Guest Column | January 28, 2021

You're A Small Biotech — How Should You Implement A Pharmacovigilance System?

By Steve Knowles, chief medical officer, Halozyme Therapeutics


Learnings on how to implement drug safety protocols effectively both time-wise and cost-wise

When it comes to implementing strong pharmacovigilance (PV) practices at your company, there are a variety of components and capabilities that will be necessary to put in place. Having worked in this space for the majority of my pharmaceutical industry career, I know that it can be incredibly difficult to understand the intricacies of integrating these processes — especially with a constantly shifting regulatory landscape. The task can be quite daunting.

Let’s take a step back. What does pharmacovigilance entail? It’s a catchall phrase used to describe anything that falls underneath the drug safety umbrella — detection, assessment, understanding, and prevention of adverse effects that may be associated with a medicine. For obvious reasons, this is a critical component in the drug development process. It ensures that patients experience as little harm as possible when taking medications (clinically validated ones or otherwise).

For large pharmaceutical companies, these pharmacovigilance capabilities can usually be found in-house, with entire departments devoted to ensuring the drugs the company is developing are safe for patient use. However, small clinical-stage companies — such as biotech startups — may not be able to afford this luxury. If you’re heading one of these organizations, you may be asking yourself: Should I outsource these capabilities to a contract research organization (CRO)? When do I need to make pharmacovigilance a part of our internal clinical processes? And what sorts of technologies can I adopt to streamline these processes?

I’ve been on both the Big Pharma and biotech sides of this debate. With this knowledge in hand, I can help answer some of these commonly asked questions raised about pharmacovigilance best practices.

To Outsource, Or Not To Outsource?

Drug safety is a vital cornerstone of the drug development process. For this reason, perhaps the most difficult decision for small companies to navigate is which capabilities will be tackled in-house, and which will be outsourced to experts in the field.

There are two crucial capabilities to weigh when making this difficult decision: the first is related to the collection and processing of clinical trial serious adverse events (SAEs) and adverse events of special interest (AESI) cases in the global safety database and maintaining regulatory compliance with safety reporting. The options include hiring internal case processors or hiring a CRO to accomplish these tasks for you. From my experience, small companies can go either way here, depending on their unique needs. Given that early clinical trials tend to be small and, in non-oncology indications, do not elicit high numbers of SAEs — and the complexities of global clinical trials from collecting SAEs to a multitude of different reporting requirements in different countries — outsourcing of case processing and reporting to a CRO is the most expedient choice. It is also advisable to have SAEs from all clinical trials and all indications in a single safety database rather than divided between different CRO safety databases. Having just one safety database ensures clear sight of all information for signal detection and enables a much smoother process for compiling data for the annual Development Safety Update Report (DSUR).

And the second component of this difficult decision: How do you make smart safety decisions based on these cases? For this, companies must hire scientists who are experienced enough to understand and analyze this complex information, in order to make the correct safety judgments. Sophisticated medical judgement is necessary when reviewing safety data and looking for safety signals. It’s a skillset that requires experience and knowledge of all sources of safety data and a working knowledge of statistical analytical approaches. Even in clinical trials, data can be incomplete and the number of cases can be low, which places a premium on medical judgement when making decisions and on the ability to communicate conclusions with authority. From my experience, this medical capability is best kept in-house and supplemented when necessary with medical consultant input for specific safety issues that may arise from time to time.

Whether or not you decide to outsource the above activities, it is vital to have an in-house quality management system (QMS). This consists of hiring employees in safety and quality who have oversight of all safety activities and monitoring compliance. Detailed standard operating procedures and work instructions, along with clear governance structures (whether in-house or outsourced), help to enable the escalation of safety issues, including non-compliance issues, and ensure clear decision-making rights within the company. Remember, the company is ultimately responsible for all activities and decisions carried out under its name, even if carried out by a third party.

I cannot stress enough how critical this is. Without the proper QMS and governance in place, companies will be unable to make the appropriate safety decisions — ultimately impacting (and jeopardizing) the path to a drug’s regulatory approval. Because of its critical nature, this oversight, governance, and decision-making process should always be maintained within the organization, rather than delegated to an outside entity. This process is central to a company’s clinical strategy and, as such, it should be central to the organization. The reality is that no one will care about the clinical future of your company as much as you do — even the best CROs. While this may be a steep investment for a small company, it is well worth it in my experience.

When Should I Implement Pharmacovigilance??

Drug safety is not something that can be an afterthought in the development process. As such, it is critical for biotech companies to implement pharmacovigilance practices sooner rather than later. For example, for those companies close to completing Phase 3 trials, it’s not possible to make the shift to regulatory approval overnight. It takes significant time to prepare for this process, especially on the pharmacovigilance front. And for those that wait too long to implement pharmacovigilance into their strategies, they wind up paying a significant price down the line. It is going to be very challenging to implement a high-quality QMS, governance structure, and single safety database whilst conducting pivotal global registration trials. Remember, your PV system has to support regulatory submissions (NDA/BLA/MAA) around the world and will be inspected by regulatory agencies such as the FDA and EMA to ensure you have an adequate, well-functioning system that provides good safety oversight in clinical trials and can support a marketed product.

As a drug developer, it is crucial to start thinking about this early in your drug’s clinical development path, so that when studies in patients begin, there is a functioning quality system and decision-making governance in place, with decision-making being in-house. The system obviously develops as trials become larger and global, but setting a solid basis for a PV system early will reap benefits in the long term.

Are There Technologies That Can Streamline These Processes?

When it comes to drug safety, technologies that can help enhance our current capabilities are few and far between. It’s true there are different databases we use to help identify literature and examine adverse events that have occurred in drugs in the past. But a significant limitation here is that these databases are huge — terabyte on terabytes huge. The amount of information is much too vast to sort through to uncover significant data points and certainly too vast for the human brain to process.

For small biotech companies conducting clinical trials, I would recommend focusing on technologies that help in the review of safety data from trials. It can be challenging to review the many pages of line listings, lab data, and patterns, so visualization tools can be very useful. For example, Spotfire and Tableau are two visualization tools that provide a high-level overview, allow data to be combined or split, and allow the user to focus on individual patients when necessary. For visualizing hepatic safety data, I recommend using the evaluation of drug-Induced serious hepatotoxicity (eDISH) approach.

I must stress that these technologies should serve as aids and do not replace a carefully crafted pharmacovigilance system. Until the technology advances and is embraced by the regulatory bodies, it is crucial to maintain well-thought-out integrated pharmacovigilance processes within your company. Emerging biotech or Big Pharma, outsourcing capabilities or not, this is true for any life sciences company developing a drug with a potential to be on the market.

About The Author:

SteveSteve Knowles, MB.BS, MRCP, MFPM, has deep pharmacovigilance and medical affairs experience gained over a career spanning almost 20 years. He joined Halozyme in January 2018 as VP of drug safety and pharmacovigilance. He is responsible for the company’s Medical, Regulatory and Drug Safety organizations. Prior to Halozyme, Dr. Knowles spent 16 years at Eli Lilly & Co., most recently serving as senior medical director of global patient safety and benefit risk management. Before joining Lilly, he spent more than 17 years in clinical practice in the UK in both hospital-based and general practice roles. Dr. Knowles received his Bachelor of Medicine and Surgery degrees (MB.BS) from the University of Newcastle Upon Tyne and is a member of the Royal College of Physicians (MRCP) and the Faculty of Pharmaceutical Medicine (MFPM).