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Communicable risk

As regulatory communities move forward in the areas of risk assessment and management, there is a move to harmonise protocols across geographies.

PowerlinesAs regulatory communities move forward in the areas of risk assessment and management, there is a move to harmonise protocols across geographies. For a number of years, the International Congress on Harmonization (ICH) has attempted to create universal guidance on how to conduct clinical research and has sought to standardise the reporting of adverse events, discovered either in clinical trials or after marketing approval.

ICH's recommendations have sparked new regulations in the European Union (EU) and the US. In December 2001, EU Directive 2001/20/EC created a Europe-wide data processing network and adverse event management system. It incorporated ICH guidance and made possible the exchange of post-authorisation pharmacovigilance data among pharma firms, the Competent Authorities and the European Medicines Agency (EMEA).

Under the regulation, any market approved drug must be registered in the EurdraVigilance Medical Product Dictionary. For the first time, Competent Authorities will have access to information regarding all marketed products. The public will also have access, but only to a limited subset of the information registered for a drug.

With regard to reporting requirements and methods for serious adverse events linked to marketed products in the EU, there are a few significant changes. While the holder of a marketing authorisation (pharmaceutical company) must still notify the Competent Authorities of Member States in which an incident has occurred, they are now also required to notify the EMEA.

Adverse information within the European community and reports from outside should be reported to the EMEA. In addition, if a medicinal product is suspected in the transmission of any infectious agent, there is also a reporting requirement. For the reporting of serious adverse events, the directive created two reporting modules: the EudraVigilance Post-Authorization module (EVPM), for the reporting of Individual Case Summary Reports (ISCRs) for marketed products, and the EudraVigilance Clinical Trial module (EVCTM), for the reporting of suspected serious unexpected adverse reactions (SUSARs) in clinical trials.

Even though there is demarcation between marketed products and clinical trials in the names of these modules, the final reporting of an adverse event is dictated by the source of the event. The largest impact to the industry is the November 20, 2005 deadline that requires all reportable events to be submitted electronically to the EudraVigilance system.

Another aspect of the European regulation is the requirement for the use of a single coding dictionary, the Medical Dictionary for Regulatory Activities (MedDRA). The use of a single dictionary harmonises the naming of events, medications and anatomical locations, allowing international comparisons. Using broad-based comparisons across many countries provides valuable insight for labelling and risk management.

Finally, for periodic reporting of adverse events to Member States and the EMEA, there are several new requirements. Pharmaceutical companies are responsible for maintaining detailed records of all suspected adverse events reported by healthcare professionals inside and outside of the European Community. These Periodic Safety Update Reports (PSURs), which must be submitted to the appropriate authorities in each Member State, and the EMEA, should be accompanied by a scientific evaluation of the data, clearly outlining any risks identified and their impact on the riskbenefit equation.

For a newly authorised medicinal product, a PSUR must be prepared every six months for the first two years, then annually for two years, and at three-year intervals thereafter. In addition, the EMEA can request the collection of specific pharmacovigilance data from targeted patient populations for a period of five years, allowing information to be gathered on adverse events of concern for specific drug classes.

In March 2003, the Food and Drug Administration (FDA) proposed a new rule for the Safety Reporting Requirements for Human Drug and Biological Products.

This draft regulation incorporates ICH guidance and combines a number of existing regulations and guidances issued during the past 10 years. This proposed rule is a draft and is not currently binding; finalisation is pending the review and consideration of public comments gathered during the 90-day period after the proposed rule was made public.

The draft proposes four major changes from current regulations governing reporting requirements:

1 A new definition of adverse events designed to harmonise the regulation with ICH
2 A requirement for health professionals to conduct active follow-up
3 A mandated coding dictionary
4 Changes in expedited reporting.

The first major change is to combine the definition for both pre- and post-approval adverse events, and this is expected to increase the number of reports substantially. The proposed name is Suspected Adverse Drug Reaction (SADR), defined as a noxious and unintended response to any dose of a drug

product for which there is a reasonable possibility that the product caused a response. The term reasonable possibility means that a relationship cannot be ruled out.

In essence, for pre-market SADRs, the burden of proof has shifted from showing a potential causality to proving no involvement. For post-market SADRs, there is leeway to prove no causality. Also under the proposed regulation, only healthcare professionals, defined as a doctor, nurse, pharmacist or anyone with healthcare training, can conduct a follow-up.

Follow-up, or active query, must include direct verbal contact with the reporter of the event and involve a focused line of questioning to ensure the capture of all relevant clinical information. In addition, the management of reported SADRs falls under the responsibility of a physician who is licensed to prescribe medication. It is not clear whether the physician must be licensed in the country in which they are currently working. This could potentially place a huge burden on the industry, which may employ foreign trained doctors in these roles.

Similar to the EU directive, the proposed FDA rule mandates the use of MedDRA as the preferred coding dictionary for individual clinical and post-market case safety reports.

In essence, regulatory agencies worldwide can share information in a manner that allows easy and meaningful comparisons. The definition of what constitutes a serious `unlisted' event is relatively unchanged from prior regulations; there remains a 15-day reporting requirement for serious unlisted events and a seven-day reporting requirement for fatalities. However, there is now a requirement for a follow-up on expedited reports to be made within 30 days.

Also, a new classification of always expedited reports has been created, which includes adverse events that must be reported within 15 days of receipt, no matter how serious the event or whether it is officially listed. Examples include congenital abnormalities, Torsades de pointe, aplastic anaemia, acute liver failure and liver necrosis. This new regulation significantly increases the number of expedited reports that will be required for submission to the regulatory agency.

Risk assessment and risk management of pharmaceutical products have become important topics during the past few years. The FDA issued final guidances in March 2005, entitled Premarketing Risk Assessment, Development and Use of Risk Minimization Action Plans, and Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. In a similar manner, the European community has discussed and will address risk assessment and risk management in planned guidance from the EMEA.

Risk management is iterative and involves assessing a product's benefit-risk balance, developing and implementing tools to minimise risk (while preserving benefits) and evaluating tool effectiveness, reassessing the benefit-risk balance and making adjustments as appropriate to the risk minimisation tools. The FDA's guidance further outlines that risk assessment involves identifying and characterising risk frequency and severity.

The Premarketing Risk Assessment document looks at risk assessment during product development. There is an emphasis on the need to develop an appropriately-sized safety database using consistent terminology (MedDRA) with consistent information for rigorous data analyses. This will allow the assessment of dose-related side effects, temporal association with side effects, and potential causality.

Clinical information populating a safety database should have representation from a diverse population (ie, gender, age, race) which is expected to have sufficient variability in the disease state in order to be of the most predictive use. In addition, the database should represent a variety of doses, concomitant medications, and appropriate timelines to mimic the intended pattern of treatment.

These clinical trial safety databases should address potential serious safety issues, such as QT prolongation, liver toxicity, nephrotoxicity, bone marrow toxicity, drug-drug interactions and polymorphic metabolism. The use of a large, simple safety study may be appropriate during development to assess a specific outcome or safety concern.

Finally, the Premarketing Risk Assessment guidance recommends that companies assess all medication errors and their root cause, which might relate to dosage form, or packaging and product labelling, including the proposed trade name.

The Development and Use of Risk Minimization Plans guidance makes clear the additional steps that can be taken for specific products having potential risk not mitigated by traditional product labelling. In order to be effective, a RiskMAP should have specific, measurable and evaluable goals. Examples of RiskMAP tools include: educational materials targeted to various audiences; reminder systems aiming to reduce risks in prescribing and use; and performance-linked access systems that guide prescribing, dispensing and use of the product.

Targeted educational materials can include training programmes for healthcare professionals or patients, medication guides or package inserts. Reminder systems provide acknowledgement of understanding (consent forms for patients), and performance-linked access tools can control prescribing and dispensing by confirming certifications before a product is dispensed.

It is recommended that objective, well-defined and evidencebased performance measures are evaluated in order to determine whether a RiskMAP is meeting the original goal. When designing a RiskMAP, it is recommended that the tools are tested prior to implementation via a pilot programme in conditions close to the anticipated use in practice.

Finally, the Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment guidance addresses the ability to assess a product after approval. Usually, there are large increases in patient exposures (with the additional caveats of comorbidity and concomitant medications) which can allow the detection of unlabelled and rare, yet serious, side effects.

Another methodology to evaluate or detect safety signals is the use of the Observational Study. The goal is to observe real-world use of the product without influencing how the product is used. Three types of Observational Studies include: registries, surveys and pharmacoepidemiologic studies.

The EMEA has been working in many of the same areas regarding drug safety and the protection of public health. On May 11, 2005, it issued a report listing five key priorities, including the development of guidance on risk management. From November 2005, new EU legislation will provide for regulatory authorities to use new tools, including risk management plans (developed by pharma firms) to be included in marketing applications, the possibility to take urgent measures (product withdrawal from the market), and assessment of product risk via life cycle management. These actions emphasise the detection, assessment, minimisation and communication of risk.


Melanie A Bruno PhD, MBA, is vice president, regulatory affairs, Kendle (US)
Ken Hintze PhD, is director global safety & pharmacovigilance, Kendle (US)
Martina Gerl is assistant director, safety, Kendle (Germany)

2nd September 2008


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