Tackling Pharmacovigilance Issues In The Clinical Trial Stage Of Product Development
By Sandra Blumenrath, Drug Information Association (DIA), and Catherine Baldridge, Essential Pharmacovigilance (EPV)
Pharmaceutical and device manufacturing companies often outsource their pharmacovigilance (PV) activities to vendors and consultants to meet their safety, medical information, and regulatory needs. When doing so, these companies have a regulatory obligation to oversee the activities and quality of their vendors. However, vendor audits conducted by these companies can yield a wide range of results due to differences in auditors, scope, and understanding of PV principles and operations. The same is true for company inspections by different regulatory authorities. Finding solutions to achieve quality compliance and consistency in PV as well as streamlining the process of signal detection and risk management by shifting the focus to premarket product development and the clinical trial stage are important goals and topics of intense debate among PV professionals and company leadership. This piece will take a closer look at these issues and discuss how collaborations and ongoing education can work to advance the industry in this space.
Tackling Inconsistencies
The issue: Much of the effort in PV is focused on identifying, collecting, evaluating, and transforming relevant safety data into usable information for regulators and companies. To sustain growth and keep up with the increasing data volumes and the growing workload overall, pharmaceutical companies are frequently outsourcing much of their PV activities to consultants, contractors, and vendors who specialize in these activities. Once a company activity is outsourced, however, the vendor should be audited on an ongoing basis for oversight and quality purposes. Many vendors that offer PV services, especially large pharmaceutical support services capable of hosting large safety databases, are used by multiple companies. Yet, contrary to what one might expect, company audits of the same vendor don’t necessarily lead to the same findings. Similarly, for each regulatory authority conducting audits and inspections (including the FDA, Health Canada, MHRA, Swiss Medic, and ANSM), a company may receive different results for the same PV system.
Although there is a wide range of factors that can contribute to these differences, they can often be traced back to the auditors and inspectors themselves, who may have different professional backgrounds and varying degrees of experience with PV and the requirements involved. For example, a PV audit may be conducted by an auditor who primarily only has quality assurance (QA) or manufacturing experience. As a result, although the resulting audit could have had a solid focus on the CAPA (corrective and preventive action) and deviation process, it did not clearly investigate the safety system or case processing metrics and process.
Potential solution: While overcoming these differences is challenging, it offers thus far untapped opportunities for greater collaboration and alignment across industry and regulatory authorities. For example, the most important requirement from a quality compliance and PV operations standpoint could be to develop quality standards or checklists that companies can adhere to. Furthermore, an entity, or PV quality group, consisting of individuals who are vetted or voted into the position by a consortium of companies, could ensure a more streamlined and consistent auditing process. By making findings from the group’s company and vendor audits publicly available, other companies or regulatory authorities could then decide not to audit the same vendor or company in the same year. In addition to greater consistency of findings, the creation of a PV quality group or consortium would also reduce overhead internally and externally. For example, if such a process or program existed, companies could potentially reduce the financial burden of auditing widely used vendors on a regular basis, which in turn would reduce the overall costs of a PV audit program. Furthermore, it could potentially reduce the cost and burden of our vendors having to host, correct, and maintain multiple audits, CAPAs, and deviations across multiple clients.
Challenges: Representatives from pharmaceutical companies are often working together, for example, to set good practices. They therefore already have a platform in place that — in theory — could also address quality standards. But consortia like these may not be interested in being in the business of setting data standards. What’s more, for any working group collaborating toward a common goal, the work is typically voluntary and unpaid, and individual members may decide to opt out of this working relationship at any time. Another, and arguably more important, roadblock is experience: Identifying professionals with a well-rounded background in PV is key but difficult; only very few have sufficient knowledge and experience across the PV development life cycle as well as true PV operational experience. Ideally, individuals in these roles would have a diverse amount of experience across the product life cycle, including experience within clinical, data management, statistics, medical, and regulatory. This breadth is extremely challenging to find, as companies often will silo their employees in a particular path, without giving them the experience of other functional areas.
Additionally, the main challenge would be to get companies to accept this model and be more transparent to the community about their inefficiencies and deviations. Some may believe this transparency could have a negative impact on the market; others may be concerned with proprietary information or trade secrets. However, the building blocks of a PV system should be relatively harmonized, so there is hope this stigma and perception of hoarding quality events and audit and inspection results goes away.
