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Real World Evidence (RWE) 101 – The Common Rule

RWE 101 – The Common Rule

The Common Rule plays a significant role in the governance of observational studies. The Common Rule refers to a set of regulations and ethical principles designed to protect human subjects participating in research studies conducted or supported by federal agencies in the United States. It sets the standards for the ethical conduct of research and ensures the protection of individuals involved in research studies.

Observational studies, which are a type of study design used in RWE research, involve the collection and analysis of data from participants in their real-world settings. These studies aim to assess outcomes and associations between various factors, such as treatments, interventions, or exposure to certain conditions, without any intervention or manipulation by the researcher.

The Common Rule establishes the following key principles and requirements:

Informed Consent: The Common Rule emphasizes the importance of obtaining informed consent from individuals participating in research studies. Researchers must provide participants with clear and understandable information about the study, its purpose, risks, potential benefits, and any other relevant details. Informed consent ensures that participants have the necessary information to make an informed decision about their participation.

Institutional Review Board (IRB) Oversight: The Common Rule requires that all research involving human subjects undergo review by an IRB. The IRB evaluates the study’s ethical implications, safeguards the rights and welfare of participants, and ensures that the research adheres to the Common Rule’s principles. IRBs play a critical role in assessing the risks and benefits of observational studies and determining whether they meet ethical standards.

Privacy and Confidentiality: Observational studies often involve the collection of sensitive data from participants, such as medical records or personal information. The Common Rule mandates that researchers take appropriate measures to protect the privacy and confidentiality of individuals involved in the study. This includes implementing safeguards to prevent unauthorized access, use, or disclosure of participant data.

Balancing Risks and Benefits: The Common Rule requires researchers to conduct a thorough risk-benefit analysis of the observational study. They must assess the potential risks associated with data collection and analysis and weigh them against the potential benefits of the research. This analysis helps ensure that the benefits of the study justify any potential risks to the participants.

By adhering to the Common Rule, researchers can ensure that observational studies in RWE are conducted ethically, with proper safeguards for participant rights, welfare, and privacy. The Common Rule helps maintain the integrity of research and promotes public trust in the scientific community’s ability to generate reliable and valuable real-world evidence.

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Real World Evidence (RWE) 101 – The Common Rule2023-08-07T13:58:31+00:00

Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study – Supplement

RWE 101 – The Tuskegee Syphilis Study – Supplement

 

The Tuskegee Syphilis Study, conducted between 1932 and 1972 by the United States Public Health Service (USPHS), stands as one of the most infamous and ethically questionable experiments in the history of human research. The study intended to observe the natural history of untreated syphilis. Researchers did not collect informed consent from participants. Researchers did not offer treatment, even after it was widely available. The study was terminated after 40 years following publication of news articles about the study.

“The government induced these men to participate in a study in which the government represented that the participants were being treated for whatever their ailments were…They were never told what their ailment was…They never gave their consent to be involved in a study…Nor did they realise they were part of a study until the story broke in July 1972…Treatment was knowingly withheld for 40 years” – Fred D Gray – Attorney, 8th April 1997

Its repercussions have had far-reaching effects on the regulation of observational studies, medical ethics, and trust in healthcare institutions, especially among minority communities.

