Pharmacovigilance in Emerging Markets

Pharmacovigilance is subject to a number of developments including electronic reporting, mandatory reporting by companies with registered products (also called Marketing Authorization Holders - MAHs), inspections of pharmacovigilance activities of MAHs, risk management planning, development safety update reports, data-mining and specialized staff training in pharmacovigilance.

As originally set up in many countries, pharmacovigilance depended on the submission of case reports of suspected adverse effects of medicines in individual patients by their doctors, dentists and, generally and more recently, by pharmacists, other health care practitioners and consumers. The reports are sent to national centers, many of which are members of an international collaborative program under the auspices of the World Health Organization (WHO), based at the Uppsala Monitoring Center (UMC), Sweden. This reporting of individual cases remains an essential part of pharmacovigilance today.

Technological Assistance
In the more developed countries in the Asia Pacific region (Australia, Korea, New Zealand, Singapore), doctors and pharmacists increasingly utilize computers in their daily work. To capitalize on this, national centers in those countries are introducing electronic methods of reporting, such as web-based report forms and encrypted email reporting.

With the growth of the use of new active substances in the past four decades, many national regulatory authorities have made regulations requiring MAHs to submit reports of individual cases that come to the attention of any of their staff, including those that promote products to doctors. Some regulatory authorities in the Asia Pacific region require reporting by MAHs. Company reports, as a proportion of all reports submitted, vary between Asia Pacific countries, ranging from a few percent to about 85 percent in Japan. It can be expected that as pharmacovigilance assumes greater importance in individual countries in the region, other countries will be likely to mandate the reporting of all, or perhaps only serious cases as they become known to the MAHs.

Concern about compliance of MAHs with reporting requirements has led to the introduction of pharmacovigilance inspections in Europe and the US. In 2007, Australia, New Zealand, Malaysia, Singapore and Thailand did not have a legislated basis for undertaking pharmacovigilance inspections. Australia is in the process of legislating and other regulatory authorities should follow as their laws and resources permit.

The required behavior of companies in pharmacovigilance has been increasingly codified as, for example, in the European Union's "Requirements for Pharmacovigilance Systems, Monitoring of Compliance and Pharmacovigilance Inspections" (Volume 9A of The Rules Governing Medicinal Products in the European Union).

Two organizations have been involved in the introduction of developments in pharmacovigilance. The Council of International Organizations of Medical Sciences (CIOMS), co-located with WHO in Geneva, has sponsored a series of working parties with broad membership from industry and regulatory authorities to investigate and develop recommendations for innovations in pharmacovigilance.

Laying Down the Rules
The reports of CIOMS working parties have often then formed the basis for the development of guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH brings together the regulatory authorities of Europe, Japan and the US, and experts from the pharmaceutical industry in those three regions.

The adoption of ICH guidelines by these three regions, albeit on occasions with some variations between regions, usually results in the documentation and the activities set out in the guidelines being followed by industry worldwide. Europe (combining the resources of the European Medicines Evaluation Agency (EMEA) and the national regulatory agencies) and the US Food and Drug Administration (FDA) have staffing resources with which to implement developments, and such resources are not available at the individual regulatory agencies in Asia Pacific.

At the time of authorization, information on the safety of a medicinal product is relatively limited. Internationally, there has been recognition that the reliance on the duo of analysis of clinical trial safety data prior to registration and case reporting after registration is insufficient to ensure the safety of marketed medicines.

Particularly driven by initiatives of the US FDA some years ago, attention has turned to the need to monitor the safety of medicines throughout their life cycle and to manage identified real and potential risks. Europe now requires the inclusion of a Risk Management Plan (RMP) in a wide range of registration applications including new active substances, amendments to indications, biosimilar products and some generic medicines. An RMP may also be required if an important safety issue arises during the post-registration (marketing) period.

In summary, the RMP must include a safety specification for identifying known and potential safety issues and missing information about safety. The RMP must justify that routine adverse reaction monitoring will be sufficient, or propose additional pharmacovigilance measures that need to be implemented by the applicant company in the post-marketing period.

