.gov/files/drugs/published/Best-Practices-for-Conducting-and-Reporting-Pharmacoepidemiologic-Safety-Studies-Using-Electronic-Healthcare-Data-Sets.pdf]
USA Context
According to recent draft FDA Guidance… An Interventional study (also referred to as a clinical trial) is a study in which participants, either healthy volunteers or volunteers with the disease being studied, are assigned to one or more interventions, according to a study protocol, to evaluate the effects of those interventions on subsequent health-related biomedical or behavioral outcomes. One example of an interventional study is a traditional randomized controlled trial, in which some participants are randomly assigned to receive a drug of interest (test article), whereas others receive an active comparator drug or placebo. Clinical trials with pragmatic elements (e.g., broad eligibility criteria, recruitment of participants in usual care settings) and single-arm trials are other types of interventional study designs [ref 1].
Whereas…a non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of non-interventional study designs include [ref 1]:
(1) observational cohort studies, in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified, and
(2) case-control studies, in which patients are identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are identified.
Ref1: Section II of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Non-interventional studies are not clinical trials
This seems like an obvious statement, but international standards, such as ICH GCP (ICH E6) would have us believe that terms ‘clinical study’ and ‘clinical trial’ or synonymous (as per Section 1.12 of ICH E6). The key here is context. In the context of a clinical trial (i.e., the ICH (E) Efficacy Series), the terms ‘clinical trial’ and ‘clinical study’ are synonymous. In the context of a non-interventional study, these two terms are not synonymous [ref 1] [ref 2].
NIS are not clinical trials. Therefore, clinical trial regulations are not applicable. However, this cannot be assumed, it must be proven and documented. Non-interventional studies are clinical studies, but not clinical trials. Clinical trials intervene (as per protocol) in the diagnosis and/or treatment of patients, whereas non-interventional studies do not intervene in the diagnosis or treatment of the patient. Hence, the regulatory definition under the EU Clinical Trials Regulation (Regulation EU/536/2014), which states “non-interventional study means a clinical study other than a clinical trial” [ref 3] [ref 4].
Ref1: ICH Guideline for Good Clinical Practice E6(R2) [https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf]
Ref2: ICH (E) Efficacy Series [https://www.ich.org/page/efficacy-guidelines]
Ref3: Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC [https://eur-lex.europa.eu/eli/reg/2014/536]
Ref4: McCully S. Regulatory considerations for real-world research studies in Europe. Regulatory Focus. Published online 28 July 2021.
It depends on what you intend to use the data for i.e., for regulatory submissions to support of new drug application (NDA).
The emphasis on the intended purpose of the non-interventional study (NIS) is important because it determines which legal standards are applicable to the study (see Figure).
There are additional regulatory requirements, recommendations and considerations for non-interventional studies that are designed with the intent of supporting an NDA or biologics license application (BLA).
Regardless of a study’s interventional or non-interventional design, the evidence submitted by a sponsor in a marketing application to support the safety and/or effectiveness of a drug must satisfy the applicable legal standards for the application to be approved or licensed [ref 1].
Ref1: Section III.B.1 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (December 2021) [https://www.fda.gov/media/154714/download]
21 CFR 11
For a marketing application containing a non-interventional study submitted to support regulatory decisions regarding the safety or effectiveness of a product, the electronic systems used by the sponsor to manage the data and produce required records must comply with 21 CFR part 11 [ref 1] [ref 2] [ref 3].
Ref1: Section III.B.6 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Ref2: FDA Guidance – Part 11, Electronic Records; Electronic Signatures — Scope and Application (August 2003) [https://www.fda.gov/media/75414/download]
Ref3: Draft FDA Guidance – Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers (June 2017) [https://www.fda.gov/media/105557/download]
21 CFR 50 and 21 CFR 56
Non-interventional studies are not clinical investigations (clinical trials) as defined under § 312.3 and do not require an IND [ref 1].
Although many non-interventional studies involve only the analysis of data reflecting the use of a marketed drug in routine medical practice, certain non-interventional studies include ancillary protocol-specified activities or procedures (e.g., questionnaires laboratory tests, imaging studies) that collect additional data to help address questions of interest in these studies. FDA does not consider these types of studies to be clinical investigations under part 312, and an IND is not required. Nonetheless, the protection of human subjects under these circumstances is critical, and sponsors must ensure that applicable requirements per FDA regulations under 21 CFR parts 50 (Protection of Human Subjects) and 56 (Institutional Review Boards) are met [ref 2] [ref 3] [ref 4].