  1. Introduction of Ethical Guidelines: The Tuskegee study helped accelerate the development of ethical standards for observational studies, notably the Belmont Report in 1979. The report outlined three basic principles: respect for persons, beneficence, and justice. It prescribed informed consent, an understanding of potential risks and benefits, and the equitable selection of research subjects. These principles, born out of a response to the unethical practices in Tuskegee and other studies, have become the bedrock of research ethics.
  2. Introduction of Regulations: In 1974 the National Research Act was signed into law and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was formed. In 1991 the Federal Policy for the Protection of Human Subjects (‘Common Rule’) (45 CFR 46) was implemented.
  3. Informed Consent: One of the main lessons from the Tuskegee study was the importance of informed consent. In the study, participants were not told they had syphilis, nor were they informed about the nature of the experiment. As a result of public outcry, it is now mandatory for researchers to provide potential participants with comprehensive information about the study and its potential risks and benefits.
  4. Protection for Vulnerable Populations: The Tuskegee study highlighted the need for special protections for vulnerable populations in observational studies. The mostly poor, uneducated African American men involved were exploited due to their socioeconomic status and lack of access to quality healthcare. The fallout from Tuskegee led to additional safeguards for marginalized populations to prevent similar abuses.
  5. Institutional Review Boards (IRBs): After the Tuskegee study, the requirement for Institutional Review Boards became more widespread. IRBs are responsible for reviewing and monitoring research involving humans to ensure ethical standards are met. Their role is to protect the rights and welfare of the research subjects.
  6. Transparency and Accountability: The Tuskegee Syphilis Study was marked by a lack of transparency and accountability. The study was conducted without adequate oversight or scrutiny. This led to the development of regulations requiring transparency in the conduct of studies, data sharing, and mechanisms for accountability in the case of ethical breaches.
  7. Public Trust and Participation: The Tuskegee study severely damaged public trust, particularly among African Americans, in medical research and healthcare institutions. This has implications for the regulation of observational studies, as it underscores the importance of building and maintaining public trust for successful research participation.
  8. Cultural Competency: The racial implications of the Tuskegee study brought to light the importance of cultural competency in research. Researchers are now required to respect the cultural norms and values of the populations they study, and training in cultural competency has become a norm in many research settings.
  9. Training in Research Ethics: Following the Tuskegee study, training in research ethics became a requirement for investigators conducting human subject research. This training typically includes a discussion of the Tuskegee study as an example of what not to do.
  10. International Impact: The Tuskegee study had a global impact on observational study regulation. The Declaration of Helsinki, a set of ethical principles regarding human experimentation, was updated in response to the ethical violations in Tuskegee and similar studies.

“Medical professionals willingly and intentionally let human beings suffer from a treatable, and then later a curable illness. These researchers knew that mercury and arsenic compounds could treat the disease, but the Tuskegee men did not receive the medicine. Later the researchers knew that penicillin could cure the disease, but again, the Tuskegee men did not get the medicine. They didn’t get treated until the 40 year study was discovered and stopped amid public outcry in 1972. It was a disgraceful episode for American Scientists” – Vice President Al Gore, 16th May 1997 [See also…Presidential Apology]

In conclusion, the Tuskegee Syphilis Study has had a profound impact on the regulation of observational studies in the USA.

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Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study – Supplement2023-08-07T13:51:32+00:00

Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study (the reason we have the Belmont Report and the Common Rule)

RWE 101 – The Tuskegee Syphilis Study (the reason we have the Belmont Report and the Common Rule)

The Tuskegee Syphilis Study, conducted from 1932 to 1972, stands as a notorious example of unethical human research. Its fallout had substantial implications on the regulation of observational studies:

Ethical Guidelines: The Tuskegee study expedited the development of ethical standards, including the Belmont Report (1979). The report emphasized respect for persons, beneficence (acting in a way that brings about positive outcomes and promotes the welfare of others), and justice (the principle of treating people fairly and equitably), all crucial in research ethics.

Informed Consent: The Tuskegee study underscored the importance of informed consent. It is now required for researchers to provide comprehensive information about the study and its potential risks and benefits.

Protection for Vulnerable Populations: The study highlighted the need for protections for vulnerable populations. Additional safeguards have since been implemented to prevent similar abuses.

Institutional Review Boards (IRBs): Post-Tuskegee, the requirement for IRBs became more prevalent. IRBs review and monitor research involving humans to ensure ethical standards.

Transparency and Accountability: The study led to regulations mandating transparency, data sharing, and mechanisms for accountability in the case of ethical breaches.

Public Trust and Participation: The Tuskegee study damaged public trust, particularly among African Americans. This underlines the importance of building and maintaining public trust for research participation.

Cultural Competency: The racial implications of the Tuskegee study highlighted the importance of cultural competency in research. Training in cultural competency has since become a norm.

Training in Research Ethics: The study led to mandatory training in research ethics for investigators conducting human subject research.

International Impact: The study had a global impact on observational study regulation. It influenced updates to the Declaration of Helsinki, an international set of ethical principles regarding human experimentation.

