EU Clinical Trials NIS Definition
A non-interventional study is a study fulfilling cumulatively the following requirements:
- The medicinal product is 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; and
- No additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data.
Non-interventional studies are defined by the methodological approach used and not by the scientific objectives. Non-interventional studies include database research or review of records where all the events of interest have already happened (e.g. case-control, cross-sectional and cohort studies). Non-interventional studies also include those involving primary data collection (e.g. prospective observational studies and registries in which the data collected derive from routine clinical care), provided that the conditions set out above are met.
In this context, interviews, questionnaires and blood samples may be performed as normal clinical practice.
(as per Annex I of the EMA Guideline on good pharmacovigilance practices (GVP), 2012 )
Post-Authorisation Safety Study (PASS)
Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures (Article 1(c)(15) of 2001/83/EC as amended by Directive 2010/84/EU )
A post-authorisation study should be classified as a PASS when the study includes any of the following objectives:
- to quantify potential or identified risks, e.g. to characterise the incidence rate, estimate the rate ratio or rate difference in comparison to a non-exposed population or a population exposed to another drug or class of drugs, and investigate risk factors and effect modifiers;
- to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (e.g. pregnant women, specific age groups, patients with renal or hepatic impairment);
- to provide evidence about the absence of risks;
- to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (e.g. indication, dosage, co-medication, medication errors);
- to measure the effectiveness of a risk minimisation activity.
(as per Section VIII.B.3 of the EMA Guideline on good pharmacovigilance practices (GVP), 2012 )
PASS Study Designs
Post-authorisation safety studies may adopt different designs depending on their objectives. A brief description of the main types of studies, as well as the types of data resources available, is provided hereafter. However, this Appendix is not intended to be exhaustive and should be complemented with other information sources, such as the ENCePP Guide for Methodological Standards (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Active surveillance, in contrast to passive surveillance, seeks to ascertain more completely the number of adverse events in a given population via a continuous organised process. An example of active surveillance is the follow-up of patients treated with a particular medicinal product through a risk management system. Patients who fill a prescription for this product may be asked to complete a brief survey form and give permission for later contact. In general, it is more feasible to get comprehensive data on individual adverse event reports through an active surveillance system than through a passive reporting system. Automatic detection of abnormal laboratory values from computerised laboratory reports in certain clinical settings may also provide an efficient active surveillance system (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Intensive Monitoring Schemes
Intensive monitoring is a system of record collation in designated areas, e.g. hospital units or by specific healthcare professionals in community practice. In such cases, the data collection may be undertaken by monitors who attend ward rounds, where they gather information concerning undesirable or unintended events thought by the attending physician to be causally related to the medication. Monitoring may also be focused on certain major events that tend to be drug-related such as jaundice, renal failure, haematological disorders, bleeding. The major strength of such systems is that the monitors may document important information about the events and exposure to medicinal products. The major limitation is the need to maintain a trained monitoring team over time (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Intensive monitoring may be achieved by reviewing medical records or interviewing patients and/or physicians/pharmacists in a sample of sentinel sites to ensure complete and accurate data on reported adverse events. The selected sites may provide information, such as data from specific patient subgroups that would not be available in a passive spontaneous reporting system. Further, collection of information on the use of a medicinal product, such as the potential for abuse, may be targeted at selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with selection bias, small numbers of patients, and increased costs. Intensive monitoring with sentinel sites is most efficient for those medicinal products used mainly in institutional settings such as hospitals, nursing homes, and haemodialysis centres. Institutional settings may have a greater frequency of use for certain products and may provide an infrastructure for dedicated reporting. In addition, automatic detection of abnormal laboratory values from computerised laboratory reports in certain clinical settings may provide an efficient active surveillance system (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Prescription Event Monitoring
In prescription event monitoring, patients may be identified from electronic prescription data or automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or patient at pre-specified intervals to obtain outcome information. Information on patient demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical events, and reasons for discontinuation can be included in the questionnaire [VIII.App 1. References 6-7]. Limitations of prescription event monitoring include incomplete physician response and limited scope to study products which are used exclusively in hospitals. More detailed information on adverse events from a large number of physicians and/or patients may be collected (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Post-Authorisation Efficacy Study (PAES)
Any study conducted where concerns relating to some aspects of the efficacy of the medicinal product are identified and can only be resolved after the medicinal product has been marketed (Article 21(a) of 2001/83/EC as amended by Directive 2010/84/EU )
Pre-authorisation term used when determining whether an investigational medicinal product will work
Post-authorisation term used when determining whether a drug or treatment works in real-world terms
European (EMA) Definition
An organised system that uses observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition or exposure (as per Annex I of the EMA Guideline on Good Pharmacovigilance Practices (GVP) - July 2012 )
