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Real World Evidence (RWE) 101 – ‘Interventional’ Clinical Trial vs Non-Interventional Study

RWE 101 – ‘Interventional’ Clinical Trial vs Non-Interventional Study

Interventional Clinical Trial: In this type of study, researchers actively intervene by assigning participants to different groups, administering specific treatments, or manipulating variables. The primary objective is to assess the safety and efficacy of new interventions e.g., drug or medical device.
 
Key characteristics of interventional clinical trials include:
 
Randomization: Participants are randomly assigned to different groups, such as the experimental group receiving the intervention and the control group receiving a placebo or standard treatment.

Intervention: Researchers actively administer a specific treatment or intervention to the participants.

Control Group: There is often a control group that receives a placebo or standard treatment for comparison.

Primary Outcomes: Trials are designed to measure predefined primary outcomes, such as improvements in health outcomes, survival rates, or reduction in symptoms.

Regulatory Oversight: Interventional trials require regulatory approval and are usually subject to stricter (risk-proportionate) regulations than non-interventional studies.
 
Non-interventional Study: These studies focus on collecting data without any active healthcare or treatment intervention imposed by the researchers. Researchers observe and collect information from participants in their natural settings (real world settings) or through retrospective analysis of existing data (secondary use of existing data).
 
Key characteristics of non-interventional studies include:
 
Observation: Researchers observe participants and collect data without actively intervening in the healthcare management of the participant or administering any specific treatment (treatment intervention).

Natural Setting: Data is collected in the real-world clinical practice or from existing databases, medical records, surveys, or interviews.

Descriptive Analysis: Non-interventional studies often aim to describe and analyze associations, relationships, patterns, or risk factors in the population under study.

Retrospective or Prospective: Data can be collected retrospectively by analyzing past records or prospectively by following participants over time.

No Randomization: Participants are not randomly assigned to groups, and treatment decisions are made by healthcare providers according to routine clinical practice.

Regulatory Oversight: Every country regulates non-interventional studies differently. The regulatory burden can therefore be much higher than expected.
 
Both ‘interventional’ clinical trials and non-interventional studies play important roles in advancing medical knowledge. Interventional trials provide more rigorous evidence for evaluating new interventions, while non-interventional studies offer insights into real-world effectiveness, population health, and long-term outcomes.

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Real World Evidence (RWE) 101 – ‘Interventional’ Clinical Trial vs Non-Interventional Study2023-08-07T12:55:06+00:00

RWR Insights | Regulatory Considerations for Non-Interventional Study Protocols

RWR CONTEXT

Both RWE and clinical trials play critical roles in healthcare research. While clinical trials provide the highest level of evidence for determining a treatment’s efficacy, RWE studies complement this by providing evidence on real-world effectiveness and long-term safety.

Real-world evidence (RWE) study protocols and clinical trial protocols both outline the design and conduct of a study. However, they are distinctly different in several ways given the differences in objectives, methodologies, settings, and populations involved in clinical trials versus RWE studies.

The HARPER framework is a valuable resource for researchers and clinicians who are planning or conducting RWE studies. The framework can help to ensure that protocols are well-designed and will produce high-quality evidence.

Real-world evidence (RWE) study protocols and clinical trial protocols both outline the design and conduct of a study. However, they are distinctly different in several ways given the differences in objectives, methodologies, settings, and populations involved in clinical trials versus RWE studies.

[1] Objectives: The main objective of a clinical trial is to evaluate the efficacy and safety of a medical intervention in a controlled environment, usually by comparing it to a placebo or standard treatment. On the other hand, RWE studies typically aim to understand how an intervention works in routine clinical practice, often focusing on outcomes such as long-term effectiveness, side-effects, quality of life, and cost-effectiveness.

[2] Study Design and Methodology: Clinical trials, especially phase III, are predominantly randomized controlled trials (RCTs) where subjects are randomly assigned to the intervention or control group to minimise bias. They follow a pre-specified protocol and are conducted under tightly controlled conditions. RWE studies, on the other hand, are typically observational in nature and analyse data from sources like electronic health records (EHRs), claims databases, or patient registries.

[3] Setting: Clinical trials are conducted in specific, controlled environments and follow a strict protocol. RWE studies are conducted in routine clinical practice settings, making them more representative of ‘real-world’ conditions.

[4] Population: Clinical trials often have strict inclusion and exclusion criteria, resulting in a relatively homogeneous group of participants. This can limit the generalisability of the results. RWE studies, in contrast, involve broader, more diverse populations (including those often excluded from trials like the elderly, people with multiple co-morbidities, etc.), making the findings more generalisable to everyday practice.

[5] Data Collection: In clinical trials, data collection is rigorous, detailed, and specific to the trial endpoints. Adverse events are actively sought and documented. RWE studies primarily rely on existing data sources such as EHRs, patient registries, or insurance claims data. This can potentially lead to incomplete or inaccurate data.

[6] Intervention: In clinical trials, the intervention (dosage, frequency, duration, etc.) is pre-specified and strictly monitored. In RWE studies, interventions reflect routine clinical practice and may vary widely.