For more details about the Tuskegee Syphilis Study see the RWE 101 Supplement I published today…

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Real World Evidence (RWE) 101 – The Tuskegee Syphilis Study (the reason we have the Belmont Report and the Common Rule)2023-08-07T13:45:24+00:00

Real World Evidence (RWE) 101 – Observational Study vs Non-Interventional Study

RWE 101 – Observational Study vs Non-Interventional Study

In the context of real-world evidence (RWE), the terms “observational study” and “non-interventional study” are often used interchangeably to refer to studies that collect data outside the controlled environment of a clinical trial. However, it’s worth noting that some subtle differences can exist based on the specific context or regulatory guidelines. Here’s an overview:

[1] Observational Study: An observational study is a research design where researchers observe and collect data on participants without intervening or administering any specific treatment. Observational studies aim to analyze associations, correlations, or patterns in real-world settings. They can be prospective (following participants over time) or retrospective (analyzing existing data or medical records).

[2] Non-interventional Study: A non-interventional study is a study type (EU and US regulatory definition)  that does not involve any healthcare or treatment interventions imposed by researchers. It is often used as an umbrella term for studies that collect data in real-world settings, without manipulating variables. Non-interventional studies are primarily focused on describing, analyzing, or assessing outcomes, exposure, or associations.

It’s important to note that regulatory guidelines and definitions may vary across different regions and agencies. For instance, the US FDA’s guidance on RWE refers to “real-world studies”, “observational Studies”, and “non-interventional (observational) studies”, while the European Union Clinical Trials Regulation (Regulation EU/536/2014) uses the term “non-interventional studies.” However, in practice, the intent of these studies—collecting data without actively intervening—is often similar.

In the context of RWE, both observational studies and non-interventional studies typically leverage real-world data sources such as electronic health records, claims databases, registries, surveys, or patient-reported outcomes. They aim to generate evidence (real world evidence) on treatment outcomes, comparative effectiveness, safety profiles, and other healthcare-related factors.

Ultimately, the precise terminology used may vary, but the fundamental principle is that observational studies and non-interventional studies within the context of RWE both involve the collection and analysis of real-world data without actively imposing healthcare or treatment interventions on participants.

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Real World Evidence (RWE) 101 – Observational Study vs Non-Interventional Study2023-08-07T13:29:05+00:00

Real World Evidence (RWE) 101 – Are Non-Interventional Studies Regulated?

RWE 101 – Are Non-Interventional Studies Regulated?

Yes, non-interventional studies (NIS) are regulated. While the specific regulations and requirements may vary by country, there are generally guidelines and provisions in place to ensure the conduct and reporting of non-interventional studies meet certain standards.

Here are some key points related to the regulation of non-interventional studies:

Ethical Considerations: Non-interventional studies involving human participants must adhere to ethical principles and guidelines (i.e., Declaration of Helsinki) and be approved by an ethics committe (IRB/REC). These guidelines often cover aspects such as informed consent, confidentiality, privacy protection, and the rights and welfare of study participants.

Data Protection: Regulations related to data protection and privacy, such as the EU General Data Protection Regulation (GDPR), are applicable to non-interventional studies. Researchers must ensure that the collection, storage, and processing of personal data comply with these regulations.

Regulatory Oversight: Regulatory authorities may have oversight over non-interventional studies, particularly when the studies are the results of a regulatory commitment (e.g., PMRs and PASS). In the EU, for example, the EMA provides guidance on non-interventional post-authorisation safety studies (PASS) (GVP Module VIII).

Good Pharmacovigilance Practices (EU): Non-interventional studies focused on post-authorization safety assessments of medicinal products are subject to good pharmacovigilance practices. These practices include the collection, analysis, and reporting of adverse drug reactions and safety data.

Reporting Requirements: Non-interventional studies may have reporting requirements (e.g., EU PAS Register) to ensure transparency and accountability. This may include the submission of study protocols, study results, safety updates, or other relevant data to regulatory authorities or ethics committees.

It’s important to note that the specific regulations and requirements for non-interventional studies can vary between countries and regions. Researchers conducting non-interventional studies should be familiar with the applicable regulations in their jurisdiction and seek guidance from regulatory authorities, ethics committees, or relevant professional organizations to ensure compliance with the required standards.