The RMP must also justify the product that the usual circumstances of marketing the medicine (usually on prescription) are appropriate to ensure safe use, or propose additional educational activities or access controls. Risk management planning in the US is applied to fewer products than in Europe. When applied in the former country, such planning is currently called a Risk Evaluation and Mitigation Strategy (REMS).

A key outcome of European RMPs and US REMS is that the sponsor company will on occasions commit to undertaking additional pharmacovigilance studies of the newly marketed drug. These can range from intensified case reporting to studies of large numbers of users of the medicine in computerized medical record databases (possible principally in Canada, UK and US) and even to additional blinded, randomized, controlled clinical trials.

Differing Requirements
For the Asia Pacific region, it can be anticipated that some national regulators will require the inclusion of RMPs in registration applications. Australia has implemented this requirement since April 2009. It is probable that regulators in Asia will not often demand additional unique pharmacovigilance commitments, as the needed facilities for most studies, such as large medical record databases, do not yet exist in the region.

More likely, perhaps, is that many regulators in Asia Pacific will demand and to be informed of the commitments for further pharmacovigilance given in Europe and the US and to receive the results of those activities. The European Public Assessment Reports (EPARs) for products approved in the past year, available on the EMEA website, are a source of useful insights into the outcomes of RMPs.

It can be argued that the load on post-registration pharmacovigilance would be reduced through greater attention to the safety of a medicine during its pre-registration development. CIOMS Working Parties VI and VII have considered the management of safety information during clinical trials, and have proposed the implementation of a Development Safety Update Report (DSUR).

Such a report, prepared annually, would summarize for the company, clinical investigators and regulators, the evolving safety profile. The ICH has its final draft guideline (termed E2F) under revision following a period for comment, which is expected to be finalized this year. Once E2F is adopted by ICH, regulators in Asia who authorize or control the clinical trials of new drugs being conducted in their countries can be expected to require the submission of DSURs.

At some national pharmacovigilance centers and some large pharmaceutical companies, the databases holding records of individual case reports of adverse drug reactions are now large, with at least 100,000 or more reports. It is possible to look at the proportion of all reports in the database that are represented by a single adverse reaction descriptor term - for example, hepatitis.

A comparison may then be made of the proportion that the same term makes up for a single drug. A finding that the proportion is higher for the single drug indicates that the reaction is more commonly reported with that drug, and may represent a signal that the drug is a cause of the reaction.

Data Mining
This comparison of proportions is a means of signal generation and, when the process is undertaken repeatedly, may be referred to as "data-mining". Internationally, several methodologies have been developed and their output measures include Proportional Reporting Ratios (UK) and Multi-item Gamma Poisson Shrinker signal scores (US FDA). Commercial data-mining software is available. None of these output scores confirms a causal role for a drug. Instead, significant scores point to a drug/reaction combination that requires a review of the clinical information.

With the exception of a small number of countries, the databases at national pharmacovigilance centers in the Asia Pacific region are too small to warrant the use of datamining software. Notwithstanding this, the staff of pharmaceutical companies and regulatory authorities will encounter reports of the outcomes of data-mining and will need to understand their derivation and significance. In this context, the publication by CIOMS Working Group VIII of a report titled "Application of Signal Detection in Pharmacovigilance" is expected and will hopefully be a useful explanatory document.

The increased emphasis by pharmaceutical companies and regulators on pharmacovigilance in Asia Pacific is being accompanied by a need for expert training. An encouraging development is the delivery of training in the region by professional associations and societies. For example, the International Society of Pharmacovigilance (ISoP) presented two parallel training courses in Bangkok in March 2008 with about 100 participants from the region. The society has established a Western Pacific Chapter and is planning for further training in this region in 2010.

"Pharmacovigilance" is a word that was originally used in France in 1972 to describe a national system for the vigilance of the unintended and toxic effects of medicines. It was referred to as "Systeme National de Pharmacovigilance." It is now used in technical English to describe the surveillance, monitoring and investigation of adverse drug reactions. In 2002, the World Health Organization (WHO) published the following definition:

"Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem."