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#9 Practical RWE – Connecting the Dots: How to Identify Country-Specific Requirements for Non-Interventional Studies (NIS)

#9 Practical RWE – Connecting the Dots: How to Identify Country-Specific Requirements for Non-Interventional Studies (NIS)

 

Psstt…this is a secret…so please don’t tell anybody! 😳 🤔 😂

How do we identify the country-specific requirements for non-interventional studies? Much of our work with non-interventional studies involves determining what is NOT applicable.

We start with clinical trials…and run through this series of questions:

  1. What are the Requirements for Clinical Trials?
  2. Are NIS Covered in the Clinical Trial Regulations?
  3. Are There Specific Regulations for NIS?
  4. Are There Specific Regulations for Biomedical Research?
  5. Is There Local Guidance for Biomedical Research?

The answers to these questions help us to build our country-specific regulatory compliance roadmaps. Part of the process includes contacting competent supervisory authorities (e.g., IEC/IRB) to confirm (verify) NIS requirements.

Simple!

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#9 Practical RWE – Connecting the Dots: How to Identify Country-Specific Requirements for Non-Interventional Studies (NIS)2024-02-01T15:14:59+00:00

#8 Practical RWE – Connecting the Dots: The Declaration of Helsinki

#8 Practical RWE – Connecting the Dots: The Declaration of Helsinki

 

How often have you wondered “what do I need to do” when you’ve been faced with the prospect of running a non-interventional study?  Especially, if you are more familiar and comfortable with running clinical trials.

This is where I think we are missing a trick when we train team members in the requirements of ICH GCP.  Most GCP training skims over the foundational aspects…the ‘why’ we need to do the training (= prevent a reoccurrence of the Nazi doctor experiments)….why the Nuremberg Code and the Declaration of Helsinki were needed (= before they were created no international law or informal statement existed that differentiated between legal and illegal human experimentation).

The Declaration of Helsinki [ref 1] defines the “ethical principles for medical research involving human subjects”. This Declaration is the ethical foundation for:

  1. Clinical trials of drugs
  2. Non-interventional studies of drugs
  3. Observational studies (no drugs)
  4. Clinical trials and observational studies of medical devices

The Declaration of Helsinki forms the basis for ICH GCP (drugs) and ISO 14155 (GCP for medical devices)…and is the framework for non-interventional study regulations…globally.

Once you understand this, you will see the global similarities in the requirements for running non-interventional studies, which include:

  1. Study participation must be voluntary
  2. Voluntary informed consent is essential
  3. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information.
  4. Researchers must have appropriate education, training, and qualifications
  5. Design and performance must be clearly described and justified in a protocol
  6. Protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed
  7. Protocol must be submitted for approval to a research ethics committee before the study begins
  8. The research study must be registered in a publicly accessible database before recruitment of the first subject.
  9. No amendment to the protocol may be made without approval by the research ethics committee.
  10. At the end of the study, researchers must submit a final report to the research ethics committee containing a summary of the study’s findings and conclusions.
  11. Researchers have a duty to make publicly available the results of their research are accountable for the completeness and accuracy of their reports.

 

References:

  1. World Medical Association (WMA) – Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects (October 2013): https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
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#8 Practical RWE – Connecting the Dots: The Declaration of Helsinki2024-02-01T15:02:45+00:00

#7 Practical RWE – Clinical Study Classification: Interventional or Non-Interventional?

#7 Practical RWE – Clinical Study Classification: Interventional or Non-Interventional?

 

And so…we come to the most painful, controversial, and confusing of the definitions… ”intervention” and “interventional”.

Ideally, we would classify studies according to the level of intervention i.e., interventional, low intervention, and non-interventional. However, most regulators have been hesitant to define ‘intervention’ in their regulations. Only a few countries (e.g., USA, France, and South Africa) [refs 1 to 3] have defined “intervention” in the context of clinical trials.

If ‘intervention’ isn’t defined in the regulations of the region of interest it becomes difficult (impossible) to define what is, and is not, an intervention, and therefore what is, and is not, a clinical trial.

There is a simple solution.  Most countries define a ‘clinical trial’.

