Interventional Study (Clinical Trial), Non-interventional Study (Observational Study), and Registry Study

 FDA recently issued two separate guidance documents for industry: 

• Considerations for the use of real-world data and real-world evidence to support regulatory decision-making for drug and biological products” 
• Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products

While these two guidance documents are focused on real-world data (RWD) and real-world evidence (RWE), they also provided the definitions for distinctions for interventional study, non-interventional study, and registry study. 

Some of the terms are confusing and non-distinguishable, for example, we use clinical study and clinical trial interchangeably and we use registry and non-interventional study interchangeably, Based on FDA guidance documents, these different terms are for describing different types of studies. 

The term clinical study means research that evaluates human health outcomes associated with taking a drug of interest. Clinical studies include interventional (clinical trial) designs and non-interventional (observational) designs. 

Interventional Study (also referred to as a Clinical Trial): 

the term interventional study (also referred to as a clinical trial) is a study in which participants, either healthy volunteers or volunteers with the disease being studied, are assigned to one or more interventions, according to a study protocol, to evaluate the effects of those interventions on subsequent health-related biomedical or behavioral outcomes. One example of an interventional study is a traditional randomized controlled trial, in which some participants are randomly assigned to receive a drug of interest (test article), whereas others receive an active comparator drug or placebo. Clinical trials with pragmatic elements (e.g., broad eligibility criteria, recruitment of participants in usual care settings) and single-arm trials are other types of interventional study designs.

Non-interventional study (also referred to as an observational study)

a non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of  non-interventional study designs include (1) observational cohort studies, in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified and (2) case-control studies, in which patients are identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are identified.

Registry study

a registry is defined as an organized system that collects clinical and other data in a standardized format for a population defined by a particular disease, condition, or exposure. Establishing registries involves enrolling a predefined population and collecting prespecified health-related data for each patient in that population (patient-level data). Data about this population can be entered directly into the registry (e.g., clinician-reported outcomes) and can also include additional data linked from other sources that characterize registry participants. Such external data sources can include data from medical claims, from pharmacy and/or laboratory databases, and from EHRs, blood banks, and/or medical device outputs. Trained staff should follow standard operating procedures to aggregate data for a registry and carry out data curation.

Registries range in complexity regarding the extent and detail of the data captured and how the data are curated. For example, registries used for quality assurance purposes related to the delivery of care for a particular health care institution or health care system tend to collect limited data related to the provision of care. Registries designed to address specific research questions tend to systematically collect longitudinal data in a defined population, on factors characterizing patients’ clinical status, treatments received, and subsequent clinical events. The data collected in a given registry and the procedures for data collection are relevant when considering how registry data can be used. 

Registries have the potential to support medical product development, and registry data can ultimately be used, when appropriate, to inform the design and support the conduct of either interventional studies (clinical trials) or non-interventional (observational) studies. Examples of such uses include, but are not limited to: 

• Characterizing the natural history of a disease
• Providing information that can help determine sample size, selection criteria, and study endpoints when planning an interventional study 
• Selecting suitable study participants—based on factors such as demographic characteristics, disease duration or severity, and past history or response to prior  therapy—to include in an interventional study (e.g., randomized trial) that will assign a drug to assess that drug’s safety or effectiveness 
• Identifying biomarkers or clinical characteristics that are associated with important  clinical outcomes of relevance to the planning of interventional and non-interventional studies
• Supporting, in appropriate clinical circumstances, inferences about safety and  effectiveness in the context of: 
• A non-interventional study evaluating a drug received during routine medical practice  and captured by the registry 
• - An externally controlled trial including registry data as an external control arm

An existing registry can be used to collect data for purposes other than those originally intended, and reusing a registry’s infrastructure to support multiple interventional and non-interventional studies can generate efficiencies. Before designing and initiating an interventional or non-interventional study using registry data for regulatory decisions, sponsors should consult with the appropriate FDA review division regarding the appropriateness of using a specific registry as a real-world data source. 

Registries can generally be categorized as

(1) disease registries that use the state of a particular disease or condition as the inclusion criterion,

(2) health services registries where the patient is exposed to a specific health care service, or

(3) product registries where the patient is exposed to a specific health care product. 

The guidance documents also provided definitions for other types of studies: 

Natural history study

a natural history study is a non-interventional (observational) study intended to track the course of the disease for purposes such as identifying demographic, genetic, environmental, and other (e.g., treatment) variables that correlate with disease development and outcomes. Natural history studies are likely to include patients receiving the current standard of care and/or emergent care, which may alter some manifestations of the disease. Disease registries are common platforms to acquire the data for natural history studies.

Externally controlled trial

An externally controlled trial, as one type of clinical trial, compares outcomes in a group of participants receiving the test treatment with outcomes in a group external to the trial, rather than to an internal control group from the same trial population assigned to a different treatment. The external control arm can be a group, treated or untreated, from an earlier time (historical control) or a group, treated or untreated, during the same time period (concurrent control) but in another setting.

Further Reading: 

• FDA guidance for industry "Rare Diseases: Natural History Studies for Drug Development"
• FDA guidance for industry "Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products"
• EMA "Guideline on registry-based studies"
• AHRP "Registries for Evaluating PatientOutcomes:A User’s Guide"
• PCORI "Standards in the Conduct of RegistryStudies for Patient-Centered OutcomesResearch" 
• CTTI: Registry Trials
• Clinical Trials vs Registries