Non-interventional Clinical Studies

For interventional clinical trials, there are clear regulatory guidelines to govern the development of the study protocol, the conduct of the study, and the layout of the clinical study report. The requirements for clinical study protocol are specified in ICH E6 (Guideline for Good Clinical Practice) and for clinical study report are specified in ICH E3 (Structure and Contents of Clinical Study Reports).

However, there are also non-interventional clinical studies such as Post-Marketing Surveillance (PMS), Post Authorization Safety Study (PASS), Pharmacovigilence study, Pharmacoepidemiologic Study, Drug utilization study, Retrospective and Prospective registry studies. They are clinical studies because the patient information is collected from various clinical sites. They are non-interventional because the sponsor does not provide the study drug and provide no specific requirements how the patients should be treated. The regulatory guidelines for this type of non-interventional clinical studies can sometimes be vague and not as clear as those for clinical trials. The ICH guidelines that were developed for clinical trials may not all be applicable to this type of non-interventional clinical studies.

Post-Marketing Surveillance (PMS) studies are non-interventional, observational, post-authorization studies where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorization (i.e. no study medication). The assignment of the patient to a particular therapeutic strategy is not decided in advance by the 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.

Post Authorization Safety Study (PASS) in EU: A post-authorization safety study (PASS) is defined in Directive 2001/83/EC (DIR) Art 1(15) as any study relating to an authorized medicinal product conducted with the aim of identifying, characterizing or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.

Pharmacoepidemiology study: A pharmacoepidemiology study applies epidemiological methods to studies of the clinical use of drugs in populations. A modern definition of pharmacoepidemiology is: «the study of the use and effects/side-effects of drugs in large numbers of people with the purpose of supporting the rational and cost-effective use of drugs in the population thereby improving health outcomes».

Drug utilization research: drug utilization study was defined by WHO in 1977 as «the marketing, distribution, prescription, and use of drugs in a society, with special emphasis on the resulting medical, social and economic consequences». Since then, a number of other terms have come into use and it is important to understand the interrelationships of the different domains.

Pharmacovigilance are terms used to refer to the monitoring of drug safety, for example, by means of spontaneous adverse-effect reporting systems, case-control and cohort studies.

Retrospective Registry: A retrospective study uses information on events that have taken place in the past. In most cases some or most of the data has already been gathered and stored in the registry. However and also in most cases, new data, but always on past events, may have to be requested. The data collection is typically through the medical charter review

Non interventional prospective studies: Non interventional prospective studies are prospective studies which are set up to investigate events that will take place after the study has been initiated. Post-marketing surveillance study may fall into this category. The main and very important difference between a clinical trial and a non interventional prospective study is that the data collection or patient-participation in the non interventional study does not interfere with the choice of treatment, sample collection, procedures, and the treatment itself, which should entirely follow standard hospital practices. Typically a non interventional prospective study behaves like a “fly on the wall” and will aim to collect information on how different centres deal with the same problem or type of patient. A non interventional prospective protocol cannot in any way set up conditions modifying either the treatment of the patient or the number or type of investigations the patients needs to be subjected to. It excludes the possibility of determining which treatment protocol should be used, randomiation or other types of patient allocation to a specific treatment, specified sample collection schedules, or collection of additional samples not included in the center’s routine procedures.

In terms of the elements required for the study protocol and the study report, there are different guidelines than the clinical trials. For PASS study, EMA: Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies  should be followed for developing the study protocol and the study report. There are also recommendations on data collection, data quality, data analysis.

For general pharmacoepidemilogy studies, International Society of Pharmacoepidemiology: Guidelines for Good Pharmacoepidemiology Practices (GPP)  should be followed.

In the United States, the most relevant guidance is Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment and E2E Pharmacovigilance Planning which is mainly focusing on the post-marketing data collection on adverse events or adverse drug reactions.

The recent passed PDUFA V also emphasize the importance of pharmacovigilance:

 C. Conduct and support activities designed to modernize the process ofpharmacovigilance
1. Continued use of expanded database resources: A critical part of the
transformation of the drug safety program is maximizing the usefulness of
tools used for adverse event signal detection and risk assessment. Use of data
other than passive spontaneous reports, including population-based
epidemiological data and other types of observational data resources will
continue to enhance FDA’s capability to conduct targeted post-marketing
surveillance, evaluate class effects of drugs, and potentially conduct signal
detection using data resources other than reports from the Adverse Event
Reporting System (AERS).  FDA will continue training and development of
existing staff on the use of these resources, and develop the information
technology infrastructure needed to support access and analysis of data from
these resources.