For example, in Europe:  ‘Clinical trial’ means a clinical study which fulfils any of the following conditions [ref 4]:

(a)  the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned;

(b)  the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or

(c)  diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects

So…when classifying a clinical study, the recommendation is to determine whether the proposed study is a clinical trial.

If the study isn’t a clinical trial, then what is it?

In Europe, a ‘non-interventional study’ is a clinical study other than a clinical trial [ref 4].

Therefore, in Europe both clinical trials and non-interventional studies (NIS) are investigations in humans that involves a medicinal product.  Whereas, clinical trials involve protocol-defined healthcare interventions, and NIS do not.

 

References:

[1] Section III.A of the FDA Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (August 2023): https://www.fda.gov/media/171667/download

[2] Article L1121-1 of the Public Health Code (CSP): https://www.legifrance.gouv.fr/codes/article_lc/LEGIARTI000032722870/

[3] Glossary of the Department of Health – Ethics in Health Research Guidelines: Principles, Processes and Structures (2015): https://www.health.gov.za/wp-content/uploads/2022/05/NHREC-DoH-2015-Ethics-in-Health-Research-Guidelines-1.pdf

[4] Article 2 of the EU Clinical Trials Regulation (Regulation EU/536/2014): https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02014R0536-20221205

In essence, definitions lay the groundwork for accurate, consistent, and meaningful research, especially in areas where the data and its sources are as diverse and complex as in RWD and RWE.

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#7 Practical RWE – Clinical Study Classification: Interventional or Non-Interventional?2024-02-01T14:57:36+00:00

#6 Practical RWE – Clinical Study Classification: Non-Interventional Study or Low Intervention Clinical Trial?

#6 Practical RWE – Clinical Study Classification: Non-Interventional Study or Low Intervention Clinical Trial?

 

Ideally, we would classify studies according to the level of intervention i.e., interventional, low intervention, and non-interventional.

However, although we assume clinical trials are the opposite of non-interventional studies and are therefore ‘interventional’, most regulators have been hesitant to define ‘intervention’ in their regulations.

In Europe, the EU Clinical Trials Regulation [ref 1], defines ‘clinical trials’, ‘low interventional clinical trials’, and ‘non-interventional studies’.

By definition [ref 1], a clinical trial is an investigation in humans that involves a medicinal product and the assignment of the patient to a therapeutic strategy is decided in advance  by the trial protocol i.e., protocol-defined healthcare intervention.

In a low intervention clinical trial (LICT), the assignment of the patient to a therapeutic strategy is still decided in advance  by the trial protocol, but the medicinal product is approved and used as per marketing authorisation.  So once again there is a protocol-defined healthcare intervention. In the case of a LICT, there are additional patient safety considerations i.e., any additional diagnostic or monitoring procedures that are implemented as part of the LICT must pose no more than minimal additional risk or burden to the safety of the trial participants compared to normal clinical practice.  Why?  If you increase the degree of risk to the patient above normal clinical practice…you have exceeded the ‘low risk’ threshold and the trial reverts to a ‘normal’ clinical trial.

Another consideration for LICT is that there is allowance for using medicinal products off-label (e.g., paediatric or oncology drugs), but their use in this context must be supported by “published scientific evidence on the safety and efficacy of those investigational medicinal products”…and again…the trial must meet the ‘low risk’ requirements such that any additional diagnostic or monitoring procedures applied to the patient poses no more than minimal additional risk or burden to the safety of the trial participants compared to normal clinical practice. 

Put simply, clinical trials and low intervention clinical trials involve protocol-defined healthcare interventions.

What about non-interventional studies?

By definition [ref 1], a non-interventional study is an investigation in humans that involves a medicinal product and the assignment of the patient to a therapeutic strategy is NOT decided in advance  by the trial protocol i.e., there is NO protocol-defined healthcare intervention. This means there are NO protocol-specified activities or procedures that alter the patients’ treatment regimens or plans i.e., there are no additional diagnostic or monitoring procedures applied to the patient that impact the patients’ treatment.

In summary, in Europe both low intervention clinical trials (LICT) and non-interventional studies (NIS) are investigations in humans that involves a medicinal product.  LICT involve protocol-defined healthcare interventions, whereas NIS do not.

