The Lengthening Arm of Pharmacovigilance

Pharmacovigilance’s influence has begun to encompass more than regulatory compliance, as can be seen by the number of trends identified by those on the front line. The most fundamental of them is a growing emphasis on quality. “Inspections are increasing,” says Julia Appelskog, qualified person for pharmacovigilance (QPPV) and head of pharmacovigilance at Bluefish Pharmaceuticals. Although that presents challenges, she says, it also prompts firms to achieve better systems and better processes, “because the leadership now understands how important pharmacovigilance is and is allocating more resources.”

There’s a balance to be struck, however. “It can feel as though we’re feeding a hungry compliance animal rather than focusing on patient safety,” says David Ferguson, head of international pharmacovigilance at Shire Pharmaceuticals. 

Breaking down global silos and establishing closer collaboration between pharmacovigilance and quality operations is becoming an increasing priority. “Inspectors expect to see a good quality system and a good pharmacovigilance system and that those systems’ processes are in alignment,” says Lesia Tontisakis, director of pharmacovigilance at Allergan.

Such cooperation is also essential for maintaining a high-level perspective, says Mariska Kooijmans, head of drug safety and pharmacovigilance international and European Union (EU) QPPV at Amicus Therapeutics. “The quality group needs to be part of pharmacovigilance decision-making and vice versa,” she explains.

Quality requirements can be particularly challenging for small companies, according to Laura Dalsasso, regulatory affairs office and pharmacovigilance manager at E-Pharma. The evaluation of a company’s pharmacovigilance system tends to be outsourced, which

creates its own set of complications. “You have to audit your partners, spending time preparing agreements with each,” she says. E-Pharma markets only a limited number of packages so it can avoid a sunset clause, but it must still maintain a full pharmacovigilance system for evaluating the safety data of those products, which is resource intensive. 

So, who’s responsible for pharmacovigilance? Ferguson says a pharmacovigilance system can touch almost any department in a pharma organization-as well as affiliates. “It’s a system for which others have responsibility as well,” he says, though that message can be a challenge to convey.

Risk–benefit balance

A growing emphasis on balancing the risk–benefit ratio requires companies to consider any benefit in terms of what it means to patients. “For example, a cholesterol drug might demonstrate that it lowers cholesterol levels, but determining the benefit means asking, do patients live longer? What’s the cost? And does your drug work better than others currently out there?” says Ferguson.

The risk–benefit profile isn’t static, either, which adds tasks to the workload. Beyond the point of clinical trials, any new data is almost exclusively safety data, says Lesley Wise, managing director of Wise Pharmacovigilance and Risk Management, suggesting that pharmacovigilance or medical safety should be driving the risk–benefit discussion. 

Wide decision net

The more comprehensive the picture that pharmacovigilance activities develop, the greater the value to the business. Tontisakis says  companies today are increasingly bringing in safety experts at the earliest stages of potential acquisitions in order to help them assess the matter. “It doesn’t make sense to bring in a product that isn’t safe and would cost in the long run.”

It’s surprising, then, that pharmacovigilance doesn’t usually have a full seat during the due diligence process. “It’s often assumed that it will be all right-until you hear it’s not,” says Ferguson. 

At Bluefish, senior management seeks advice from pharmacovigilance before deciding to initiate a new product registration. “We’re asked what the implications will be for risk minimization activities, will a post-authorization safety study be required, and what are the potential costs,” says Appelskog.

Key differentiator?

One commercially interesting trend is the potential to use safety as a differentiator against other brands. Kooijmans used to work at Biogen, which recently had its first product approved for an orphan indication (nusinersen, for spinal muscular atrophy) because the drug’s safety profile was better than that of the already approved  product for the indication, thereby leading to a superior risk–benefit profile. Amicus, her current company, meanwhile, has been granted approval for an oral drug, Galafold (migalastat), for treating Fabry disease. Galafold was found to be easier to tolerate and had fewer side effects compared with already approved and marketed intravenous treatments. “For companies focused on ‘me-too’ products, having a safety focus would be a good approach,” says Kooijmans. “If you aren’t developing targeted, personalized medicine, you need to think about the two other areas to make your drugs stand out: better and safer-or both.”

When a company is looking to differentiate itself in the area of safety, such activities will be part of the clinical development plan, says Wise. This is typically managed by clinical rather than by safety, especially in smaller or mid-sized companies. In larger companies, medical safety-as distinct from the operational aspects of pharmacovigilance-is firmly embedded in clinical development. “Using safety as a differentiator is an argument in a product’s risk–benefit profile,” says Wise. “If your risk–benefit ratio is positive because your risks are lower-but the benefits are the same-that’s an important thing to know.”

Cross-border action

The European Medicine Agency’s (EMA) good pharmacovigilance practices (GVPs) are being actively considered by other regional markets. They are likely to adopt many of the same principles in time-but with their own individual emphases, thereby creating more work for global players. Appelskog pointed out the importance of good, ongoing dialogue, which is well established within the EMA. “I’m concerned that in Eurasia and the Middle East, GVP will be brought in without discussion or willingness to adapt,” she says. “A lot still has to happen to agree on standards.”

Other complexities include the requirement to have a responsible person for pharmacovigilance, even in markets in which a product might not be marketed. “Shire works in the area of rare diseases, and it might be that we don’t have even a single patient in a small country such as, say, Cyprus, but because we have Europe-wide marketing authorization, which is applicable to all EU member states, we’re legally obliged to have a responsible person for pharmacovigilance in that market,” says Ferguson. 

Role revision

Finally, there are skills issues to consider, stresses Wise. For instance, pharmacovigilance leaders will have to possess certain new business skills if they’re to play full roles in clinical risk–benefit decision-making. They’ll also need strategic skills in order to support the evolution of a pharmacovigilance department that has an integral role to play in R&D. 

For Kooijmans, the role of the QPPV has evolved too; here, quality assurance has become the chief concern. “When I started out in a QPPV role, the focus was more on discussing the minimal safety side with regulators,” she says. “Now it’s much more on being ready for inspections, making sure your system works, and keeping the pharmacovigilance system master file up-to-date. All of those things serve to attract different kinds of people to pharmacovigilance.”

The management of affiliates has become another priority for pharmacovigilance heads, adds Ferguson. In the past, in the hiring of a safety person in an emerging market, those roles would have focused on operational activities such as receiving adverse event data, doing the translation, entering the data into the database, and making sure the events were reported to the authorities on time. “Now I’ve brought those operational activities into the center and hired third parties to manage them,”  says Ferguson. “The skill set I need now from someone at the affiliate has changed from in the past; now I look for people with pharmacovigilance and quality experience. I need people who can ensure compliance, who are familiar with all of the regulations, and who know how those regulations affect everything we do.”

A further development is that the QPPV, traditionally a European role, has become a requirement in more and more markets, says Wise. “That raises questions as to who that QPPV is going to be, because on one hand, few QPPVs would be willing to take responsibility in markets outside Europe, given the legal liabilities. But, because on the other hand there’s only one pharmacovigilance system, it doesn’t make sense for a global company to have multiple QPPVs.” 

It’s too early to tell how these new developments in pharmacovigilance will pan out, but these are interesting times for a fast-evolving discipline. 

Cheryl Key is Head of Practice PV Platform Services/Principal Medic at ProductLife Group. She can be reached at ckey@productlife-group.com