[7] Follow-up: Clinical trials have a defined follow-up period while RWE studies can often provide information on long-term outcomes, given they use data from routine clinical practice over longer periods.

Despite these differences, both RWE and clinical trials play critical roles in healthcare research. While clinical trials provide the highest level of evidence for determining a treatment’s efficacy, RWE studies complement this by providing evidence on real-world effectiveness and long-term safety.

HARPER PROTOCOL TEMPLATE

Regulatory agencies, health technology assessors, and payers are increasingly interested in studies that make use of real-world data to inform regulatory and other policy or clinical decision-making. However, concerns over the credibility of real-world evidence studies have led to calls for more transparency on the design and conduct of RWE studies.

A joint task force between ISPE and ISPOR created a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making [1]. The HARPER template provides clarity, structure, and a common denominator regarding the level of operational detail, context, and rationale necessary in a protocol.

HARPER = HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects

Link: https://onlinelibrary.wiley.com/doi/10.1002/pds.5507 

Four protocol templates were identified for RWE studies: 

      1. The European Medicines Agency’s (EMA) Guideline on Good Pharmacovigilance Practices (GVP) Module VIII – post-authorisations safety studies (PASS) template,
      2. ISPE’s guidelines for good pharmacoepidemiology practice (ISPE GPP) section on protocol development, 
      3. The National Evaluation System for health Technology (NEST) protocol guidance, and
      4. The Structured Template and Reporting Tool for Real World Evidence (STaRT-RWE).

The HARPER protocol contains nine sections, including a title page, abstract, and a table for amendments and updates. Each section includes structured free text, a structured table, or a figure, and a free-text section to lay out context and rationale for scientific choices.

The study design diagram shows the context and rationale for the study setting, time 0 (index date), inclusion criteria, exclusion criteria, variables, exposure, outcome, follow up, covariates, sensitivity analyses, data sources, metadata, and software used in the study.

The data sources section includes a free text component followed by a structured table for specifying data sources. The data sources section can also include a detailed evaluation of the fitness-for-purpose of data source options.

Overall, the HARPER framework is a valuable resource for researchers and clinicians who are planning or conducting RWE studies. The framework can help to ensure that protocols are well-designed and will produce high-quality evidence.

References

1. Wang, SV, Pottegård, A, Crown, W, et al. HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force. Pharmacoepidemiol Drug Saf. 2023; 32( 1): 44- 55. doi:10.1002/pds.5507

Link: https://onlinelibrary.wiley.com/doi/10.1002/pds.5507 

RWR Insights | Regulatory Considerations for Non-Interventional Study Protocols2023-08-04T13:06:33+00:00

USA | 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 

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USA | 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 2022-08-07T16:57:47+00:00

Insights | Bulgaria – ‘How To’ Guide for Non-Interventional Studies

RWR CONTEXT

Summary of the requirements for conducting prospective non-interventional studies (NIS) in Bulgaria. Includes the updates implemented by the recent NIS Ordinance (Ordinance № 8 of March 31, 2021).

June 2021 – Our three (3) step ‘How To’ guide for conducting prospective voluntary NIS in Bulgaria:

  1. Study Classification – Clinical Trial or Non-Interventional Study?
  2. Submission Requirements – Approvals, Notifications and Registration
  3. Submission Documents – Initial Application and Substantial Amendments

Definition: A non-interventional study shall be conducted with medicinal products authorised for use in the Republic of Bulgaria where these are studied in order to obtain additional information about the product prescribed in the usual manner in compliance with the conditions determined in the marketing authorisation. No additional diagnostic or monitoring procedures, different from the usual practices shall be applied to the patients in non-interventional studies, and epidemiological methods should be used for the analysis of the collected data (as per Article 145(1) of the Medicinal Products in Human Medicine Act)[1].

Regulatory Consideration 1: Study Classification – Is your study a non-interventional study or a clinical trial?

Use the following simple decision tree to determine whether your proposed clinical study is a clinical trial or a non-interventional study

Regulatory Consideration 2: Approvals, Notifications and Registration

Bulgaria is one of the few European countries where the competent authority for medicinal products (Bulgarian Drug Agency)[2] must approve non-interventional studies (see below).

Approvals:

  1. Bulgarian Drug Agency (BDA)[2]
  2. Ethical Commission for Clinical Trials (ECKI)[3]

Notifications: Not Applicable

Registration: EU PAS Register (Optional)

Fee: BGN 400

Regulatory Consideration 3: Submission Documents

Initial Application[4]:

1. Administrative documentation
. Administrative documentation
– Application form^
– Cover letter
– List of the regulatory bodies to which an application has been submitted and their decision
– List of all planned centers, principal investigators and research teams for the territory of the Republic of Bulgaria
– Copy of the recommendations of the Scientific Committee of the European Medicines Agency for consultation on trial planning (if applicable)
– Assignment letter or contract for authorization of the person who submits the application on behalf of the sponsor, when the applicant is not the sponsor
– Document for current registration, issued by a competent authority, to the contracting authority and the applicant on the territory of the European Union
– Declaration that the documentation submitted to the BDA and the Ethics Commission contains the same information.
2. Information for Participant:
– Information about the patient / participant and a form of informed consent – original and in Bulgarian
– Description of the procedures for recruiting patients / participants
– Description of the procedures for obtaining informed consent from a legal representative, where foreseen
– Ethical justification in case of recruitment of participants who are not able to give informed consent
– Any other information that will be used to recruit participants and / or provide to a participant before or during the non-interventional study.