Tackling Inefficiencies
The issue: Inefficiencies in PV activities are not only slowing down product development pre- and post-market, but they also pose operational and budgetary strains—expenses that will ultimately trickle down to the patient. One of the root causes of these inefficiencies lies with what could be considered important “missing links” within the corporate structure of some pharmaceutical companies and a lack of awareness of the various PV requirements at the top. For example, top management is often not aware of the legal requirements for managing a product or the financial commitment a company would need to maintain PV staff that is knowledgeable and able to handle the oncoming workload. A lack of communication and planning between departments often means that the PV department is involved too late in the drug development process — for example, after submission of an NDA. Once on the market, however, companies are typically flooded with cases, and they inevitably find themselves in urgent need of contractors and consultants to reduce the workload. Tackling PV at this stage, however, is highly inefficient and costly.
Potential solution: An important step in addressing these inefficiencies is for companies to shift their focus to premarket development and plan for potential signals, audits, and inspections early by involving the PV department at the clinical trial stage. Preparing their PV systems up front will allow companies to collect better and more consistent data prior to market release and be better positioned to enter the market safely while meeting regulatory requirements. Also, involving PV leadership in business development discussions is key. For example, before expanding access into the European Economic Area (EEA), companies should make sure to have sufficient staff in place, such as QPPVs (qualified person responsible for pharmacovigilance) and local PV support, to help prepare for potential changes to the system. Global PV requirements vary and sometimes require significant personnel support to maintain — even for just a single product.
Challenges: Planning ahead and investing in staff and quality PV systems up front may pose significant financial and budgetary constraints. Early planning requires a balanced approach of bringing in the right team at the right time. However, it is often difficult to identify the potential cost savings and return on investment (ROI) of doing so. Not only are companies frequently unaware of the overhead and administrative burden accompanied by handling the outcomes of audits and inspections when there are numerous findings, but it’s also difficult to equate those activities with a certain “cost.” Finding the best approach to bringing in the right team at the right time may also mean that for a short period of time the actual workload is very light. Here, training and team building are important activities that could fill those gaps.
Another challenge is not having a clearly defined organizational structure and a proper understanding of each department’s roles and responsibilities. Quality and regulatory departments, for example, that may not understand why PV needs to be involved, often push back and don’t take part in key discussions.
The Role Of Education For Long-Term Solutions
To cause an overall shift toward greater compliance, consistency, and efficiency, ongoing education is key. In the U.S., there are currently very few degree programs with a concentration in PV. And while there are certain certificate programs or courses in PV, actual PV certifications and degree programs are rare or lacking. However, individuals with titles such as chief medical officer and VP of safety, as well as medical review physicians, heads of business development, quality, clinical development, and R&D, need to be sufficiently educated to understand PV requirements and enable a company’s PV department to collaborate efficiently with the various other departments. Market and patient access should be considered in tandem with PV requirements to ensure proper management of the safety profile of the drug in different regions.
A solid education about PV requirements will also be an important tool in shifting a company’s focus to premarket activities and investing in PV early in the development cycle. Understanding that there is an actual ROI by preparing in advance will drive home this message even more clearly, if the amount spent on contractors and consultants to take on PV-related tasks late far exceeds the net costs of planning early and reducing risk.
Overall, the successful integration of pragmatic PV approaches into the organizational structures of both pharmaceutical companies and regulatory authorities will ultimately rest on the knowledge and experience of PV professionals. Thorough education specific to PV will be vital for creating consistent and efficient auditing and inspection processes and an important first step toward greater alignment across the industry.
About The Authors:
A biologist by training, Sandra Blumenrath, Ph.D., M.S., serves as science writer for DIA. She brings extensive experience in scientific research, education, and communication to her role at DIA, where she produces scientific and healthcare-related content for a variety of audiences. She graduated with an M.S. from the University of Copenhagen and earned her Ph.D. at the University of Maryland, College Park. Prior to joining DIA, Blumenrath worked as a scientist, educator, and content developer at the University of Maryland, CP; the Howard Hughes Medical Institute (HHMI), and the American Association for the Advancement of Science (AAAS).
Catherine Baldridge, M.S., is a safety and pharmacovigilance consultant with more than 15 years in the industry. She is an active DIA member, former chair of the DIA CSP Community, and currently serves as a member of the DIA Community Leadership Counsel and the DIA Program Committee. Baldridge received her undergraduate degree in psychology at Hollins University, and her M.S. degree in clinical research and health evaluation from the University of Virginia. She also serves as adjunct faculty at Temple University School of Pharmacy, instructing pharmacovigilance in their Regulatory Affairs and Quality Assurance (RAQA) program.