Disease/outcome registries, such as registries for blood dyscrasias, severe cutaneous reactions, or congenital malformations may help collect data on drug exposure and other factors associated with a clinical condition. A disease registry might also be used as a base for a case-control study comparing the drug exposure of cases identified from the registry and controls selected from either patients within the registry with another condition or from outside the registry, or for a case-only design (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Exposure registries address populations exposed to medicinal products of interest (e.g. registry of rheumatoid arthritis patients exposed to biological therapies) to determine if a medicinal product has a special impact on this group of patients. Some exposure registries address exposures to medicinal products in specific populations, such as pregnant women. Patients may be followed over time and included in a cohort study to collect data on adverse events using standardised questionnaires. Simple cohort studies may measure incidence, but, without a comparison group, cannot evaluate any association between exposures and outcomes. Nonetheless, they may be useful for signal amplification particularly for rare outcomes. This type of registry may be very valuable when examining the safety of an orphan drug indicated for a specific condition (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
US (FDA) Definition
An organized system for the collection, storage, retrieval, analysis, and dissemination of information on individual persons exposed to a specific medical intervention who have either a particular disease, a condition (e.g., a risk factor) that predisposes [them] to the occurrence of a health-related event, or prior exposure to substances (or circumstances) known or suspected to cause adverse health effects. Whenever possible, a control group or comparison group should be included, (i.e., individuals with a disease or risk factor who are not treated or exposed to medical interventions other than the intervention of interest) (as per Section V.B of the FDA Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment - March 2005 )
Sponsors electing to initiate a registry should develop written protocols that provide:
- Objectives of the registry
- A review of the literature, and
- A summary of relevant animal and human data
FDA suggest that protocols also contain detailed descriptions of:
- Plans for systematic patient recruitment and follow-up
- Methods for data collection, management and analysis, and
- Conditions under which the registry will be terminated
Monitoring of Registries
A registry-based monitoring system should include carefully designed data collection forms to ensure data quality, integrity, and validation of registry findings against a sample of medical records or through interviews with healthcare providers.
Design of Registries
FDA recommends that the size of the registry and the period during which data will be collected be consistent with the safety questions under study and encourage sponsors to discuss their registry development plans with FDA.
Traditional epidemiological methods are a key component in the evaluation of adverse events. There are a number of observational study designs that are useful in validating signals from spontaneous reports, active surveillance programmes or case series. Major types of these designs are cross-sectional studies, case-control studies, and cohort studies, based on primary data collection or secondary use of existing data (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Cross-Sectional Study (Survey)
Data collected on a population of patients at a single point in time (or interval of time) regardless of exposure or disease status constitute a cross-sectional study. These types of studies are primarily used to gather data for surveys or for ecological analyses. A drawback of cross-sectional studies is that the temporal relationship between exposure and outcome cannot be directly addressed, which limits its use for etiologic research unless the exposures do not change over time. These studies are best used to examine the prevalence of a disease at one time-point or to examine trends over time, when data for serial time-points can be captured. These studies may also be used to examine the crude association between exposure and outcome in ecologic analyses (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
In a cohort study, a population-at-risk for an event of interest is followed over time for the occurrence of that event. Information on exposure status is known throughout the follow-up period for each patient. A patient might be exposed to a medicinal product at one time during follow-up, but non-exposed at another time point. Since the population exposure during follow-up is known, incidence rates can be calculated. In many cohort studies involving exposure to medicinal product(s), comparison cohorts of interest are selected on the basis of medication use and followed over time. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. Multiple adverse events may also be investigated using the same data source in a cohort study. However, it may be difficult to recruit sufficient numbers of patients who are exposed to a product of interest (such as an orphan drug) or to study very rare outcomes. The identification of patients for cohort studies may come from large automated databases or from data collected specifically for the study at hand. In addition, cohort studies may be used to examine safety concerns in special populations (the elderly, children, patients with co-morbid conditions, pregnant women) through over-sampling of these patients or by stratifying the cohort if sufficient numbers of patients exist (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
In a case-control study, cases of disease (or events) are identified and patients without the disease or event of interest at the time of selection, are then selected as controls from the source population that gave rise to the cases. The exposure status of the two groups is then compared using the odds ratio, which is an estimate of the relative risk of disease among the exposed as compared to the non-exposed. Patients may be identified from an existing database or using data collected specifically for the purpose of the study of interest. If safety information is sought for special populations, the cases and controls may be stratified according to the population of interest (the elderly, children, pregnant women, etc.). Existing large population-based databases are a useful and efficient means of providing needed exposure and medical outcome data in a relatively short period of time. Case-control studies are particularly useful when the goal is to investigate whether there is an association between a medicinal product (or products) and one specific rare adverse event, as well as to identify risk factors for adverse events (or actually, effect-modifiers). Risk factors may include conditions such as renal and hepatic dysfunction, which might modify the relationship between the drug exposure and the adverse event. Under specific conditions, a case-control study may also provide the absolute incidence rate of the event. If all cases of interest (or a well-defined fraction of cases) in the catchment area are captured and the fraction of controls from the source population is known, an incidence rate can be calculated (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
