#15 Practical RWE – Ethical and Moral Obligations: Informed Consent
#15 Practical RWE – Ethical and Moral Obligations: Informed Consent
Informed consent for non-interventional studies is a crucial ethical requirement, deeply rooted in the principles established by the Nuremberg Code (1947) and later reinforced and expanded by the Declaration of Helsinki (1964).
[1] Nuremberg Code Context: The Nuremberg Code, was one of the first documents to set the ethical principles for (permissible) human experimentation in response to the atrocities committed in Nazi concentration camps. Key among its principles is the requirement of voluntary informed consent. The Code stipulates that participants should be able to exercise free power of choice and should have sufficient knowledge and comprehension of the elements of the subject matter involved to enable them to make an understanding and enlightened decision.
[2] Declaration of Helsinki Context: The Declaration of Helsinki, first adopted in 1964 by the World Medical Association, is a set of ethical principles for the medical community regarding human experimentation. It sets the ethical principles for all human research. It emphasizes the importance of informed consent, stating that every person has the right to make informed decisions regarding their participation in research. The Declaration makes clear that this consent should be obtained freely and should be based on adequate information. It also adds that the welfare of research participants must always take precedence over the interests of science and society.
In the context of non-interventional studies:
– Informed Consent is Essential: Even though non-interventional studies do not involve active healthcare intervention, they often involve the collection and analysis of personal data or biological samples, which can have implications for privacy and autonomy. Informed consent ensures that participants are aware of what the study involves, including the purpose, procedures, risks, and benefits.
– Respecting Participant Autonomy: By obtaining informed consent, researchers respect and uphold the autonomy of participants, acknowledging their right to make decisions about their own bodies and personal information.
– Building Trust: Informed consent also helps in building trust between researchers and participants. When participants understand the study’s aims and methods, they are more likely to trust the researchers and cooperate fully.
– Ethical and Legal Compliance: Following these principles helps ensure compliance with ethical standards and legal (regulatory) requirements, which is essential for the validity and legitimacy of the research.
Informed consent in non-interventional studies is not only a moral obligation but also a practical necessity for ensuring respect for participant autonomy, building trust, and maintaining ethical and legal standards in research.
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#14 Practical RWE – Documentation: 1572s
#14 Practical RWE – Documentation: 1572s
It’s a question that still (frustratingly) comes up in the context of non-interventional studies conducted in Europe…”Do I need a signed 1572 from my investigators?”
Form FDA 1572, also known as the “Statement of Investigator,” is a document that is specifically used in the context of clinical trials conducted under the regulations of the United States Food and Drug Administration (FDA). This form is a contract between the principal investigator and the FDA, indicating the investigator’s commitment to conduct the trial in accordance with FDA regulations.
FDA 1572 forms (1572s) are not applicable to clinical trials or non-interventional studies conducted in Europe.
In 2019, the Spanish Competent Authority (AEMPS) joined the position of other European Agencies (Denmark, Germany, Norway, Sweden and Switzerland) by releasing a statement, announcing that the FDA 1572 forms should not be signed by Spanish investigators. The main reason being that 21 CFR 312 is not the regulation in force in EU/Spain:
“The investigators in Spain cannot commit to comply with the established requirements by FDA 1572 form. A clinical trial carried out in Spain, the rest of EU, and EEE must not follow any third-country’s legislation. The clinical trial must be carried out in accordance with Spanish legislation that transposes EU directives 2001/20/EC, 2001/83/EC and 2005/28/EC, and EU regulation no. 536/2014 (once this will be in force)… It should be noted that The inspectors of clinical trials in Spain will consider the signature of FDA 1572 form as a serious finding applicable to the Sponsor of the clinical trial and to the Principal Investigator too as s/he will be the signatories of this form.”
Source: https://www.chcuk.co.uk/aemps-statement-regarding-use-of-fda-1572-forms/
European clinical trials are governed by different regulations and guidelines to those in the USA, primarily the EU Clinical Trials Regulation (EU) No 536/2014, and the ICH Good Clinical Practice (GCP) guidelines.
For non-interventional studies in Europe, the relevant local and EU regulations and guidelines apply, and the FDA 1572 form is NOT relevant or required.
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#13 Practical RWE – Documentation: Trial Master File vs Study Master File
#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:
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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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#12 Practical RWE – Training: Study Team Training
#12 Practical RWE – Training: Study Team Training
Study team training is crucial in both Real-World Evidence (RWE) studies and clinical trials, but the importance and focus of the training can vary significantly due to the different natures and objectives of these two types of studies.
- Nature of Data Collection:
– In clinical trials, data is collected under controlled conditions with predefined protocols. Training emphasizes adherence to these protocols, ensuring uniformity and minimizing bias.
– RWE studies, on the other hand, use data from sources like electronic health records, insurance claims, or patient registries. Training here focuses on understanding these data sources, identifying relevant data, and ensuring its quality and integrity.
- Regulatory Compliance and Guidelines:
– Clinical trials are highly regulated with strict guidelines for conduct. Training ensures compliance with these regulations, including patient safety and reporting requirements.
– RWE studies, while still subject to regulatory considerations, have different compliance requirements. Training helps in understanding these nuances and applying appropriate methodologies.
- Study Design and Methodology:
– Training for clinical trials includes detailed study design, placebo controls, blinding methods, and other experimental procedures.
– In RWE studies, training focuses more on observational study designs, statistical methods for handling real-world data, and techniques for reducing bias in non-randomized settings.
- Patient Interaction and Consent:
– Clinical trials usually require direct patient interaction, informed consent, and continuous monitoring. Training includes effective communication with participants and managing adverse events.