 

References:

[1] EU Clinical Trials Regulation (Regulation EU/536/2014): https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02014R0536-20221205

In essence, definitions lay the groundwork for accurate, consistent, and meaningful research, especially in areas where the data and its sources are as diverse and complex as in RWD and RWE.

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#6 Practical RWE – Clinical Study Classification: Non-Interventional Study or Low Intervention Clinical Trial?2024-02-01T14:52:04+00:00

#5 Practical RWE – Clinical Study Classification: Retrospective or Prospective?

#5 Practical RWE – Clinical Study Classification: Retrospective or Prospective?

 

We often get confused when we use the terms ‘retrospective’ or ‘prospective’ in the context of a non-interventional study.

By definition [ref 1], a retrospective study collects data that was generated before the study was approved and a prospective study collects data that was generated after the study was approved.  Seems simple enough! 

In Europe, countries such as Germany [ref 2], Italy [ref 3], and Spain [ref 1] use the terms ‘retrospective’ and/or ‘prospective’.  Whereas, Austria has revised their non-interventional study guidance [ref 4] to state that:

“Retrospective data evaluations are studies that are carried out exclusively on data already collected for other reasons (in particular on the occasion of a curative treatment). Since retrospective data collection does not  involve a human study – which is required for the ‘clinical study’ under Article 2(2)(1) of the EU CTR – the  term  ‘clinical study’ (and thus also the legal definition of ‘non-interventional study’) is not fulfilled.”

Similarly, the research system in France focuses on research directly involving humans (RIPH e.g., clinical trials and non-interventional studies) [ref 5] and research which doesn’t (Non-RIPH e.g., secondary use of existing data).

Meaning?  In Austria and France, retrospective non-interventional studies aren’t actually…non-interventional studies. No wonder we get confused!

It could be argued that France is a leader in terms of the pivot from ‘retrospective and prospective’ to more contextual descriptors of ‘primary data and secondary data’.

This is very topical in the context of the European Health Data Space (EHDS) [ref 6], where ‘primary use of electronic health data’ means the processing of personal electronic health data for the provision of health services etc, and ‘secondary use of electronic health data’ means the processing of electronic health data for purposes such as scientific research.

Clearly, there is much work to do at the local level before we see the terms ‘retrospective’ and ‘prospective’ phased out and replaced with unified (and less confusing?) data descriptors, such as  ‘primary data’ and ‘secondary data’.  Until then…let the confusion abound!

 

References:

[1] Article 2(1)(b) of Royal Decree 957/2020 of November 3: https://www.boe.es/eli/es/rd/2020/11/03/957/con

[2] BfArM and PEI Joint Recommendations (Dec 2022): https://www.pei.de/SharedDocs/Downloads/DE/regulation/klinische-pruefung/awb-nis-pass-empfehlungen.pdf?__blob=publicationFile&v=4

[3] AIFA Determination March 20, 2008 – Guidelines for the classification and conduct of observational drug studies: https://www.medicoeleggi.com/argomenti000/italia2008/400078-a1.htm

[4] Federal Office for Safety in Health Care (BASG) – Guideline for the Differentiation of Clinical Studies: https://www.basg.gv.at/fileadmin/redakteure/06_Gesundheitsberufe/Klinische_Studien/NIS/Leitfaden_NIS_BMSGPK_BASG_2022-10-11_v01.pdf

[5] Article L1121-1 of the Public Health Code (CSP): https://www.legifrance.gouv.fr/codes/article_lc/LEGIARTI000032722870/

[6] European Commission – European Health Data Space: https://health.ec.europa.eu/ehealth-digital-health-and-care/european-health-data-space_en

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#5 Practical RWE – Clinical Study Classification: Retrospective or Prospective?2024-02-01T14:44:05+00:00

#4 Practical RWE – Clinical Study Classification: Non-Interventional Study or Observational Study?

#4 Practical RWE – Clinical Study Classification: Non-Interventional Study or Observational Study?

 

It’s a simple question. Actually…no it isn’t.

The EU defines a non-interventional study as a “clinical study other than a clinical  trial” 😳 [ref 1].  Whereas the US FDA talks about “non-interventional (observational) studies”[ref 2].

