Observational PMCF Study

In a Prospective PMCF Study

The assignment to an exposure/treatment was already made by the physician and is the basis for the inclusion of the population of interest into the clinical investigation. After the subject signed the informed consent form, medical history, treatment and outcome data are collected from that point forward.

The start of the study is defined as the time the clinical investigation plan (CIP) for the specific questions to be answered by the clinical investigations is initiated. Observational clinical investigations might be another way to generate Real-World Evidence (RWE) relevant to effectiveness determinations. Therefore, the RWE Program will also consider the evaluation of observational clinical studies using Real-World Data (RWD) to support product effectiveness determinations.

Retrospective Observational PMCF Study

Retrospective observational PMCF studies, or cohort reviews, use data already collected by the institution and documented in medical records of subjects meeting specified exposure criteria.

Advantages and Challenges

The advantage of setting up a retrospective observational clinical investigation is being less prone to patchy subject compliance than patient surveys but remains susceptible to positive selection bias unless the methodology prevents that. Eliminating bias entirely from retrospective reviews is challenging, requiring strict controls on data collection methods.

5 Tips to Implementing a Valid Retrospective Medical Device PMCF Study

Limitations and When to Choose a Retrospective PMCF Study

Implementing a retrospective study requires the sponsor to have identified the centres that host the clinical data needed. The willingness of the investigator to be part of the study and the absence of competitors running studies simultaneously in the same centres are critical factors.

Feasibility Assessment

When considering a retrospective study, it is recommended to implement a feasibility study in one centre to evaluate if the study design is adequate to the research question. For example, for vascular prostheses, long-term safety evidence requires follow-up data over three years. If the sponsor is looking to generate evidence of long-term safety using a retrospective study, knowing that long-term data follow-up will not exist in the hospital data warehouse, this becomes problematic. In practice, the protocol post-operation on follow-up for vascular prostheses is limited to three months if there is no serious complication.

Data Quality and Statistical Power

Another limitation is the quality of the data and the data gaps you might identify at the end of the research, which will reduce the quality of the study and the statistical power. Additionally, the site and population need to be representative to limit the biases of the study. If one site includes more than 50% of patients compared to the other centres, the quality and the evidence will be impacted.

Current Frameworks and Guidance Documents on RWE and PROs

Regulatory Authority	Guidance Document	Focus Area
European Medicines Agency (EMA)	Guideline on Registry-Based Studies (Sep 2020)	Focuses on studies based on disease or condition registries to examine the use, safety and effectiveness of medicines. Outlines regulatory considerations for establishment and management of patient registries.
EMA	Use of Patient Disease Registries (Nov 2018)	Discusses methodological and operational aspects of patient disease registries and registry studies for regulatory purposes.
MHRA (UK)	Guidance on Real-World Data in Clinical Studies	Provides guidance on the use of real-world data in clinical studies to support regulatory decisions. Focus on medicines with applicable principles for devices.
MHRA	RCT Using Real-World Data	Aimed at sponsors planning to conduct an RCT using RWD for medicinal products. Some applicable principles for devices.
FDA (USA)	Submitting Documents Using RWD and RWE (May 2019)	Encourages applicants using RWD/RWE to provide information in a simple, uniform format for regulatory submissions.
FDA	Rare Diseases: Natural History Studies (Mar 2019)	Describes the broad potential uses of natural history studies in all phases of drug development for rare diseases, with practical frameworks for conduct.
FDA	Framework for FDA's RWE Program (Dec 2018)	Clarifies definitions and establishes a 3-part approach for evaluating RWE: fit for use, adequate scientific evidence, and FDA requirements compliance.
FDA	Use of RWE to Support Regulatory Decision-Making for Medical Devices (Aug 2017)	Clarifies how FDA evaluates real-world data to determine sufficiency for generating real-world evidence for medical device regulatory decisions.
FDA	Use of Electronic Health Record Data (Jul 2018)	Assists sponsors and clinical investigators on the use of electronic health record data in FDA-regulated clinical investigations.
Health Canada	Framework: Optimizing RWE (April 2019)	Invites industry submissions using high-quality RWE for expanded indications, rare diseases, and unfeasible or unethical clinical trials.
Health Canada	RWD/E Quality Throughout Product Life Cycle (Mar 2019)	Provides overarching principles for generating real-world evidence consistent with regulatory standards, including protocol development guidance.
Health Canada	RWE Strategy for Medical Device Life Cycle (Mar 2020)	Sets out a strategy to improve accessibility, affordability and appropriate use of medical devices through optimisation of RWE across the device life cycle.