Archive for the ‘PSURs’ Category

A discussion of the advantages and disadvantages of the different methods used in pharmacovigilance.

Wednesday, October 17th, 2012

Medicines should fulfill the aspects of quality, safety and efficacy. The objectives of obtaining pharmacovigilance data are to improve patient care and safety, to improve public health and safety in relation to the use of medicines, to contribute to the assessment of benefit, harm, effectiveness and risk of medicines, to encourage their safe, rational and more effective use by identify signals of previously unidentified adverse reactions to medicines, to promptly identifying events that are likely to affect adherence to treatment and to determine their rates and the risk factors that make these events more likely. It is important to be able to estimate rates of events so that risk can be measured and informed decisions can be made regarding appropriate treatments where comparables exist, whilst considering the risks they carry. There is relatively little data available regarding the safety of medicines in pregnancy or lactation, nor indeed in paediatric populations, so data obtained in these subgroups is extremely valuable.

Case reports are often the main source of information from which data is derived to trigger the withdrawal of a drug from the market for safety reasons. However, in order to have quality evidence to support such decisions, it is necessary to improve the volumes of reports received. More and more focus is being placed on pharmacovigilance, and over the last few years this has driven change for example via policies on risk management plans, and also by pharma companies via pharmacogenomics in development programs. More efforts are now being placed on predicting risk, rather than minimising negative outcomes in a reactive manner. This move is very promising and in order to ensure a consistent approach for both pre-marketing and post-marketing pharmacovigilance activities, companies are beginning to incorporate risk management planning at the inception of Phase I and to consider consolidating both their pre- and post-marketing pharmacovigilance activities into a single department.

The method of monitoring of trials should be carefully chosen and should reflect the requirements of the study. Monitoring can involve cohort event monitoring, spontaneous reporting and special phase IV studies or post marketing surveillance studies. The phase of the drug in its lifecycle will often determine the post appropriate method. For example, a new chemical entity at pre-marketing authorisation stage should be subjected to clinical trials and at this stage all suspected unexpected serious adverse reactions (SUSARs) are reported. The sponsor is obliged to report such events to the concerned member state, the ethics committees and via the Eudravigilance system electronically.(1) Post receipt of marketing authorisation, adverse reports are required to be submitted as “Individual Case Safety Reports” (ICSRs) within specified timelines. A serious unexpected ADR must be reported within 10 working days of receipt. (2) Post-marketing surveillance is very important, because the safety database for newly licensed drugs is limited by both the number and characteristics of the patients involved.(3) Periodic safety update reports (PSURs) are required from marketing authorisation holders to be submitted to the competent authorities as per the timescale applicable to the active and drug in questions. These consist of non-serious, serious, not related and deaths.(4) Unfortunately, in reality, no one method can be relied upon for global signal detection, but rather they all complement each other in building the bigger picture.

Randomised clinical trials cannot provide an adequate safety profile; they are short-term studies with often short comings when it comes to recording delayed reactions, withdrawal effects, changes in death rates, dose variations, data on women and in unlabelled use. Trials are generally not designed for the purpose of assessing adverse events. Premarketing clinical trials include too few patients and are too short to detect every outcome that will affect public health and individual patient safety. In addition, clinical trials are carried out in controlled settings that differ from real world practice. This reduces their power to detect ADRs, such as those that are due to drug-drug interactions or that affect only susceptible subgroups. Safety needs to be evaluated continuously throughout the life-cycle of a medicinal product and adverse event data derived from such clinical trials may suggest that further research on adverse events is worthwhile. For this reason, a study cohort may be chosen with variables. Where cohort event monitoring is selected as the principal means of monitoring, there are distinct advantages to encouraging spontaneous reporting also. Contemporaneous cohorts of other medications may provide some kind of control, but the lack of specially selected controls is a drawback in both determining causality and attributable risk. Coding strategies may obscure outcomes, as they may with ICSRs. However, the advantages of cohort monitoring outnumber any disadvantages and include the fact that it data can be used to derive rates of adverse events, to obtain an adverse event profile for the medicine, to identify early signals and to characterise adverse events in relation to age, sex and duration to onset and thus produce risk factors. This may lead to the collection of other relevant data, such as weight, or co-morbidity, to enable other risk factors to be determined. The disadvantages are due to this method being more labour intensive and more costly than spontaneous reporting. Cohort event monitoring allows for a different capture of events which may or may not be medication related. As such, unusual clinical events may be found to have a relationship to a medication, which might not be obvious to the users and reporters. These signals may be seen by the remote observer evaluating collated cases, quantified in a continuous known cohort of exposed individuals. It enables accurate comparisons to be made between medicines and allows a pregnancy register to be established that can be used to define and calculate rates of any abnormalities. The routine follow-up enables quite a confident detection of reduced or failed therapeutic effect and thus can raise suspicion of inaccurate diagnosis of disease, programme failure, or poor quality or counterfeit medicines. Details of deaths can be recorded and examined and it provides data on death rates. It has the ability to produce rapid results in a defined population. It enables the collection of comprehensive and near-complete data that will provide for the special needs of the program including effects in pregnancy, specific toxicities and safety in children. Because the method looks intensively at new medicines of great interest in a specific area of need, and provides clinically significant results rapidly, it stimulates interest in medicine safety in general. The method provides sound evidence with which to deal with any medicine scares.

