Registries

A registry according to the US FDA is - 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 that predisposes to the occurrence of a health related event or prior exposure to substances or circumstances known or suspected to cause adverse health effects. The creation and analysis of registries is particularly useful for examining outcome information not available in large automated databases from multiple sources. The collection of spontaneous case reports either reported or published detailing specific adverse effects are among the common application of registries and is commonly used to complement signal detection by national PV centers.

4.3.3 Surveys

Surveys such as questionnaire studies are being increasingly used as a tool in PV. Surveys are frequently used to gather and assess information on various issues such as:

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1. Evaluating a safety signal

2. Evaluating knowledge about adverse reactions, AEs and various other knowledge and attitudes of/towards PV among health practitioners and the public [137, 138].

3. Assess the use of products/drugs in regards to safety, efficacy, quality and adherence to guidelines.

4. Gathering information or data regarding a specific area of interest.

Surveys are subject to a number of biases and confounding factors, with low participation being their main weakness. Various methods are used to encourage participation including payment or providing certain benefits for respondents; however this practice in itself may lead to bias and could be ethically challenging. Surveys are best validated or piloted before implementation to give credence and an idea of what to expect, as well as to identify any shortcomings that may need to be addressed. A well planned and piloted survey will often yield high-quality results.

4.4 Discussion

In this chapter we have summarized a structured framework approach proposed by the Cochrane AEMG [47], for conducting systematic reviews that include harms. In this framework, the starting point for structuring the review is determined entirely by the scope of research question: a broad overview of safety problems associated with the drug (‘hypothesis generating’), or to evaluate the magnitude of risk and clarify the characteristics of the adverse effect (‘hypothesis testing/strengthening’). Each of these approaches requires

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careful consideration to determine which study designs and data sources to include in the systematic review.

Systematic reviews of RCTs to assess harms are usually most common. However RCTs are usually insufficiently powered, or too brief, to detect rare but serious adverse effects or modest but important increases in the risk of common disease outcomes that can have a major population impact in absolute terms. Most RCTs also tend to exclude the elderly, patients with co-morbidity or pregnancy, and this reduces the generalizability of these data. Therefore, at the time of product launch, there are often limited harms data of any new drug, in both the short- and longer-term which is directly applicable to that of the target population. Drugs in use therefore need to remain under constant surveillance (Post- marketing) and studied by observation in PV systems to identify safety signals and thus serve to generate hypothesis. PV systems however possess many strengths and weaknesses as summarized in Table 14.

Spontaneous reporting is the principle PV system in use worldwide with proven effectiveness and a good track record resulting in the avoidance of many potential disasters and the identification of new or previously unknown drug related adverse effects. They encompass the main advantages including a wide population, relatively low costs and resource utilization, and well established methodology. However spontaneous reporting systems depend on voluntary reporting of health care professionals, hence the reporting rate or under- reporting rate becomes the limiting factor.

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Table 14: Key strengths and limitations for each PV system.

Type Passive systems Active systems Heath databases

Key Strengths

Proven with good track record Wide population coverage

National PV reporting

mechanism for most countries.

Relatively easy to implement Low resource utilization and cost Covers all

population, drugs and health settings

Does not depend upon voluntary reporting-able to capture high incidence of harms Able to shorten lag time from marketing of drug to detection of new ADR Provide a numerator and denominator Proven with good track record

Contains huge amounts of health data with wide population coverage- considerable statistical power

Does not depend on voluntary reporting – able to capture high incidence of ADRs

Data are frequently update and validated

Maybe able to follow through to secondary care if data linkage is available Low resource and cost requirement once setup

Limitations

Depends on voluntary reporting Reporting rate is very low even in developed countries Does not provide a denominator Long lag time between marketing of drug to detection of new ADR

High resource and cost requirement Implementation limited to selected drugs only

Population selection bias and conceal bias of doctors reporting may occur Validation mechanism is unclear/difficult

Utilization is relatively new and not proven

Implementation is not possible if national large health databases is not available