So…let’s simplify things…for the sake of your sanity and mine.

In Europe, by definition [ref 1], a non-interventional study must involve a drug.  If your clinical study does not involve a drug…then by regulatory definition it cannot be a non-interventional study. Meaning?  Any other type of study with a non-interventional design will be an observational study…which may or may not be defined at the local level.

The EMA list of metadata for the Real World Data catalogues (which go live in February 2024) [ref 3] define the drug study types as ‘clinical trial’ or ‘non-interventional study’.  The non-interventional study, study designs are defined as: cohort| case-control| case-only| cross-sectional| ecological| cluster design| systematic review and meta-analysis.  Note the absence of ‘observational’.

In the USA, the terms ‘non-interventional study’ and observational study are used interchangeably:

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 (as per Section II of the FDA Guidance) [ref 2].

However, the FDA definition implies that a non-interventional study must involve a drug.

In summary, in both Europe and America, a non-interventional study must involve a drug.  If your clinical study does not involve a (marketed) drug…then by regulatory definition it cannot be a non-interventional study.

 

References:

[1] Article 2.2(4) of Regulation EU/536/2014: https://eur-lex.europa.eu/eli/reg/2014/536

[2] Section II of the FDA Guidance – Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (August 2023): https://www.fda.gov/media/171667/download

[3] Section 2.2(II) of the EMA List of Metadata for Real World Data Catalogues (May 2022): https://www.ema.europa.eu/en/documents/other/list-metadata-real-world-data-catalogues_en.pdf

In essence, definitions lay the groundwork for accurate, consistent, and meaningful research, especially in areas where the data and its sources are as diverse and complex as in RWD and RWE.

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#4 Practical RWE – Clinical Study Classification: Non-Interventional Study or Observational Study?2024-02-01T14:38:55+00:00

#3 Practical RWE – Clinical Study Classification: What is it?

#3 Practical RWE – Clinical Study Classification: What is it?

 

Running a clinical study is complicated.  From a regulatory compliance…perspective you need to know what type of study it is. This drives the direction of ‘what you need to do’ (regulatory compliance) versus what you ‘should’ do (best practice considerations).

As discussed previously, definitions, or more correctly ‘regulatory definitions’, are very important.  These definitions (e.g., non-interventional study) describe the boundaries of the study (what the study is and is not) and direct researchers to the applicable regulations and guidelines (hopefully).

When you intend to conduct of clinical study to answer a research question, it is important that you understand what the clinical study is.  Is it…(1) a clinical trial, (2) a non-interventional (drug) study, or (3) an observational study (e.g., natural history study)?

Why are these questions important?  Each of these three clinical study types are regulated differently…and to make matters worse…the regulatory framework for non-interventional (drug) studies and observational (disease) studies is different…in every country…globally.

For example, regulatory compliance considerations include:

[1] Clinical Trials = Clinical trial regulations + compliance with ICH GCP (very similar requirements globally)

[2] Non-Interventional Study = Local biomedical research regulations + pharmacovigilance requirements + consideration of/ compliance with best practices (e.g., ISPE GPP, ENCePP Guide on  Methodological Standards in Pharmacoepidemiology etc )

[3] Observational Study = Local biomedical research regulations

As you can see, the regulatory requirements for clinical trials are very different to those for non-interventional (drug) studies and observational (not drug) studies. Knowing what type of clinical study (regulatory classification) you intend to run is key to understanding what your regulatory obligations are, who you need to get approvals from, who you need to notify, what you need to notify…and what you need to tell patients so that they are adequately informed before they make the decision to participate in your research.

In summary, recognizing (correctly classifying) the study type is crucial for fulfilling regulatory obligations, obtaining necessary approvals, notifying relevant parties, and ensuring informed patient participation.