When the source population for the case-control study is a well-defined cohort, it is then possible to select a random sample from it to form the control series. The name “nested case-control study” has been coined to designate those studies in which the control sampling is density-based (e.g. the control series represents the person-time distribution of exposure in the source population). The case-cohort is also a variant in which the control sampling is performed on those persons who make up the source population regardless of the duration of time they may have contributed to it (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
A case-control approach could also be set up as a permanent scheme to identify and quantify risks (case-control surveillance). This strategy has been followed for rare diseases with a relevant aetiology fraction attributed to medicinal products, including blood dyscrasias or serious skin disorders (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Other designs have been proposed to assess the association between intermittent exposures and short-term events, including the self-controlled case-series, the case-crossover and the case-time-control studies. In these designs, only cases are used and the control information is obtained from past person-time experience of the cases themselves. One of the important strengths of these designs is that those confounding variables that do not change within individuals are automatically matched (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Drug Utilisation Studies (DUS)
Drug utilisation studies (DUS) describe how a medicinal product is, prescribed and used in routine clinical practice in large populations, including elderly patients, children, pregnant women or patients with hepatic or renal dysfunction, who are often excluded by randomized clinical trials. Stratification by age, gender, concomitant medication and other characteristics allows a comprehensive characterization of treated patients, including the distribution of those factors that may influence clinical, social, and economic outcomes. From these studies, denominator data may be derived for use in determining rates of adverse reactions. DUS have been used to describe the effect of regulatory actions and media attention on the use of medicinal products, as well as to develop estimates of the economic burden of adverse reactions. DUS may be used to examine the relationship between recommended and actual clinical practice. These studies may help to monitor use in everyday medical practice and medication error and to determine whether a medicinal product has potential for abuse by examining whether patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat prescribing (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Pharmacoepidemiological studies may be performed using a variety of data sources. Traditionally, field studies were required for retrieving the necessary data on exposure, outcomes, potential confounders and other variables, through interview of appropriate subjects (e.g. patients, relatives) or by consulting the paper-based medical records. However, the advent of automated healthcare databases has remarkably increased the efficiency of pharmacoepidemiologic research. There are two main types of automated databases, those that contain comprehensive medical information, including prescriptions, diagnosis, referral letters and discharge reports, and those mainly created for administrative purposes, which require a record-linkage between pharmacy claims and medical claims databases. These datasets may include millions of patients and allow for large studies. They may not have the detailed and accurate information needed for some research, such as validated diagnostic information or laboratory data, and paper-based medical records should be consulted to ascertain and validate test results and medical diagnoses. Depending on the outcome of interest, the validation may require either a case-by-case approach or just the review of a random sample of cases. Other key aspects may require validation where appropriate. There are many databases in place for potential use in pharmacoepidemiological studies or in their validation phase (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Marketing authorisation holders should select the best data source according to validity (e.g. completeness of relevant information, possibility of outcome validation) and efficiency criteria (e.g. time span to provide results). External validity should also be taken into account. As far as feasible the data source chosen to perform the study should include the population in which the safety concern has been raised. In case another population is involved, the marketing authorisation holder should evaluate the differences that may exist in the relevant variables (e.g. age, sex, pattern of use of the medicinal product) and the potential impact on the results. In the statistical analysis, the potential effect of modification of such variables should be explored (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
With any data source used, the privacy and confidentiality regulations that apply to personal data should be followed (as per Appendix 1 of EMA GVP Module VIII - July 2012 ).
Summary of Product Characteristics (SmPC)
Part of the marketing authorisation of a medicinal product setting out the agreed position of the product as distilled during the course of the assessment process which includes the information described in Article 11 of Directive 2001/83/EC. It is the basis of information for healthcare professionals on how to use the product safely and effectively. The package leaflet is drawn in accordance with the summary of product characteristics (based on A Guideline on Summary of Product Characteristics, Volume 2C of the Rules Governing Medicinal Products in the EU) (as per Annex I of the EMA Guideline on Good Pharmacovigilance Practices (GVP) - July 2012 )