Incomplete information input by data managers Does not cover

population/drugs/setting where information is not collected

High cost to access data

To help overcome the limitations of spontaneous reporting, active systems have been introduced. Among the main active system in the UK is the M-PEM, which requires participation by healthcare professionals, although participation is encouraged by providing payments to reporters. Therein lies the main weakness

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of M-PEM, the high cost and resource required for implementation. Monitoring a single drug using M-PEM requires tens of thousands of green forms to be sent out to GPs, and the cost can therefore be considerable. Therefore, M-PEM has to carefully select drugs which it intends to monitor or investigate, thus limiting its usefulness as a fully-fledged PV system.

The advent of large anonymized health databases brings forth other possible systems. The arrival of more comprehensive patient health databases containing individual demographic data, health records, prescription records and even laboratory results and other associated health information have increased the usefulness of these data sets for PV purposes. The use of health databases is not only confined to just hypothesis generation, but also hypothesis testing. With promise of huge population coverage, complete prescribing and health event records from UK primary care practices and hospitals, quick access to information, the elimination of voluntary reporting by health professionals and low cost. It is easy to see why many are excited and hopeful for the use of health databases for PV, with examples in the past of studies using data from the CPRD/GPRD to inform regulatory decisions [139]. In many cases, such studies have provided reassurance about the safety of medicines, though studies are also used to triage safety signals identified through spontaneous reporting schemes by providing ready background incidence rates of diseases and drug exposure (denominator) data. Health databases are still in its infancy with many deficiencies including validation of data, linkage between databases, cost of public accessing the data, and the privacy of data which needs to be ironed out.

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In the past decade, development in the field of PV has progressed tremendously with many governments highlighting it as a priority area. There is recognition that early identification of unknown serious adverse reactions for all drugs is impossible, adverse reactions cause high morbidity and mortality, represent a burden to the national cost of healthcare and continuous monitoring for adverse effects for all drugs is essential. A recent study [140] was conducted to determine the nature of evidence used to support the withdrawal of marketing authorization of drug products for safety reasons throughout the EU between 2002 and 2011. The study reports that the level of evidence used to support drug withdrawal has improved during the past 10 years, with an increased use of case-control studies, cohort studies, RCTs and meta-analysis. The research demonstrates that such studies have contributed to decision-making in almost two-thirds of cases. Previously, only one-third of decisions used evidence from observational studies or clinical trials [141].

There is also recognition of the many limitations of current PV monitoring systems that must be improved. Among the main issues for current PV systems are; 1) Increase coverage of population (including special populations such as children and the elderly) and drugs monitored, 2) Reduced cost and resource requirements, 3) Increased participation from health professionals, 4) Reduction in the lag time between drug launch, detection of adverse effects and the issue of appropriate warnings or appropriate regulatory actions, and 5) overlap between databases. In Europe, the Eudravigilance system consists of one common electronic reporting point within the EU that is advanced. This

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harmonized system is compliant with ICH E2 standards. The advantage of this system is the ease of use and fast reporting (pre and post-authorization) mechanisms both from reporters, but also between health authorities. Unfortunately, despite significant globalization of pharmaceutical companies and many of the same drugs being available in the main territories, harms data including SUSARs are not shared routinely between territories. Further efforts are needed to improve access to such systems like the Eudravigilance.

Pharmacovigilance will not function without a good monitoring system or available data sources, and will lose its effectiveness with long lag times and will not be feasible if the cost and resources required are too high. Consequently, in spite of more than 50 years of PV, efforts are still currently in place to improve upon existing systems and to develop new systems. Weaknesses in PV systems are being addressed with encouragement from national monitoring bodies. Developments to address a deficiency in a PV system frequently generate further new issues. Creating the perfect PV system may not be possible, however new systems must continue to be developed and improvements upon the current ones in place to reduce the recognized limitations and deficiencies when detecting harms in the future.

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Chapter 5: A Survey of current