Ref1: Section III.A of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Ref2: Section III.B.1 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Ref3: 21 CFR 50 – Protection of Human Subjects [https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-50]
Ref4: 21 CFR 56 – Institutional Review Boards [https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-56]
21 CFR 314
Defines the post-marketing safety reporting requirements for non-interventional studies that involve approved drugs (as per 21 CFR 314.80 and 21 CFR 314.81) [ref 1] [ref 2].
Ref1: 21 CFR 314.80 – Postmarketing reporting of adverse drug experiences [https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-B/section-314.80]
Ref2: 21 CFR 314.81 – Other postmarketing reports [https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-B/section-314.81]
Legally (21 CFR 11) = No (unless you intend to submit documents to the FDA)
Draft FDA Guidance (November 2021) = Yes (if you are using RWD/RWE from registries to support regulatory decisions)
Draft FDA Guidance (December 2021) = Yes (if you are intending to submit RWD/RWE from NIS to support regulatory decisions)
What is 21 CFR 11?
Simply put…21 CFR 11 is a regulation that was implemented to ensure that electronic records and electronic signatures are considered trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper [ref 1] [ref 2].
21 CFR 11 applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted under any records requirements set forth in FDA regulations e.g., clinical trial records created under 21 CFR 312 (Drugs and Biologics), 21 CFR 812 (Devices), New Drug Applications (NDAs as per 21 CFR 314), or Biologics Licence Applications (BLAs as per 21 CFR 600) [ref 1] [ref 3].
Is 21 CFR 11 Applicable to Non-Interventional Studies (NIS)?
Generally, non-interventional studies (NIS) do not fall within the scope of the FDA, unless they are specifically required by the FDA (e.g., post-marketing requirements) …meaning 21 CFR 11 is not applicable and compliance is not required.
However, in recent years we have seen increased use of real-world evidence (RWE) to support new drug applications (NDA) and label extensions….which has raised the question…If we intend to submit this data to the FDA, are these types of studies now within the scope of the FDA regulations/governance and do we need to comply with 21 CFR 11?
FDA (Draft) Guidance on 21 CFR 11 Compliance When Using Real-World Data or Real-World Evidence to Support Regulatory Decisions
According to the November 2021 draft FDA Guidance – Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products: “…sponsors should ensure there are processes and procedures to govern registry operation…Such governance attributes help ensure that the registry can achieve its objectives and should include, but not be limited to…Conformance with 21 CFR part 11, as applicable, including maintenance of access controls and audit trails to demonstrate the provenance of the registry data and to support traceability of the data” (as per Section III.C of the FDA Draft Guidance) [ref 4].
In their December 2021 draft guidance, the FDA made their position very clear by stating that “for a marketing application containing a non-interventional study submitted to support regulatory decisions regarding the safety or effectiveness of a product, the electronic systems used by the sponsor to manage the data and produce required records MUST comply with 21 CFR part 11” (as per Section III.B.2 of the draft FDA Guidance) [ref 5].
Ref1: 21 CFR 11 – Electronic Records, Electronic Signatures [https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11]
Ref2: FDA Guidance for Industry – Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers (June 2017) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-electronic-records-and-electronic-signatures-clinical-investigations-under-21-cfr-part-11]
Ref3: FDA Guidance for Industry – Part 11, Electronic Records; Electronic Signatures — Scope and Application (August 2003) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-application]
Ref4: Draft FDA Guidance – Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products (November 2021) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/real-world-data-assessing-registries-support-regulatory-decision-making-drug-and-biological-products]
Ref5: Draft FDA Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug]
Short Answer = No.
Applicability of 21 CFR Part 312 [Investigational New Drug Application] to Non-Interventional Studies
According to the recent FDA guidance, non-interventional studies are not clinical investigations as defined under § 312.3 and do not require an IND [ref 1].
Although many non-interventional studies involve only the analysis of data reflecting the use of a marketed drug in routine medical practice, certain non-interventional studies include ancillary protocol-specified activities or procedures (e.g., questionnaires, laboratory tests, imaging studies) that collect additional data to help address questions of interest in these studies. FDA does not consider these types of studies to be clinical investigations under part 312, and an IND is not required [ref 2].
Ref1: Section III.A of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Ref2: Section III.B.1 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Short answer = No.
Non-interventional studies are not an ‘applicable clinical trial’ in the context of 42 CFR 11 (as per 42 CFR 11.10), which means there is no legal mandate to publish the study on clinicaltrials.gov.
FDA Guidance: However, according to recent draft FDA guidance…To ensure transparency regarding their study design, sponsors should post their study protocols on a publicly available website, such as ClinicalTrials.gov or the web page for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) for post-authorization studies [ref 1] [ref 2].
Ref1: Section III.B.2 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [https://www.fda.gov/media/154714/download]
Ref2: The European Union electronic Register of Post-Authorisation Studies (EU PAS Register) [https://www.encepp.eu/encepp/studiesDatabase.jsp]
Declaration of Helsinki: According to the latest version of the Declaration of Helsinki…”Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject” [ref 1]
Ref1: Paragraph 35 of the Declaration of Helsinki (2013) [https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ ]
In the USA, Postmarketing requirement and commitment studies (and clinical) trials occur after a drug or biological product has been approved by FDA [ref 1].
The 2007 Food and Drug Administration Amendments Act (FDAAA) specifically provides FDA with authority to require drug manufacturers to conduct postmarketing safety studies and clinical trials to assess possible serious risks associated with the drugs [ref 2].
Postmarketing Requirements (PMRs)
Postmarketing requirements (PMRs) include studies and clinical trials that sponsors are REQUIRED to conduct under one or more statutes or regulations [ref 1]
These include:
- Section 505(o) of the Federal Food, Drug, and Cosmetic Act [ref 3] [ref 4] [ref 5] [ref 6]
- Pediatric Research Equity Act (PREA) [ref 7]
Ref1: FDA – Postmarketing Requirements and Commitments: Introduction [https://www.fda.gov/drugs/guidance-compliance-regulatory-information/postmarket-requirements-and-commitments]
Ref 2: FDA – Postmarketing Requirements and Commitments: Reports [https://www.fda.gov/drugs/postmarket-requirements-and-commitments/postmarketing-requirements-and-commitments-reports]
Ref3: Section 505(o)(3) of the FD&C Act (21 U.S.C. 355(o)) [https://www.govinfo.gov/content/pkg/USCODE-2019-title21/html/USCODE-2019-title21-chap9-subchapV-partA-sec355.htm]
Ref4: FDA – Postmarketing Requirements and Commitments: Legislative Background [https://www.fda.gov/drugs/postmarket-requirements-and-commitments/postmarketing-requirements-and-commitments-legislative-background]
Ref5: FDA Guidance for Industry [Draft Guidance] – Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act Guidance for Industry (October 2019) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postmarketing-studies-and-clinical-trials-implementation-section-505o3-federal-food-drug-and-0]
Ref6: FDA Guidance for Industry – Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (April 2011) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postmarketing-studies-and-clinical-trials-implementation-section-505o3-federal-food-drug-and]
Ref7: Pediatric Research Equity Act [https://www.govinfo.gov/content/pkg/BILLS-108s650enr/pdf/BILLS-108s650enr.pdf]
Postmarketing Commitments (PMCs)
Postmarketing commitments (PMCs) are studies or clinical trials that a sponsor has AGREED to conduct, but that are not required by a statute or regulation [ref 1].
For PMCs, the applicant should submit a written agreement to conduct the PMCs [ref 2].
Postmarketing studies can be required to [ref 1]:
- Demonstrate clinical benefit for drugs approved under the accelerated approval requirements
- Assess a known serious risk related to the use of the drug
- Assess signals of serious risk related to the use of the drug
- Identify an unexpected serious risk when available data indicate the potential for a serious risk
Ref1: FDA – Postmarketing Requirements and Commitments: Introduction [https://www.fda.gov/drugs/guidance-compliance-regulatory-information/postmarket-requirements-and-commitments]
Ref2: FDA Guidance for Industry – Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (April 2011) [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postmarketing-studies-and-clinical-trials-implementation-section-505o3-federal-food-drug-and
The International Committee of Medical Journal Editors (ICMJE) has developed recommendations to review best practice and ethical standards in the conduct and reporting of research and other material published in medical journals, and to help authors, editors, and others involved in peer review and biomedical publishing create and distribute accurate, clear, reproducible, unbiased medical journal articles [ref 1] [ref 2].
According to the ICMJE Recommendation on the ‘Protection of Research Participants’ [ref 3]:
- All investigators should ensure that the planning, conduct, and reporting of human research are in accordance with the Helsinki Declaration as revised in 2013 [ref 4].
- 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.
- Patients have a right to privacy that should not be violated without informed consent. Identifying information, including names, initials, or hospital numbers, should not be published in written descriptions, photographs, or pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that an identifiable patient be shown the manuscript to be published. Authors should disclose to these patients whether any potential identifiable material might be available via the Internet as well as in print after publication. Patient consent should be written and archived with the journal, the authors, or both, as dictated by local regulations or laws. Applicable laws vary from locale to locale, and journals should establish their own policies with legal guidance. Since a journal that archives the consent will be aware of patient identity, some journals may decide that patient confidentiality is better guarded by having the author archive the consent and instead providing the journal with a written statement that attests that they have received and archived written patient consent.
- Nonessential identifying details should be omitted. Informed consent should be obtained if there is any doubt that anonymity can be maintained. For example, masking the eye region in photographs of patients is inadequate protection of anonymity. If identifying characteristics are de-identified, authors should provide assurance, and editors should so note, that such changes do not distort scientific meaning.
- The requirement for informed consent should be included in the journal’s instructions for authors. When informed consent has been obtained, it should be indicated in the published article.
- When reporting experiments on animals, authors should indicate whether institutional and national standards for the care and use of laboratory animals were followed.
Ref1: The International Committee of Medical Journal Editors (ICMJE) [http://www.icmje.org/]
Ref2: ICMJE – Recommendations [http://www.icmje.org/recommendations/browse/about-the-recommendations/purpose-of-the-recommendations.html]
Ref3: ICMJE – Recommendations: Protection of Research Participants [http://www.icmje.org/recommendations/browse/roles-and-responsibilities/protection-of-research-participants.html]
Ref4: Declaration of Helsinki (2013) [https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/]
Seeding Studies…according to the FDA
“Typically, these trials [Seeding trials] involve introducing a new drug in a crowded therapeutic class” [Kessler et al., 1994]
Some company-sponsored trials of approved drugs appear to serve little or no scientific purpose. Because they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company, they are often referred to as “seeding trials” [ref 1].
Features that distinguish such trials [studies] from scientifically rigorous studies include [ref 1]:
- the use of a design that does not support the stated research goals
- the recruitment of investigators not because they are experts or leading researchers but because they are frequent prescribers of competing products in the same therapeutic class
- disproportionately high payments given to “investigators” for their work (although the only work may be to write prescriptions for the drug)
- sponsorship of the studies by the company’s sales and marketing division rather than its research department
- minimal requirements for data, and the collection of data that are of little or no value to the company
The issue with this type of ‘research’ study is the primary purpose is marketing the drug, rather than treatment of the patients or generation of scientifically valid data, meaning it is unethical.
Pharmaceutical best-practice guidelines and national regulations were implemented to prevent this unethical form of drug promotion or marketing…which is what non-interventional studies must not be disguised promotion:
- Non-Interventional Studies must be conducted with a primarily scientific purpose and must not be disguised Promotion (as per Section 18.01 of the EFPIA Code of Practice) [ref 2]
- All human subject research must have a legitimate scientific purpose. Human subject research, including clinical trials and observational studies, must not be disguised promotion (as per Article 9.2 of the IFPMA Code of Practice 2019) [ref 3]
- The studies [post-authorisation safety studies] shall not be performed where the act of conducting the study promotes the use of a medicinal product (as per Article 107m(3) of Directive 2001/83/EC) [ref 4]
- Based on the PRAC review of the PASS protocol version and in accordance with Article 107n(2)(b)(i) of Directive 2001/83/EC, the PRAC considers that the study is non-interventional but that, based on the following elements, it considers that the conduct of the study will promote the use of the medicinal product (as per Section 3.3. of the PRAC Rapporteur Post-authorisation Safety Study Protocol Assessment Report Template) [ref 5]
Ref1: David A. Kessler, Janet L. Rose, Robert J. Temple, Renie Schapiro, and Joseph P. Griff. Therapeutic-Class Wars — Drug Promotion in a Competitive Marketplace. N Engl J Med 1994; 331:1350-1353 [https://www.nejm.org/doi/full/10.1056/nejm199411173312007]
Ref2: Section 18.01 of the EFPIA Code of Practice [https://www.efpia.eu/relationships-code/the-efpia-code/]
Ref3: Article 9.2 of the IFPMA Code of Practice 2019 [https://www.ifpma.org/resource-centre/ifpma-code-of-practice-2019/]
Ref4: Article 107m(3) of Directive 2001/83/EC [https://eur-lex.europa.eu/eli/dir/2001/83]
Ref5: Section 3.3. of the PRAC Rapporteur Post-authorisation Safety Study Protocol Assessment Report Template [https://www.ema.europa.eu/documents/template-form/prac-rapporteur-post-authorisation-safety-study-protocol-assessment-report-template_en.doc]
Short Answer = There are no legal requirements.
According to recent draft FDA Guidance: “When a non-interventional study does not include any additional ancillary activities, study monitoring generally may be focused on maintaining the reliability of the RWD and data integrity, beginning with extraction of the data from its origin (i.e., data accrual) through data curation and transformation and reporting of results. When a non-interventional (observational) study includes additional protocol-specified activities and procedures, study monitoring should also ensure that applicable human subject protections are met and data integrity is maintained.” [ref 1]
According to recent guidance published by the working group of the Research Ethics Committee with Medicines (CEIm) and AEMPS on observational studies with medicines: “The duration of the planned monitoring should be consistent with the objectives set” [ref 2].