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Real World Evidence (RWE) 101 – Are Non-Interventional Studies Regulated?2023-08-07T13:12:49+00:00

Real World Evidence (RWE) 101 – Postmarket Requirements (PMR) vs Post-Authorisation Safety Studies (PASS)

RWE 101 – Postmarket Requirements (PMR) vs Post-Authorisation Safety Studies (PASS)

 

In the context of real-world evidence (RWE) and regulatory frameworks, postmarket requirements (PMRs) and post-authorization safety studies (PASS) are two distinct concepts that focus on monitoring and assessing the safety and effectiveness of medical products after they have been approved or authorized for use. Here’s an explanation of each:
 
Postmarket Requirements (USA): Postmarket requirements refer to the obligations imposed by the US FDA on manufacturers or sponsors of medical products (such as drugs and biologics) after they have been approved for marketing. These requirements are intended to gather additional data and monitor the product’s safety and effectiveness in real-world settings and INCLUDE observational studies that sponsors are required to conduct.
 
Compliance with these requirements ensures ongoing evaluation and surveillance of the product’s safety and effectiveness throughout its lifecycle.
 
Post-Authorization Safety Studies (EU): Post-authorization safety studies (PASS) are specific studies conducted to further assess the safety profile of a medical product in real-world settings after it has been authorized for use. PASS is a type of post-marketing study designed to gather additional safety data that may not have been captured during pre-market clinical trials due to the limited sample size, restricted patient population, or duration of the trials.
 
Key aspects of post-authorization safety studies include:

Study design: PASS typically involves observational study designs, such as cohort studies or case-control studies, to evaluate the safety outcomes associated with the product’s use in a larger patient population.

Sample size: PASS often involves a larger number of participants than pre-market clinical trials to increase the likelihood of detecting rare or long-term safety events.

Data collection: Data for non-interventional PASS is collected from real-world sources, such as electronic health records, claims databases, registries, or other healthcare databases.

Safety outcomes: The primary focus of PASS is to assess and monitor the occurrence of safety events, adverse drug reactions, or any potential safety concerns associated with the product’s use.
 
Post-authorization safety studies are typically conducted as a regulatory requirement, based on the authorization conditions set by the EMA (i.e., Category 1 and 2 PASS). The findings from these studies contribute to ongoing risk-benefit assessments of the product and inform regulatory decision-making, labelling updates, or risk management strategies.
 
Overall, postmarket requirements encompass a broader set of obligations imposed on manufacturers after a product’s approval, while post-authorization safety studies specifically focus on conducting additional studies to assess the safety profile of authorized medical products in real-world settings.

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Real World Evidence (RWE) 101 – Postmarket Requirements (PMR) vs Post-Authorisation Safety Studies (PASS)2023-08-07T13:02:45+00:00

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

Real World Evidence (RWE) 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?

RWE 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?

No, “clinical study” and “clinical trial” are not necessarily synonymous in the context of non-interventional studies in the EU.

In general, a clinical study refers to any investigation involving human participants that is intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products, or to identify any adverse reactions to one or more medicinal products. This can include both (interventional) clinical trials and non-interventional studies.

A clinical trial, on the other hand, specifically refers to a type of interventional clinical study where one or more medicinal products are tested in human participants with the aim of evaluating their safety and/or efficacy i.e., there is a treatment intervention involving a medicinal product.

Non-interventional studies (NIS) are observational studies that do not involve any treatment interventions or protocol-dictated administration of a medicinal product. They are designed to observe patients in their natural clinical setting and collect data on the outcomes of a specific drug or treatment intervention.

So, while a clinical trial is a type of clinical study, not all clinical studies are clinical trials.
 
Revision 2 of ICH GCP caused confusion to those of us who work with non-interventional studies. The glossary claimed that a ‘clinical trial’ was synonymous with a ‘clinical study’ (Section 1.12 of ICH GCP(R2)). This works if you conduct clinical trials (they are a type of clinical study), but not if you conduct non-interventional studies, which are a type of ‘clinical study other than a clinical trial’ (Article 2.2(4) of Regulation EU/536/2014).
 
