Real World Research (RWR) Regulatory Definitions

A Complex Confusion of Country-Specific Terms and Definitions…That All Mean the Same Thing…Almost

Compared to the ‘maturity’ of clinical trial legislation, which fundamentally traces its global harmonisation from the 1996 publication of ICH GCP…Real-World Research (RWR) is still in its ‘legislative’ infancy…which is why there is currently no single recognised ‘book of terms and definitions’ or glossary. Each country creates their own terms, or borrows and adapts from other countries.

The result? A complex confusion of country-specific terms and definitions…that all mean the same thing…Almost!

From a regulatory compliance perspective, it’s important to remove the ‘white noise’ of the methodological and study design terminology and focus on the regulatory terms, definitions and classification for each of the countries you plan to conduct your study in.

The following table summarises some of the regulatory definitions/ calssifications of real-world studies you will come across in the context of real-world research as you travel the world.

Page: RWR Regulatory Definitions

Regulatory Definitions and Classifications of Real-World Research Studies

wdt_ID Study Type Details Country/ Region Reference/ Source
1 Non-Interventional Study (NIS) {EU-CTD Definition} A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data (as per Article 2(c) of Directive 2001/20/EC) Europe
2 Low-Intervention Clinical Trial (LICT) ‘Low-intervention clinical trial’ means a clinical trial which fulfils all of the following conditions:
(a) the investigational medicinal products, excluding placebos, are authorised;
(b) according to the protocol of the clinical trial,
(i) the investigational medicinal products are used in accordance with the terms of the marketing authorisa­tion; or
(ii) the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and
(c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned
(as per Article 2.2(3) of Regulation EU/536/2014)
3 Non-Interventional Study (NIS) {EU-CTR Definition} ‘Non-interventional study’ means a clinical study other than a clinical trial
(as per Article 2.2(5) of Regulation EU/536/2014)
4 Clinical Study ‘Clinical study’ means any investigation in relation to humans intended:
(a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products;
(b) to identify any adverse reactions to one or more medicinal products; or
(c) to study the absorption, distribution, metabolism and excretion of one or more medicinal products;
with the objective of ascertaining the safety and/or efficacy of those medicinal product
(as per Article 2.2(1) of Regulation EU/536/2014)
5 Observational Study A non-interventional clinical study design that is not considered a clinical trial (as per FDA – Framework for Real World Evidence Program, Dec 2018) USA
6 Patient Registry An organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure and that serves one or more predetermined scientific, clinical, or policy purpose. Registries are generally defined either by diagnosis of a disease (disease registry) or usage of a drug, device, or other treatment (exposure registry) (as per FDA – Framework for Real World Evidence Program, Dec 2018) USA
7 Observational Study A type of clinical study in which participants are identified as belonging to study groups and are assessed for biomedical or health outcomes. Participants may receive diagnostic, therapeutic, or other types of interventions, but the investigator does not assign participants to a specific interventions/treatment. A patient registry is a type of observational study (as per Glossary) USA
8 Clinical Study Clinical trials are any prospective investigations in which the applicant or investigator determines the method of assigning the drug product(s) or other interventions to one or more human subjects.

Studies are all other investigations, such as investigations with humans that are not clinical trials as defined above (e.g., observational epidemiologic studies), animal studies, and laboratory experiments (as per FDA Guidance on Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act, April 2011)
9 Human Subjects Research Project The term "human subjects research project" means a research project specified by Ordinance of the Minister of Health and Welfare, such as a research project physically involving a human being as a subject, a research project conducted through communication, physical contact or other means of interaction, a research project conducted by using information with which individuals can be identified [1]

"Research prescribed by Ordinance of the Ministry of Health and Welfare" means the study of each of the following items [2]:
(i) Research involving physical intervention in humans: Research to obtain data by directly manipulating the research subject or by manipulating the environment of the research subject
(ii) Research conducted through interactions such as communication and interpersonal contact: a study that obtains data through behavioral observations and face-to-face surveys of research subjects
(iii) Research using personally identifiable information: Research using information that can directly and indirectly identify the research subject
[1] Article 2.1 of the Bioethics and Safety Act
[2] Article 2 of the Enforcement Rules of the Bioethics and Safety Act (2019)
South Korea
10 Post-Market Surveillance The term “Post-marketing Surveillance (PMS)” means a surveillance that the marketing authorization holder conducts during the re-examination period, such as the use-result surveillance, special surveillance and post-marketing clinical trial, etc. in order to collect, review, confirm, or verify the information regarding the safety, efficacy and the necessary information for the appropriate use of pharmaceutical drugs requiring the re-examination in accordance with Articles 32 and 42 (5) of the PA South Korea
Study Type Details Country/ Region Reference/ Source