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.
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 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.