Life cycle management is a set of activities performed by many groups within a company to ensure from an ethical, medical, regulatory and commercial vantage the product remains safe and effective for patients and health care practitioners (HCPs). Life cycle management entails many activities; often led by a multifunctional group from safety, regulatory, labeling, etc. with oversight from senior management. Pharmacovigilance, one of the central functional groups in life cycle management, continually monitors the safety profile of the drug to ensure the benefits of the product outweigh the risks in the population using the drug. The product’s safety profile is rarely static and often progresses through many changes due to increasing exposure, different styles of practice, new or untested drug interactions, and pharmacogenetics variations. As a result continual close monitoring of the drug’s benefit:risk profile is required and carried out in a process called Signal Management. Life cycle management and monitoring of a product’s benefit:risk profile is complex, yet we believe companies can optimize their oversight of these activities and implement processes that mitigate risk and facilitate effective collaboration.
Signal management, defined as the set of activities performed to identify new risks or changes in character or severity of a known risk, remains an essential component in assuring the safe use of a drug throughout its lifecycle. Ongoing signal management provides a continual risk assessment of the product through many coordinated activities completed both within and external to the pharmacovigilance team. The analysis/assessment and related actions following the validation of a signal are optimally managed in a multifunctional team, e.g. a safety review committee, with actions performed by many functional groups. Validated signals or identified risks must be managed and mitigated requiring actions such as communication, education, and at times changes in manufacturing.
Management of new risks or a change in character of a known risk can often be mitigated by alerting patients and HCPs to the identification of the risk and potential methods to avoid or minimize the risk. This usually requires discussions with regulators, possible changes in the label with new educational activities, and at times direct communications. If the situation becomes urgent, then in addition to regulatory communication, rapid communication such as a press release, web page or internet postings, and e-mails must be initiated, as well as subsequent educational activities. Groups such as Regulatory Affairs, Medical Affairs, Marketing, IT, Medical Information, and R&D must be involved. In certain cases, safety findings require further evaluation, necessitating studies: epidemiology, non-interventional and interventional, and thus, additional groups, epidemiology, clinical affairs, and clinical operations, must collaborate to complete these activities. In summary, signal management remains an indispensable part of life cycle management and often encompasses multifunctional expertise and activities within a company.
A label change is an example of one such regulatory activity which is closely related to and an outcome from Signal Management, subsequent to the validation or confirmation of a safety signal. It is also a good example of a critical process which has a lot of operational complexities and challenges. The label change communicates formally important and, at times, essential information to regulators, patients and HCPs, regarding the safe use of a product. In order to complete a safety driven label change, an organization must have written practices in place to organize the different functional groups with the required expertise. They must have a comprehensive strategy that identifies roles and responsibilities and a clear communication plan that captures meaningful and relevant content to progress the signal to the label and beyond.
The diagram below depicts the process from a confirmed signal to the label. Uncertainty of safety issue priority, lack of clarity in roles and responsibilities and breakdown of collaboration between groups can cause delays in getting information to market.
For example, the safety teams need to appropriately communicate the signal to regulatory and labeling. Poor communication regarding the details (i.e. a slide deck versus the actual report with the rationale that will drive the label change) can wreak havoc on the downstream process. This interface is critical. The safety team needs to understand what the labeling team needs to know to implement a change around the world. They can’t just tell the labeling team to add an Adverse Event (AE) and precaution – they need to tell them why. We believe that the following steps will help close the gap between signal detection and labeling:
- Safety issue prioritization and timeline
- Effective process integration (PV, RA, others)
- Clear roles and responsibilities in implementation
- Technology enablers
The objective of all safety and regulatory teams is to be able to effectively manage the end-to-end product lifecycle through effective collaboration with each other and other functions. A primary responsibility of the process from signal detection to package and beyond, is to ensure timely and accurate benefit: risk communications which are required for the safe and effective use of medications.