– RWE studies often use existing data where direct patient interaction is minimal. Training focuses more on data privacy, patient consent in the context of data use, and ethical considerations.
- Data Analysis and Interpretation:
– Clinical trial training includes specific methods for analyzing clinical data and interpreting results according to clinical endpoints.
– In RWE studies, training often covers a broader range of data analysis skills, including dealing with large datasets, diverse data types, handling missing data, and applying real-world evidence to clinical or policy decisions.
- Collaboration and Multidisciplinary Understanding:
– Both study types require understanding roles across disciplines. However, RWE studies often involve more diverse teams (e.g., data scientists, health economists, healthcare providers, policy makers) and thus require training in effective cross-disciplinary collaboration.
In summary, while study team training is fundamental in both clinical trials and RWE studies for ensuring quality, compliance, and reliability of results, the specific focus of the training differs to cater to the unique challenges and objectives of each study type.
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#11 Practical RWE – Documentation: Non-Interventional Study Protocols
#11 Practical RWE – Documentation: Non-Interventional Study Protocols
Having dedicated protocol templates for non-interventional studies (RWE studies) and clinical trials is a must rather than a ‘nice to have’ for several reasons:
- Different Objectives and Designs: Clinical trials and non-interventional studies have distinct objectives and designs. Clinical trials are designed to test the efficacy and safety of a new treatment under controlled conditions. In contrast, non-interventional RWE studies observe and analyse the outcomes of treatments in real-world settings without the researcher influencing or altering standard care practices.
- Regulatory Compliance: Clinical trials are subject to stringent regulatory requirements, including those set by the FDA, EMA, and other health authorities. These regulations ensure patient safety and data integrity and require specific protocol elements, such as detailed inclusion and exclusion criteria, randomization procedures, and stringent data collection methods. RWE studies, while also regulated, have different compliance requirements.
- Data Collection and Analysis: Clinical trials often involve rigorous data collection and analysis methods, including controlled environments, placebo controls, and double-blinding. RWE studies, on the other hand, typically rely on data from healthcare databases, patient registries, or routine clinical practice. Dedicated templates ensure that the protocols for each study type include appropriate guidelines for data collection, handling, and analysis.
- Risk Management: Different study types have different risk profiles. Clinical trials often involve unapproved treatments, requiring detailed risk management plans. RWE studies might involve fewer direct risks to participants but require careful consideration of data privacy and ethical concerns in observational settings. Separate templates can ensure that risk management is appropriately addressed in each type of study.
- Stakeholder Expectations: Clinical trials are often viewed as the gold standard for evidence generation, whereas RWE studies provide complementary insights into how treatments work in everyday clinical practice. Having distinct templates helps in clearly communicating the purpose, scope, and limitations of each study type to stakeholders.
- Efficiency and Clarity: Dedicated templates streamline the protocol development process for each study type. They ensure that researchers consider all relevant aspects and adhere to best practices specific to the study design. This clarity and efficiency can expedite the study approval process, reduce administrative burdens, and enhance the quality of the research.
In summary, having separate protocol templates for non-interventional studies and clinical trials is essential for aligning with specific study objectives, meeting regulatory requirements, ensuring appropriate data collection and analysis methods, managing risks effectively, meeting stakeholder expectations, and enhancing overall research efficiency and clarity.
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#10 Practical RWE – Connecting the Dots: Regulatory Assumptions
#10 Practical RWE – Connecting the Dots: Regulatory Assumptions
Let’s start by assuming that you have done your homework, which means:
- You’ve classified your study in each region e.g., non-interventional study
- You’ve identified the relevant national regulations and guidelines
Now what?
Now you need to consider whether there are any other conditions that are applicable to your study. For example:
[1] Has the study been imposed by a regulatory authority as a condition of the marketing authorisation? Is it a postmarket requirement (PMR = USA) or a post-authorisation safety study (PASS = EU)?
[2] Are there any study-specific research procedures? If so, will this impact the study classification and/or the ability conduct the study in the country of interest? Examples include the inability to take study-specific biosamples in Germany in the context of a (drug) non-interventional study.
[3] Are there any considerations specific to the patient population e.g., minors, minors who may progress to adulthood during the study term, legally incapacitated adults?
The answers to these questions allow you to start building the regulatory assumptions that form the basis of the regulatory roadmap for your study. In this instance, our study is a prospective post-authorisation safety study of a new treatment (Drug X) for prostate cancer in adults that has been imposed as a condition of the marketing authorisation by the EMA. Based on this information we would build our regulatory assumptions like this…
Regulatory Assumptions
– Non-interventional post-authorisation safety study (PASS)
– Imposed PASS (Category 1)
– PRAC endorsement of protocol required
– EMA PASS protocol and report templates must be used
– Registration on the EU PAS register is mandatory
– Prospective data collection
– Retrospective data collection = Medical history
– Expedited safety reporting (as per GVP Module VI)
– Study conduct and scientific considerations (as per GVP Module VIII)
– Compliance with national regulatory requirements for non-interventional studies required
– Drug X is approved and prescribed in the study country
– Patients are adults (18 years and over)
– Study-specific biosamples required for genetic screening via a central lab (excludes Germany unless the study is conducted as a low-intervention clinical trial there)
These regulatory assumptions provide the foundation for creating a study-specific regulatory playbook and roadmap covering the national approvals, notifications, and study conduct considerations.
Regulatory assumptions are important. They detail, in simple language, the key elements of the study that drive the regulatory requirements and operational considerations. Small changes to these regulatory assumptions can have a big impact on the study in terms of time, cost and feasibility.
Remember…small changes can have a big impact!