The (draft) Revision 3 of ICH GCP includes a new definition of ‘clinical trial’ provided in the Glossary, which removes any confusion regarding clinical trial vs clinical study.

Clinical Trial = Any interventional investigation in human participants intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.

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Real World Evidence (RWE) 101 – Are the terms ‘clinical study’ and ‘clinical trial’ synonymous in the context of non-interventional studies?2023-08-07T12:48:43+00:00

Real World Evidence (RWE) 101 – The Importance of Regulatory Definitions

RWE 101 – The Importance of Regulatory Definitions

“Words are powerful”

Regulatory definitions are important in the context of real-world evidence (RWE) studies and real-world research for several reasons:

[1] Consistency: Regulatory definitions provide a consistent framework for generating and evaluating RWE across different stakeholders, including regulatory agencies, industry, and academia. By providing a clear and consistent definition of RWE, stakeholders can ensure that they are using the same language and criteria for evaluating the quality and relevance of RWE.

[2] Standards: Regulatory definitions help establish standards for the use of RWE in regulatory decision-making. For example, regulatory definitions may specify the types of RWE that are acceptable for use in regulatory submissions, the study designs that are appropriate for generating RWE, and the quality standards that must be met to ensure the reliability and validity of RWE.

[3] Decision-making: Regulatory definitions facilitate regulatory decision-making by providing a clear framework for evaluating the quality and relevance of RWE. By establishing clear criteria for evaluating RWE, regulatory agencies can make more informed decisions about the safety, efficacy, and quality of healthcare products.

[4] Transparency: Regulatory definitions promote transparency by providing a clear and consistent framework for generating and evaluating RWE. This can help ensure that stakeholders are aware of the criteria used to evaluate RWE and can provide input into the development of regulatory definitions.

[5] Compliance: Regulatory definitions help ensure compliance with regulatory requirements. By providing a clear definition of RWE and the standards for generating and evaluating it, stakeholders can ensure that their studies and research meet regulatory requirements.

In summary, regulatory definitions are important in the context of RWE studies and real-world research because they provide consistency, establish standards, facilitate decision-making, promote transparency, and ensure compliance with regulatory requirements. By providing a clear and consistent framework for generating and evaluating RWE, regulatory definitions can help stakeholders make more informed decisions about the safety, efficacy, and quality of healthcare products.

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Real World Evidence (RWE) 101 – The Importance of Regulatory Definitions2023-08-07T12:42:16+00:00

Real World Evidence (RWE) 101 – Regulatory Compliance

RWE 101 – Regulatory Compliance

Regulatory compliance in the context of real-world evidence (RWE) refers to ensuring that the generation and use of RWE for regulatory purposes are in accordance with applicable laws, regulations, and guidelines. RWE is increasingly being used to support regulatory decision-making in healthcare, particularly in the evaluation of the safety and effectiveness of medical products.

To ensure regulatory compliance when using RWE, organizations must follow the regulatory requirements and guidelines set forth by regulatory agencies such as the FDA in the United States, the EMA in the European Union, and other national regulatory bodies. These requirements and guidelines include criteria for the selection and use of RWE sources, study design, data quality, data privacy, and transparency.

For example, the FDA has published guidance on the use of RWE in regulatory decision-making, which outlines the criteria for using RWE to support the approval of new indications for existing drugs and to satisfy post-marketing study requirements. The guidance stresses the importance of ensuring that RWE studies are designed to address the regulatory question at hand, have appropriate data quality, and include appropriate statistical analyses.

In addition, regulatory compliance in the context of RWE also requires organizations to adhere to ethical standards for the protection of human subjects and patient privacy. Organizations must ensure that RWE studies are conducted in accordance with ethical principles, and that the data collected and analyzed are anonymized, pseudoanonymised, or de-identified to protect patient privacy.

Overall, regulatory compliance in the context of RWE requires organizations to carefully follow regulatory requirements and guidelines to ensure that the RWE generated and used for regulatory purposes is of high quality, meets ethical standards, and meets the regulatory agency’s criteria for acceptability.

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Real World Evidence (RWE) 101 – Regulatory Compliance2023-08-07T12:34:31+00:00
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