The advantages associated with spontaneous reporting include the fact that it is administratively simpler and less labour intensive than cohort event monitoring, it is less costly, easy to implement, is applicable to all medicines, rare reactions can be identified and it is the method most commonly used in pharmacovigilance and National pharmacovigilance centers. Healthcare professionals are more familiar with the method also. This mechanism accepts both healthcare professional and consumer reports and both sources can contribute to the regulation of medicines. The disadvantages associated with this are that the data is often incomplete. There is often no denominator available, delayed effects may go unnoticed and sometimes common clinical problems are not linked to drug to the drug in question. These reports are reported voluntarily, bias can exist, there is no control group and there can be differential under-reporting. So unfortunately, reliable rates cannot be calculated and therefore risks and risk factors cannot be established with confidence. For this reason, there is obvious need for special studies to collect accurate information on areas of particular interest e.g. pregnancy, children and the elderly. These special studies add to the overall cost and reduce the cost advantage of spontaneous reporting.

The databases used for storing this data, also requires significant attention. The use of large databases for analyses is the most efficient and reliable method and the implementation of such databases in different countries could increase the quality of the information on adverse drug reactions (ADRs) by allowing researchers to conduct efficiently various types of studies They would also permit wider accessibility for researchers. The ability to understand and prioritize the most important data, and to use data mining to evaluate it is very advantageous. In Europe, the Eudravigilance system consists of one common electronic reporting point within the European Union that is advanced. This harmonised system is compliant with ICH E2B (M), M1 and M2 standards. The advantage of this system is ease of use and fast reporting mechanisms both from reporters, but also between health authorities. Unfortunately, despite significant globalisation of pharmaceutical companies and many of the same drugs being available in the main territories, adverse event data is not shared routinely between territories. However, the FDA for example will accept data from clinical trials carried out abroad if they are conducted ethically and in accordance with requirements.(5) It is expected that there is a possibility that the US and EU may seek to share such data going forward and this would offer a significant benefit should this happen. It would allow access to data derived from a broader exposure in these populations.

In conclusion, monitoring does carry a cost, though there are advantages to gathering data which can drive evidence-based decisions on medicine selection, produce sound data with which to respond to any medicine scares in an informed manner, minimize adverse effects which might affect patient safety and adherence by determining risk factors and the means for risk prevention, allow early identification of inefficacy or treatment failure, identify medicine–medicine, medicine–disease or medicine–food interactions. Costs are normally associated with staff, training, communication, information systems, production of promotional literature, and production of reporting forms. Monitoring involves many stakeholders including the ministers of health, regulatory authorities, national pharmacovigilance centre, the WHO monitoring centre, the European Medicines Agency (EMEA), academia, hospitals, schools of medicine, pharmacy and nursing, professional organizations, health professionals who are to participate, pharmaceutical companies, patients, media, patient support groups where these exist, general public.



1. Volume 10 Eudralex Clinical trials guidelines

2. ICH Topic E 2 A. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. Note for Guidance on Clinical Safety Data Management Definitions and Standards for Expediting and Standards for Expedited Reporting. June 1995 CPMP/ICH/377/95

3. Mann RD. Prescription-event monitoring -recent progress and future horizons. Br J Clin Pharmacol1998; 46: 195-201.

4. Volume 9A Eudralex. Pharmacovigilance guidelines.

5. Code of Federal Regulations. Title 21, Volume 5. Revised as of April 1, 2009. 21CFR312.120. Investigational New Drugs. Foreign clinical studies not conducted under an IND.