3. The protocol documentation:
– Protocol of the study with all current changes
– Summary of the protocol in Bulgarian
– Assessment of the scientific value of the study by a specialist in the relevant field, when available
– Ethical evaluation of the protocol by the principal or coordinating researcher, when it is not part of the protocol
– A page of the protocol, signed by the sponsor and the principal investigator for each of the proposed centers
4. Documentation for the Medicinal Product:
– Current brief description of the product (SmPC)
5. The Documentation for the Technical Requirements and the Personnel:
– Description of the necessary equipment and / or technical requirements for implementation of the protocol
– Documents certifying the available technical possibilities for implementation of the protocol
– Permit for carrying out medical activity under Art. 47, para. 1 of the PPA / registration certificate under Art. 40, para. 1 of the Health Insurance Act for the medical institution – center of the non-interventional research.
6. Financing and Administrative Organization of the Study:
– Insurance
– Contract between the sponsor and the medical institution
– Contract between the sponsor and the researcher
– Data on the source of funding of the study, when the contracting authority is a non-profit legal entity
– Documentation that the fee has been paid = 400 BGN

Substantial Amendments[5][*]:

1. Application form^^
2. Cover letter
3. Summary of the planned change
4. List of the updated documents
5. The updated documentation reflecting the changes
6. Pages from the documentation with marked changes, comparing the current and the new texts
7. Justification of the changes
8. Documentation that the fee has been paid = 120 BGN
9. A copy of the positive opinion of the ethics committee, when it becomes available.

* Both the BDA and ECKI need to approve any substantial amendments: https://iisda.government.bg/adm_services/services/service_provision/6858
^ NIS Application Form: https://iisda.government.bg/adm_services/service_sample_file/6844_76240
^^ NIS Substantial Amendment Application Form: https://iisda.government.bg/adm_services/service_sample_file/6858_76336

References

1. Article 145(1) of the Medicinal Products in Human Medicine Act (ZLPHM)
Link: https://www.bda.bg/images/stories/documents/legal_acts/20210208_ZLPHM_English.pdf

2. Bulgarian Drug Agency (BDA)
Link: https://www.bda.bg/bg/

3. Ethical Commission for Clinical Trials (ECKI)
Link: https://www.bda.bg/bg/%d0%b7%d0%b0-%d0%b8%d0%b0%d0%bb/%d0%b4%d1%80%d1%83%d0%b3%d0%b8-%d0%ba%d0%be%d0%bc%d0%b8%d1%81%d0%b8%d0%b8/67-cemi

4. BDA/ECKI – Approval of a Non-Interventional Study of a Medicinal Product
Link: https://iisda.government.bg/adm_services/services/service_provision/6844

5. BDA – Issuance of Approval for a Significant Change in a Non-Interventional Study
Link: https://iisda.government.bg/adm_services/services/service_provision/6858

Useful Resources:

ECKI – Issuance of an Opinion by the Ethics Committee for Clinical Trials for Making a Significant Change in a Clinical Trial or Non-Interventional Study
Link: https://iisda.government.bg/adm_services/services/service_provision/92971

NIS Ordinance – Ordinance № 8 of March 31, 2021 on the terms and conditions for conducting non-interventional studies of medicinal products on the territory of the Republic of Bulgaria
Link [Bulgarian]: https://www.bda.bg/images/stories/documents/regulations/naredbi/20210415/%D0%9D%D0%90%D0%A0%D0%95%D0%94%D0%91%D0%90%20%E2%84%96%208%20%D0%9E%D0%A2%2031%20%D0%9C%D0%90%D0%A0%D0%A2%202021%20%D0%93..pdf
Link [English]: https://nis-regs.com/wp-content/uploads/2021/06/NIS-Ordinance-2021.pdf

Medicinal Products in Human Medicine Act (ZLPHM)
Link: https://www.bda.bg/images/stories/documents/legal_acts/20210208_ZLPHM_English.pdf
Note1: Articles 81 to 144 = Clinical Trials
Note2: Article 145 = Non-interventional Studies.
Note3: Articles 183 to 194 = Pharmacovigilance

Guideline on good pharmacovigilance practices (GVP) – Module VIII Addendum I – Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev 3) (EMA/395730/2012 Rev 3; 15 June 2020)
Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-addendum-i-requirements-recommendations_en-1.pdf

Insights | Bulgaria – ‘How To’ Guide for Non-Interventional Studies2022-08-07T17:27:58+00:00
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