Planning ahead for patient safety in the postapproval period

Planning for patient safety in the postapproval period actually should begin early in the product development period. Gretchen Dieck tells us how – and why.

The process for developing medicinal compounds for clinical use and the science of identifying risks are such that only the most commonly occurring risks are identified before the drug is approved for general use. Yet, biopharmaceutical companies should proactively prepare in the development process to monitor and assess patient safety in the postapproval period when unanticipated and unknown safety issues may become apparent.

Clinical trials are conducted on a relatively homogeneous population under ideal circumstances. In the postmarketing environment a drug may be given for many years to a large number of individuals, many of whom have multiple medical problems and are on multiple concurrent medications. Therefore, it’s important to consider risk mitigation activities that can be conducted pre-approval.

“…only the most commonly occurring risks are identified before the drug is approved for general use.”


Global regulations relating to risk management

Globally, regulatory agencies are concerned about risk management, which includes risk assessment and risk mitigation. Guidance documents and regulations have been issued that have addressed these issues through pharmacovigilance, signal detection, observational studies and registries.

In the US, guidance documents include:

• Guidance for Industry: Premarketing Risk Assessment (2005)

• Guidance for Industry: Development and Use of Risk Minimization Action Plans

• Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (2005)

• Guidance for Industry and FDA Staff: Best practices for Conducting and Reporting Pharmacoepidemiology Safety Studies Using Electronic Healthcare Data Sets (2013)

The Food and Drug Administration Amendments Act (FDAAA) of 2007 significantly added to FDA authority and ensured the additional resources needed to conduct the complex and comprehensive reviews necessary to new drugs and devices.

The European Medicines Agency (EMA) requires a risk management plan (RMP) for all new submissions. Essentially, the RMP is a summary of what is known about the product and the target population at the time of the application. It contains a summary of all the important data collected during clinical development and a description of the epidemiology and natural history of the target population. It also includes missing information or data on populations that were not studied in clinical development, but who might receive the drug postauthorization. This information is important because it is needed to properly assess adverse events that are reported in the postauthorization period.

In Europe, risk management guidance includes:

Committee for Medicinal Products for Human Use (CHMP); (EU)

• Guideline on Risk Management Systems for Medicinal Products for Human Use (2005)

• Volume 9A of the Rules Governing Guidelines on Medicinal Products in the European Union: Guidelines on Pharmacovigilance for Medicinal Products for Human use (2008)

European Medicines Agency (EMA)

• Guideline on Good Pharmacovigilance Practices (GVP) (2012)

• Guidance on format of risk management plan (RMP) in the EU – an integrated format (2013)


• EU Directive 2010/84/EU of the European Parliament and of the Council of 15 Dec 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (2010)

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

• Topic E2E Pharmacovigilance Planning: Note for Guidance on Planning Pharmacovigilance Activities (2005)

Mitigation strategies to consider pre-approval

While the EMA requires an RMP for all product application, the FDA may require a Risk Evaluation and Mitigation Strategy (REMS) for some products to ensure that the benefits of the product outweigh its risk. Among the strategies that may comprise a REMS include: a Medication Guide to educate the patients about how to properly take the product and the safety risks associated with the product, a Communication Plan to educate healthcare providers about the risks associated with the product; and Elements to Assure Safe Use (ETASU), which restrict the distribution of the product in some fashion by requiring certification of prescribers and pharmacists, by restricting use to inpatient settings, by monitoring patients, by only dispensing to patients with documentation of safe-use conditions or by requiring a patient registry.

“Clinical trials are conducted on a relatively homogeneous population under ideal circumstances.”

It’s important to note that although the implementation of these activities are conducted in the postapproval arena, the design of the plans and studies as well as the development of effective postapproval tools and mitigation strategies should be carried out pre-approval.

Risk management planning: when does it begin?

Proactive risk management begins early in product development. The pre-marketing timeframe offers opportunities to:

• Develop the product’s safety profile and identify risks

• Identify special subgroups at greater risk

• Quantify benefit (including unique benefits)

• Understand populations to be included in clinical trials

• Understand how the target population may differ from randomized control trial patients

• Design and evaluate risk management interventions (including REMS)

Pre-approval risk management activities help a sponsor understand as much as possible how the clinical trial experience of a drug will differ from post-market use.

Planning risk management strategies, including the need for a REMS, earlier in the development program provides more flexibility for developing a comprehensive plan. The focus of the planning should be on those important risks, both identified and potential, that may tip the benefit-risk balance of the drug. There may be sufficient knowledge about the compound or its class that suggests certain postapproval risk minimization actions should be taken. For example, some compounds may have an interaction with other drugs or with certain foods or may be associated with significant changes in laboratory values. These circumstances may suggest obvious postapproval mitigation strategies such as informing the patient through a Medication Guide, putting stickers on the medication regarding potential interactions, or requiring monitoring for abnormal laboratory values.

If reproductive or teratogenic risk signals are seen in development, then educational materials, a REMS, a pregnancy registry, or a postapproval safety study may be needed once the drug is marketed.

“The earlier that postapproval safety is considered, more flexible and effective strategies can be developed.”

In some instances, using these types of strategies may sufficiently mitigate the postapproval risk, particularly if the sponsor is able to develop and test the effectiveness of the mitigation activity before approval.

Safety throughout the lifecycle of a product

Evaluation of safety is carried out throughout the lifecycle of a product. Establishing a well-documented process for identifying and managing risks in the pre-approval period can help ensure greater efficiencies in evaluating postapproval risks. The earlier that postapproval safety is considered, more flexible and effective strategies can be developed. While pre-approval activities will not be sufficient to prevent an unknown, serious risk being identified postapproval, proactive preparation will result in the ability to respond quickly and efficiently to unexpected safety issues in later stages of drug development and in the post-marketing period.



About the author:

Gretchen S. Dieck, PhD is Vice President, Safety, Epidemiology, Registries and Risk Management.

Dr. Gretchen Dieck joined UBC in 2010 and has more than 25 years of experience in the areas of epidemiology and risk management. As Vice President, Safety, Epidemiology, Registries and Risk Management, Dr. Dieck focuses on the development of KAB protocols and surveys, risk management consulting, epidemiology consulting, and safety related gap analysis. She has worked with one of the most diverse and prolific portfolios of drug development and brings a unique combination of strategic thinking and practical experience to the development and implementation of risk management programs.

Prior to joining UBC, Dr. Dieck was Senior Vice President, Safety and Risk Management at Pfizer Inc. where she began her 23-year tenure with the company in 1986 as a staff epidemiologist. While heading the Safety and Risk Management group, she was responsible for providing risk management support and compliance functions across the product portfolio. Included in these responsibilities were the case processing and risk management functions relating to epidemiology and medical safety evaluation as well as safety and risk management related analysis and documentation. One of her notable accomplishments while at Pfizer was the conceptualization and implementation of Pfizer’s Medicine Safety website.


Closing thought: How early should postapproval safety be considered?