Small and medium enterprises have limited resources that need to be directed towards moving their product pipeline from clinical trials to product launch, and subsequently post-marketing lifecycle support. Early on Clinical, Regulatory and Safety functions can be housed under the same department or team. In some cases, the same team has the additional responsibilities of handling the quality function. Teams are typically small, have multiple responsibilities and may find they lack the bandwidth, expertise and tools to keep up. Focus is on the near-term objectives rather than longer term ones.
As a result, these organizations may find it difficult to make informed decisions or to be adequately prepared for regulatory submissions. An example of this is in clinical trials where safety data is often stored external to the company with multiple CROs. Since the data is not centralized, it is difficult to access, analyze and perform a comprehensive safety review. Yet investing in an in-house Safety database system often doesn’t make sense as it requires in-house expertise to implement and maintain.
So what strategy should a small to medium sized company consider?
Managing an internal, resource-heavy end-to-end regulatory and safety department moves extensive time, effort and financial spend away from a company’s core activities of product development and marketing. At some point these organizations have to rethink their strategies and develop a comprehensive program that supports their current and future growth.
Challenges for Small and Medium Sized Biopharmaceutical Companies
A key issue faced by small and medium-sized enterprises is overwhelming pressure to get their product to the market as quickly as possible. When they reach the clinical trials stage, they are quick to outsource clinical trials to full service Clinical Research Organizations (CROs), who may have niche patient recruitment capabilities but may lack the required level of expertise and experience in other aspects of clinical research such as data management, biometrics, clinical writing, safety, etc. Also, when trials are outsourced they are not always to the same CRO but to several CROs. This means that pharmacovigilance (PV) activities, along with the technology infrastructure that supports it, are thus dispersed across multiple CROs. This often leads to safety data being reviewed and reported for each clinical trial rather than being reviewed and analyzed at the aggregate (product) level.
Another challenge is that safety data ends up being stored in different systems and results in a lack of integration with little or no control over data standardization. This puts organizations at risk at the time of filing of a new drug application (NDA) to obtain marketing authorization, when it’s important to review and analyze consolidated data, define the initial product label, and proactively identify and manage safety concerns.
Are small to medium sized organizations then better off setting up an in-house PV organization? Well not really. Implementing a comprehensive PV organization in-house is challenging because dedicated subject matter experts are required from both the PV operations as well as the technology infrastructure side. On the technology front, implementing validated and regulatory compliant PV systems requires an extensive quality management system (QMS) and an IT team to select, implement and support the solution(s). Yet the case volume is often relatively low and unlikely to be consistent, therefore, not always justifying the expenditure. From the PV operations side, additional core responsibilities are becoming more complex and require effort-intensive activities such as extra reporting, aggregate safety reporting, benefit-risk evaluation reports, signal detection, signal management and risk management plans.
Small to medium sized organizations can benefit by embracing newer operational strategies to manage their responsibilities during clinical development and in the post-approval phase. Using scientific process organizations (SPOs) or functional service providers (FSPs) that specialize in areas of statistical design and analysis, clinical data management and PV, while using the best-fit CROs to optimize patient recruitment and manage clinical trial conduct, is an attractive strategy to consider.
Regulatory Compliance and Safety Monitoring
Figure 1 depicts several critical safety and regulatory related activities that are part of the product lifecycle, from preclinical development through Phase IV. However, smaller organizations are often unable to prioritize these activities and may not have the expertise or resources to undertake all activities themselves. The result of not having distinct and specialized teams often impacts the appropriate prioritization of the various critical activities. For example, while compliance to safety regulations is of utmost importance, it may be compromised if the appropriate staff, standard operating procedures and working safety management practices are not in place. Sub-optimal processes and non-compliance issues can in turn lead to higher costs, through missed work, rework or low quality output (1).
The most common pitfalls in safety monitoring during the product lifecycle include failure to:
- Integrate multiple safety databases which is required for comprehensive safety review
- Develop robust written standard operating procedures (SOPs) and work instructions for safety management
- Analyze, review and document all pertinent clinical safety data (adverse events and events of interest, laboratory data and other investigations)
- Review and update Investigator Brochure (IB) on a timely basis
- Coordinate case submissions to regulators, ethics committees and investigator sites across multiple clinical studies, as required and within timelines
- Submit DSUR/IND Annual Reports per schedule and applicable regulations
- Ensure continuous audit and inspection readiness at all times
Similarly, design, analysis and reporting of clinical trials may not be of the desired quality and may cause inordinate delays in submissions even if the patient recruitment timelines are met. This would have serious resource implications for smaller companies.
Within the clinical trial environment, a comprehensive understanding of the safety proﬁle of a product often requires evaluation of safety data across all completed and ongoing clinical trials, as well as of any other drugs in the same class. Thorough review and analysis of all aggregate data in real time is particularly important in the context of the US FDA’s guidance for IND safety reporting. This timely reporting of meaningful safety information allows the FDA to consider whether any changes in study conduct should be made beyond those initiated by the sponsor and allows investigators to take any essential steps to protect subjects.
Similarly, on the PV operations side, responsibilities such as aggregate safety reporting, beneﬁt-risk evaluation, signal detection and management and development of risk management plans are becoming more complex and resource-intensive. Across Europe and several other countries (including Australia, Canada and Japan), speciﬁc regulatory mandates to have Qualiﬁed Persons responsible for PV (QPPV) and local persons responsible for PV poses additional operational challenges for small and medium organizations.
Key Triggers for Embracing Newer Strategies
Small organizations, that have a few products in the pipeline but no marketed products, may sometimes be in a position to handle many functions i.e. regulatory affairs, medical writing, biometrics, drug safety, etc. in-house. However, it’s a different beast altogether when the complexity of these functions or volume of work increase beyond capacity. It quickly becomes clear that a dedicated team and/or additional resources are a necessity. Such situations are generally triggered when clinical trials are moved outside the home country or when multiple CROs located in geographically diverse locations are involved. Another trigger is the first approval of a NDA and when a new drug enters the market. Here post-marketing regulatory and PV functions become imperatives in addition to clinical research.
Work force limitations are an important consideration for small to medium sized organizations, as external vendors can provide a flexible flow of qualified, competent and trained personnel. They are able to respond to varying workloads along with reduced costs of managing internal teams, recruitment, training and retention.
Both clinical trials and post-marketing activities for medical products continue to grow in complexity and scope. Furthermore, in this constantly evolving and more stringent regulatory environment the task of managing trials is more demanding than ever. With this in mind it is interesting to note that while most of the industry’s risk management efforts have focused on post-marketing drug safety, the clinical trial process holds a broad array of other potential risks that could jeopardize a company’s product development investment, including regulatory delays. There is a strong case for small and medium sized organizations to partner with external vendors for services such as statistical analysis, clinical data management and medical writing that can provide resources, scientific expertise, respond to varying workloads and in the process, reduce costs and offer comprehensive risk management capabilities.