Preparatory school: Prepare for the unexpected

Sally du Toit and Katherine Hutchinson, Quanticate say prepare for the unexpected and examine the importance of integration throughout the entire product life cycle with pharmacovigilance

Since their introduction in the wake of the Thalidomide tragedy in the 1960s, international pharmacovigilance systems continue evolving to meet the changing requirements for the effective protection of public health. There is now a more proactive approach, not only to identify and evaluate potential safety issues, but also to minimise risks and promote the safe and effective use of medicines.

The driving factors behind the current trends in pharmacovigilance include pharmaceutical market globalisation. Effective pharmacovigilance systems need to quickly detect and manage potential safety issues. Another factor is innovative products development with unknown safety profiles, which require careful monitoring – for example products based upon new technologies, such as biologics, gene therapy and products which act on novel targets or work through mechanisms of action previously untested in humans. Pharmaceutical companies want to halt product development, which have an unacceptable risk-benefit profile early.  Approximately five per cent of hospital admissions in the EU is thought to be due to an adverse drug reaction (1).

Integrated pharmacovigilance

Pharmacovigilance traditionally concentrated on post-marketing safety surveillance.  As recommended by the CIOMS V Working Group (2), there is a recent shift towards systematic pharmacovigilance throughout the product life cycle.

While the post-marketing use of products involves the exposure of numerous patients, and may demonstrate previously unseen, rarer adverse drug reactions, there is much to learn about potential risks in clinical trial stage and preclinical studies. The development risk management plan (DRMP) and evaluation of clinical trial safety data on an ongoing basis is more apparent.

Pharmacovigilance systems should integrate input from internal and external stakeholders.  Internal stakeholders are many and diverse, as illustrated in Figure 1. These include the clinical operations, clinical data management (CDM) and statistics teams, with their role in running clinical trials and managing and evaluating clinical trial data. Regulatory affairs, medical writing and public relations provide key roles in the implementation of labelling updates and communication of safety information.

Many pharmacovigilance activities handled by affiliate or partner companies, or outsourced to CROs, require integration to provide clearly documented, coherent, life cycle pharmacovigilance system; comprehensive safety data exchange agreements (SDEAs) can ensure this.

From the regulatory perspective, the implementation of the development safety update report (DSUR) in September 2011 harmonises clinical safety reporting across international conference on harmonisation (ICH) regions, in addition to coordinating safety reporting across the product life cycle.  Through its overlap with the periodic safety update report (PSUR), it was updated in January 2013, to the periodic benefit-risk evaluation report (PBRER) in the re-vamped post-authorisation Guideline on Good Pharmacovigilance Practises (GVP) Module VII .

Safety data

Pharmaceutical companies are challenged with managing substantial safety data from numerous sources. This volume is increasing due to growing global clinical trials and post-marketing studies.  The requirement for unblinding of suspected unexpected serious adverse reactions (SUSARs) prior to reporting to EU competent authorities and ethics committees necessitates careful planning and safety data management.  To maintain trial integrity, companies must decide which personnel will have access to unblinded data (such as members of the pharmacovigilance group) and who will not be permitted access (such as clinical and biostatistics personnel involved with the conduct and analysis of the trial).  Technological advancements give the ability to store password-protected unblinded data on the safety database. However, definition and documentation of the blinded and unblinded team and processes to maintain these are also helpful.

The use of data safety monitoring boards (DSMBs) for the monitoring and assessment of data during clinical trials is increasing due to its provision of unbiased review, which may be unblinded without affecting the trial integrity.  One consideration is the inclusion of members with knowledge of areas associated with potential risks, in addition to the therapeutic indication of the product.

Data management and statistics expertise in safety data management and evaluation is becoming apparent. Signal detection methodologies using statistical techniques adapted from manufacturing are generally applied to large post-marketing surveillance databases.  CIOMS VIII guidelines on signal detection, published in 2010, enabled some further pragmatic solutions and guidance for effective signal detection to be integrated into the recent GVP Module IX on Signal Management.

With various safety data being held on different clinical and safety databases, effective data flow and reconciliation is vital to ensure the integrity of the databases (see Figure 2).  Data integration for analysis and evaluation and inclusion in documents such as the integrated summary of safety (ISS) for a new drug application (NDA) is important and requires pooling of adverse event (AE) data across studies. Avoid introducing biases due to inappropriate pooling, such as different treatment regimens or differing lengths of treatment. Centralisation of case report form (CRF) and safety data provides efficiencies and a high quality global safety database.

One of the more significant changes in the new post-authorisation GVP legislation is the goal  to strengthen safety data collection by regulators, with the EudraVigilance database becoming the single point of receipt of individual case safety reports within the community.  As each Member State works to ratify the new legislation, marketing authorisation holders must comply with a complicated set of transitional measures to ensure regulatory case reporting compliance. The US FDA is are proposing to amend post-marketing safety reporting regulations and mandate electronic safety reporting.[MT1] 

Transparency & communication

Transparency and communication has become paramount.  Recent changes to pharmacovigilance EU legislation (Regulation 726/2004 and directive 2001/83/EC) were developed in consultation with stakeholders, including pharmaceutical companies, regulatory authorities, healthcare professionals (HCPs) and consumers.  These changes will strengthen consumer reporting and help involve consumers more in pharmacovigilance.

EU legislation proposed changes in GVP Module XV could introduce an EU web portal[MT2] , a main platform for medicinal safety announcements including links to member state web portals. [MT3] Education on monitoring and prescribing use of medicines helps identify any issues with the product name, labelling, packaging or potential medication errors.

Proactive risk management

The trend is for proactive risk management.  Pharmacovigilance systems deliver the key elements of an effective risk management system.  These are risk identification and evaluation, development of risk minimisation and mitigation strategies, and the communication of those strategies to all relevant parties.

EU regulatory changes promote proactive risk management and require RMP for MAAs involving new active substances.  EU PSURs focus on risk-benefit and the frequency of reporting is specified in the marketing authorisation (MA), depending on the risk-benefit profile of the medicine.

Pharmacovigilance has a vital part to play in public health. Pharmacovigilance systems must evolve to quickly detect and minimise risks for unexpected or inexplicable adverse drug reactions. The primary mechanism by which Thalidomide causes birth defects was only discovered recently, nearly 50 years after the link was first made (3). Current trends are shifting towards integrated pharmacovigilance throughout the product life cycle, involving input from all stakeholders.  Pharmacovigilance systems can be improved to allow more effective management of the risk-benefit profile of medicinal products. It will help achieve the ultimate shared goal of delivering the safest and most effective medicines possible and maximising its contribution to public health.

References

1. Proposal for a directive of the European Parliament and of the Council amending as regards pharmacovigilance, Directive 2001/83/EC on the community code relating to medicinal products for human use

2. CIOMS V, Current Challenges in Pharmacovigilance: Pragmatic Approaches, 2001

3. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y and Handa H, Identification of a Primary Target of Thalidomide Teratogenicity, Science 327(5971): pp1,345-1,350, 2010