Risk management systems, risk minimization plans set up.

Volume 9A states that when initially authorized, "information on the safety of a medicinal product is relatively limited. This is due to many factors, including the small numbers of subjects in clinical trials, restricted population in terms of age, gender and ethnicity, restricted co-morbidity, restricted co-medication, restricted conditions of use, relatively short duration of exposure and follow up, and the statistical problems associated with looking at multiple outcomes."

As a result, the document adds, "not all actual or potential risks will have been identified when an initial authorization is sought. In addition, there may be subsets of patients for whom the risk is greater than that for the target population as a whole."

For these reasons, "pharmacovigilance activities will be improved if planning were more closely based on product-specific issues identified from pre- or post-authorization data and from pharmacological principles. Such planning will also guide the use of electronic data, which are routinely collected within health services to provide rapid investigation of predicted or emerging safety concerns."

"A typical individual medicinal product will have multiple risks attached to it and individual risks will vary in terms of severity, and individual patient and public health impact," the guidance document continues. "Therefore, the concept of risk management should also consider the combination of information on multiple risks with the aim of ensuring that the benefits exceed the risks by the greatest possible margin both for the individual patient and at the population level.

EU legislation requires Applicants/Marketing Authorization Holders to provide Competent Authorities with a description of pharmacovigilance and risk management systems. "The risks addressed in this guidance are those related to non-clinical and clinical safety. Where the disposal of the product might pose a particular risk because of remaining active substance (e.g. patches) this should also be addressed.

The Guideline is applicable to products in both the pre-authorization and post-authorization phase and whether the product was authorized through the centralized, decentralized or mutual recognition procedures. It incorporates the concepts of the International Conference on Harmonization ICH E2E Guideline."

The EU legislation's requirements "can be met by the submission of an EU-Risk Management Plan (EU-RMP), which includes a Safety Specification, a Pharma-covigilance Plan, an evaluation of the need for risk minimization activities and a risk minimization plan.

The EU-RMP incorporates the concepts of ICH E2E regarding the Safety Specification, which summarizes the safety profile of the medicinal product at the particular point in time of its life-cycle, and the Pharmacovigilance Plan which is based on the Safety Specification. On the basis of the Safety Specification, "the Applicant/Marketing Authorization Holder should consider carefully the need for risk minimization activities to be introduced. Every time the EU-RMP is updated the Applicant/Marketing Authorization Holder should reconsider its position vis-a-vis the need for risk minimization activities and Part II should be updated accordingly," Volume 9A explains.

An EU-RMP may need to be submitted at any time of a product's life-cycle, including pre- and post-authorization phases. In particular, Volume 9A states that an EU-RMP should be submitted:

* with the application for a new marketing authorization for any product containing a new active substance, a similar biological medicinal product or a generic/hybrid medicinal product where a safety concern requiring additional risk minimization activities has been identified with the reference medicinal product;

* with an application involving a significant change in a marketing authorization, such as a new dosage form, new route of administration, new manufacturing process of a biotechnologically- derived product or a significant change in indication;

* on request from a Competent Authority (both pre- and post-authorization);

* on the initiative of an Applicant/Marketing Authorization Holder when they identify a safety

* concern with a medicinal product at any stage of its life cycle.

The Safety Specification should be a summary of the important identified and/or potential risks of a medicinal product and important missing information. It should also address the populations potentially at risk (where the product is likely to be used), and outstanding safety questions which warrant further investigation to refine understanding of the risk-benefit profile during the post-authorization period. The Safety Specification is intended to help industry and regulators identify any need for specific data collection and also to facilitate the construction of the Pharmacovigilance Plan.

Risk minimization

In the EU-RMP the Safety Specification will also form the basis of the evaluation of the need for risk minimization activities and, where appropriate, the risk minimization plan. Limitations of the safety database (related to the size of the study population, study inclusion/exclusion criteria) should be considered, and the implications of such limitations with respect to predicting the safety of the product in the marketplace should be explicitly discussed. Particular reference should be made to populations likely to be exposed during the intended or expected use of the product in medical practice.

For medications already on the market, the Applicant/Marketing Authorization Holder should provide data on patients exposed. "Exposure data based on the number of kilograms of medicinal product sold divided by the average dose is only valid if the medicinal product is always taken at one dose level for a fixed length of time--which is not the situation with most medicinal products," the guidance notes. "In pediatric populations or mixed populations of different indications or age groups, use of this measure alone is inappropriate."

The Safety Specification should discuss which populations have not been studied or have only been studied to a limited degree in the pre-authorization phase. "In discussing differences between target populations and those exposed in clinical trials it should be noted that some differences may arise through trial setting (e.g. hospital or general practice) rather than through explicit inclusion/exclusion criteria," Volume 9A states. Among other populations to be addressed are children; the elderly; pregnant or lactating women; patients with relative co-morbidities; and patients of different racial and/or ethic origins.

"For updates to the Safety Specification, specific reference should be made to how the realized pattern of exposure (including off-label use) has differed from that predicted and from the indication(s) and contraindications," the guidance advises. "Newly identified safety concerns should be mentioned--in particular any issue found in relation to a population not studied in the pre-approval phase should be discussed."

For adverse events and reactions, especially "those that are serious or frequent and that also might have an impact on the balance of benefits and risks of the medicinal product," the guidance advises detailed reporting to include "evidence bearing on a causal relationship, severity, seriousness, frequency, reversibility and at-risk groups, if available. Risk factors and potential mechanisms should be discussed. These adverse events/adverse reactions should usually call for further evaluation as part of the Pharmacovigilance Plan (e.g. frequency in normal conditions of use, severity, out-come, at-risk groups)."

Pharmacovigilance Plan

According to ICH E2E, the Pharmacovigilance Plan should be based on the Safety Specification and propose actions to address the safety concerns identified. "Early discussions between Competent Authorities and the Applicant/Marketing Authorization Holder are recommended to identify whether, and which, additional pharmacovigilance activities are needed," Volume 9A explains. "It is important to note that only a proportion of risks are likely to be foreseeable and the Pharmacovigilance Plan will not replace but rather complement the procedures currently used to detect safety signals."

For medicinal products where no special concerns have arisen, routine pharmacovigilance should be sufficient for post-authorization safety monitoring, without the need for additional actions. For medicinal products with important identified or potential risks or important missing information, the guidance advises that "additional activities designed to address these safety concerns should be considered." NIAHs "should also consider the situations when routine pharmacovigilance is likely to be inadequate, such as when a potential risk with an individual medicinal product has a significant background incidence in the target population(s). When any doubt exists about the need for additional pharmacovigilance activities, consultation with a Competent Authority should be considered. The threshold for investigating a safety concern further will depend upon the indication, the target population, and the likely impact on public health."

MAHs are advised to "routinely to consider the likelihood of medication errors," taking into account potential reasons for medication error during the product's development. The name; size, shape and coloring of the pharmaceutical form and packaging; instructions for use; and labeling are all factors that should be taken into account in efforts to prevent medication error, the guidance advises.

In particular, Volume 9A states: "If a product has life-threatening potential when administered by an incorrect route, consideration should be given as to how such administration can be avoided. This is particularly important when it is common practice to administer the product at the same time as other medicinal products given by the hazardous route." Other factors that should be considered in preventing medication errors include the possible accidental ingestion by children; whether a product is likely to be used by patients with visual impairment; and methods to distinguish, visually and/or physically, between different strengths of the same product.

"If during the post-marketing period it becomes apparent that adverse reactions are occurring as a result of medication errors, this topic should be discussed in the updated EU-RMP and ways of limiting the errors proposed," Volume 9A advises.

When an EU-RMP includes a risk minimization plan, that plan should " list the safety concerns for which risk minimization activities are proposed. The risk minimization activities, i.e. both routine and additional, related to that safety concern should be discussed." For each safety concern, the MAH should address its plans to communicate risk information to patients and health care professionals.

Post-Authorization Safety Studies

Post-authorization safety studies may be conducted to identify previously unrecognized safety concerns, investigate potential and identified risks, or confirm the known safety profile of a medicinal product under normal conditions of use. They may also be conducted to quantify established adverse reactions and to identify risk factors. Volume 9A states that "Situations where studies may be appropriate include:

* a medicinal product with a novel chemical structure or novel mode of action;

* where there is uncertainty as to the clinical relevance of a toxic effect in animals;

* where there is uncertainty as to the safety profile;

* where there is a need to better quantify adverse events identified in clinical trials and elucidate risk factors;

* where there is a need to confirm or refute safety concerns suggested by other sources (e.g. spontaneous reporting);

* where there is a concern regarding the use of the medicinal product (e.g. to quantify the off- label use); and

* when there is a need to evaluate the effectiveness of a risk minimization measure.

"The Marketing Authorization Holder who initiates, manages and/or finances the study is responsible for its conduct and should meet the pharmacovigilance obligations concerning" such studies. Marketing Authorization Holders that plan to "perform a post-authorization safety study should send the protocol to the Competent Authority of the Member State(s) in whose territory the study is to be performed."

The full document can be obtained at hitp://www.ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev9.htm