Ref1: Section III.B.4 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (December 2021) [https://www.fda.gov/media/154714/download]
Ref2: Section 2.3.1 of the AEMPS Memorandum of collaboration between the Research Ethics Committee with Medicines (CEIm) for the Evaluation and Management of Observational Studies with Medicinal Products (EOm) (November 2021) [https://www.aemps.gob.es/investigacionClinica/medicamentos/docs/estudios-PA/Memorando_CEIMS.pdf?x40511]
- Short Answer = There are no globally applicable legal requirements
- Recommendation (in the absence of national legal requirements) = At least five (5) years after final report or first publication of study results, whichever comes later (as per Section VII of ISPE GPP) [ref 1]
- Regulatory Consideration = ICH GCP is not applicable to NIS
- Different rules apply to non-interventional studies involving medical devices and in vitro diagnostic medical devices conducted in the EU
Here are some country-specific archiving/ document retention requirements for non-interventional studies:
- Argentina = 2 years
- Austria = 15 years
- Brazil = 5 years
- Germany = 10 years
- Japan = 5 years
- Netherlands = 15 years
- South Korea = 3 years
- Turkey = 5 years
Ref 1 – International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices (GPP) (June 2015)
Link: https://www.pharmacoepi.org/resources/policies/guidelines-08027/
Short answer = No
Generally, the ‘non-interventional’ aspect of non-interventional studies refers to treatment interventions. If study-specific blood samples are taken and the result from their analysis is not used to impact the treatment or health management of the patient who donated the blood, this is not a treatment intervention. The study is still non-interventional.
However, there are some country-specific considerations and limitations in the context of non-interventional studies…
Austria [Blood Sampling Not Permitted] – Measures such as calling in patients outside of the routine, randomization, additional blood collection (also in the context of a routine blood collection) are considered interventions and result in the study being classified as an AMG study. What “outside the routine” means can be found in the information for professionals. Examinations and examination times not listed there are to be rated as “outside routine”.
Ref1: Ethics Committee of the University of Vienna – NIS
Link: http://ethikkommission.meduniwien.ac.at/service/nis/
France [Minimal Volumes of Blood Sampling Allowed] – A non-interventional study is research (research in human persons – RIPH) that does not involve any risk or constraint in which all the acts are performed, and the products used, in the usual way (i.e., as per routine clinical practice) [ref 1].
The of Order of 12 April 2018 (as amended) allows for ‘additional and minimal collection of elements or products of the human body’, which includes blood samples. Appendix 2 of the Order sets out the Maximum volume of blood that can be drawn for research purposes based on body weight [ref 2].
Ref 1: Article L1121-1 of the Public Health Code (CSP)
Link: https://www.legifrance.gouv.fr/codes/article_lc/LEGIARTI000032722870/
Ref 2: Order of April 12, 2018 setting the list of research mentioned in 3° of article L. 1121-1 of the public health code
Link: https://www.legifrance.gouv.fr/loda/id/JORFTEXT000036805820/2022-11-16/
Germany [Blood Sampling Not Permitted] – The German drug law (AMG) does not make allowance for blood sampling in in the context of non-interventional studies, meaning that such studies are classed as low intervention clinical trials.
The Netherlands [Blood Sampling Changes the NIS Study Classification from non-WMO to WMO] – Medical research that involves subjecting participants to interventions outside of usual medical care (e.g., study specific blood sampling), and / or the participants are subjected to a particular behaviour (e.g., assignment to a particular treatment based on randomization) is WMO research and therefore not a non-interventional study (non-WMO study) [ref 1].
Research that falls under the Medical Research Involving Human Subjects Act (WMO) must be tested in advance by an accredited research ethics committee (MREC) or the Central Committee on Research Involving Human Subjects (CCMO) [ref 2].
WMO Research means “law about medical scientific research with human beings” (in Dutch: Wet Medisch-wetenschappelijk Onderzoek met mensen).
Ref 1: nWMO Advisory Committee (Dutch Clinical Research Foundation – DCRF)
Link: https://nwmostudies.nl/nwmo/
Ref 2: CCMO – Your research: subject to WMO or not?
Link: https://www.ccmo.nl/onderzoekers/wet-en-regelgeving-voor-medisch-wetenschappelijk-onderzoek/uw-onderzoek-wmo-plichtig-of-niet