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#3 Practical RWE – Clinical Study Classification: What is it?2024-01-09T18:19:26+00:00

#2 Practical RWE – Terminology: Real World Research (RWR), Real World Data (RWD), and Real World Evidence (RWE)

#2 Practical RWE – Terminology: Real World Research (RWR), Real World Data (RWD), and Real World Evidence (RWE)

 

Real-world research, in the context of Real-World Data (RWD) and Real-World Evidence (RWE), takes on a specific meaning, particularly in the fields of healthcare and pharmaceutical research. Let’s break down these concepts:

  1. Real-World Data (RWD): This refers to data that is collected from sources outside of traditional clinical trials. RWD can come from a variety of sources such as electronic health records (EHRs), medical claims and billing activities, product and disease registries, patient-generated data including in home-use settings, data gathered from other devices that are a part of health care and real-life environments, and data from social media platforms. Essentially, it’s data that reflects the patient experience in real-world settings, not in the controlled environment of a clinical trial.
  2. Real-World Evidence (RWE): RWE is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from the analysis of RWD. This evidence is increasingly being used to support regulatory decisions and to help develop guidelines and decision-making in clinical practice. RWE studies can provide insights on how a drug or therapy performs in a broader, more diverse population and in routine clinical practice, outside the constraints of controlled clinical trials.

When conducting real-world research in this context, the focus is on understanding and analyzing the effectiveness, safety, and value of healthcare interventions in the everyday, diverse clinical settings. The methodology of such research might include:

– Observational studies, often using large datasets.

– Pragmatic clinical trials designed to evaluate the effectiveness of interventions under the usual conditions in which they will be applied.

– Analysis of treatment outcomes, side effects, and patient adherence using RWD sources.

– Use of advanced data analytics and big data techniques to extract insights from complex, large-scale RWD.

Real-world research using RWD and RWE is becoming increasingly important in the healthcare sector. It complements findings from randomized controlled trials (RCTs), which are often the gold standard for clinical research but can be limited in terms of the diversity of participants and strict inclusion criteria. RWE, on the other hand, can provide a more comprehensive view of how treatments work in diverse populations and real-life settings, which is invaluable for healthcare providers, policymakers, and patients.

In essence, definitions lay the groundwork for accurate, consistent, and meaningful research, especially in areas where the data and its sources are as diverse and complex as in RWD and RWE.

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#2 Practical RWE – Terminology: Real World Research (RWR), Real World Data (RWD), and Real World Evidence (RWE)2024-01-09T17:44:46+00:00

#1 Practical RWE – The Importance of Harmonised Definitions (RWR, RWD, RWE)

#1 Practical RWE – The Importance of Harmonised Definitions (RWR, RWD, RWE)

 

Definitions are crucial in the context of real-world research (RWR), real-world data (RWD), and real-world evidence (RWE) for several reasons:

  1. Clarity and Precision: In research, clear definitions ensure that everyone understands exactly what is being discussed. This is particularly important in RWD and RWE, where the data comes from a variety of sources and might be interpreted in different ways.
  2. Consistency: Definitions help maintain consistency across studies. In the realms of RWD and RWE, where studies often use data collected for other purposes, having standard definitions allows for more reliable comparisons and aggregations of data.
  3. Data Quality: Good definitions help ensure high-quality data. In real-world research, where data is not collected in controlled experimental settings (e.g., randomised controlled trials), clear definitions are essential for filtering and processing data effectively.
  4. Regulatory Compliance: In many fields, particularly in healthcare and pharmaceuticals, RWE is used to support regulatory decisions. Precise definitions are critical to meet the regulatory standards for evidence.
  5. Interdisciplinary Communication: RWD and RWE often involve collaboration across various disciplines. Clear definitions facilitate better communication and understanding among diverse groups of researchers, clinicians, policymakers, and other stakeholders.
  6. Replicability and Scalability: Well-defined concepts and methods enable other researchers to replicate studies or scale up research projects. This is vital for the advancement of science and policy-making.
  7. Data Integration: In real-world research, data often comes from multiple sources. Consistent definitions allow for more effective integration and analysis of this heterogeneous data.
  8. Targeted Interventions and Policies: In applied research, such as public health or market research, clear definitions help in designing more effective interventions and policies, as they allow for a precise understanding of the phenomena being addressed.

In essence, definitions lay the groundwork for accurate, consistent, and meaningful research, especially in areas where the data and its sources are as diverse and complex as in RWD and RWE.

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#1 Practical RWE – The Importance of Harmonised Definitions (RWR, RWD, RWE)2024-01-09T17:38:50+00:00
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