The need for evolution in pharmacovigilance
Pharmacovigilance is a critical function in ensuring public health, but is our current system built to tackle the challenges of evolving science and political upheaval in the modern world? Matt Fellows investigates.
The past few years have been particularly testing for the pharmaceutical industry, especially in Europe. With the UK’s exit from the European Union at the beginning of the year, pharma and life sciences face a continuation of the perhaps unprecedented levels of uncertainty faced over the past years; a continuation of those same obstacles that plagued decision-making and scuppered the chance of materialising any kind of informed, long-term strategy. This affects almost, if not all, functions across the industry, and pharmacovigilance in particular is unfortunately one of those hardest hit.
But it’s not just Brexit that has fogged up the windshield. The natural advance of the science driving pharmaceutical innovation has begun to present its own challenge to pharmacovigilance functions, and the space is facing pressure to evolve to meet the demands posed by novel, advanced therapies for which the current system may not be fit for purpose.
Despite these challenges, things are certainly not looking bleak in the space; a 2019 report by GlobalData projected that the pharmacovigilance market will hit $11.64 billion by the year 2026. With that kind of anticipated growth, how do things look from those working in the sector? What’s driving that rise? [Pharmafocus] reached out to Professor Saad Shakir, Director of the Drug Safety Research Unit (DSRU), to get a feel for where the pharmacovigilance space is today.
“Pharmacovigilance has expanded in the last 10 to 15 years; it’s shifted from being a reactive, low-level regulatory compliance function to being more proactive, and that has happened as a result of two things,” he explained. “The first is that regulations in the last decade or so have expanded the horizons for pharmacovigilance – for example, the introduction of risk management, risk minimisation, and some systems, for example, like Eudravigilance in the UK and Europe and the Sentinel project in the United States.
“Now, we are really at the stage of embracing new technologies such as artificial intelligence (AI) and machine learning (ML), and incorporating advances in new therapies, such as gene therapies and biotechnology products, into pharmacovigilance,” he continued. “So, yes, there has been expansion in pharmacovigilance from being a state regulatory compliance type of function to a more proactive activity, and obviously that will require money internally and externally; that has resulted in the increasing size of pharmacovigilance’s market status.”
Getting up to par
These expanded horizons mean great things for patient safety around the world, which is (or should be) the top priority for any pharmaceutical or life sciences player. The evolving sophistication of the systems currently in place ensure that any potential health risks or adverse events are identified quickly in traditional products, and from there action can be taken swiftly. This can include interventions requiring that manufacturers recall their products in order to protect public health, as the FDA, for instance, did last year to mitigate the risk of valsartan medications for high blood pressure after some batches were found to contain N-nitrosodiethylamine (NDEA) or N-nitrosodimethylamine (NDMA): chemicals suspected to cause cancer.
However, with new forms of novel therapies emerging all the time, are our current systems equipped to adequately identify potential risks in these products? Professor Shakir outlined the key challenges facing the space as he sees them.
“The biggest challenge is not to over-regulate to ensure that the balance is correct between allowing scientific activity and the care and protection of patients, and the appropriate level of regulation,” he said. “Another challenge (or opportunity) is to test whether our methods, which have been established in the last 60 years and expanded in the last two decades and which have focused on small molecules, can be adapted or modified to cover this new era of technology products and advanced therapies.”
This is the crux of the matter: as biological medications and gene therapies become more mainstream in treatment, is there a need to reassess the suitability of existing processes, or will entirely new methods need to be designed?
“I don’t think they will need entirely new methods, but they will require modification of existing ones,” Professor Shakir responds. “With these new therapies, they are more complex, many of them are used in conditions where the patients are more sick and they have other concurrent illnesses; they may be taking other medications. So, these are things which need to be sorted to assure that we focus on the effects of the new therapy and differentiate that from the effects of the underlying or concurrent illnesses and medications. With these therapies, especially when they are personalised for gene therapy and so on – the numbers of patients who receive them are smaller than, say, a tablet or statin which is taken by tens if not hundreds of thousands of people. So we need to modify our message to identify drug safety issues a smaller number of patients.
“Also, the nature of adverse reactions which they may cause are different; for example, conventional methods affect the kidney function; liver function; cardiovascular function; CNS function, while the new therapies have a different profile of effect: they have immunogenic effects because they are effectively proteins and they reduce immunity and make patients susceptible to infections and tumours – the nature of the adverse action with them is different. We need to not invent new methods, but notify our existing methods to ensure that we can address the different nature and frequency of adverse events associated with these advanced therapies.
“All the monoclonal antibodies which are used in a range of conditions – rheumatoid arthritis, inflammatory bowel disease, psoriasis – they do share the characteristics which I mentioned: they tend to be used by a smaller number of people, they may alter a patient’s immunity and therefore make them susceptible to infections,” he continued. “For example, everybody in the world is talking about the coronavirus. Would contact with a carrier of coronavirus result in a different response or more susceptibility by a patient that is immunosuppressed compared to a patient that isn’t? It may or may not be, but these are the things which we need to act on; we are now in a more proactive era.
“What I am a bit cautious about is to talk about the challenges in a dramatic way as if we are heading into unknown intergalactic territory,” he added. “It isn’t – it’s just modifications of what we already have to be ready for the kinds of differences that new therapies offer.”
So we know that the groundwork to adapt these systems has already been laid and it’s clear where the challenge facing pharmacovigilance originates, but how exactly can this be achieved? Well, to modernise and adapt to evolving challenges such as these, you need an adaptive solution; in this case, burgeoning technologies and analytic techniques could be the answer.
Professor Shakir explains: “There is increasing use of registries today, where every patient who uses a certain medication or has a certain disease is included in the registry. Information about them is obtained – their age, sex, pre-existing conditions and so on – and then they are followed up over a period of time to see what happens to them, adversely or beneficially, when they take one of these new medications. This is as opposed to depending on spontaneous reporting systems which we use for existing products.”
As this is an approach already being practiced across patient care, and given the fact that the number and size of medical registries in play at any one time is only going to increase, this method is going to become more pertinent and more effective as time goes on and the demands placed upon pharmacovigilance functions continue to evolve.
However, this can be taken even further, Professor Shakir notes: “Another development which will need to happen is ‘linking’. if reduced immunosuppression leads to patients developing certain kinds of cancers, this doesn’t happen the second week after you take the medication – there is a time lag, and the best way to record it is to link exposure of the new therapies to, say, cancer registries. So, when a person takes a drug and then at some point in the future they develop a cancer that is included in the registries, we now have data linking the drug exposure to the development of the cancer and we can study them. This is what I mean by modification: we already have an increasing number of registries, but at the same time, we are in various parts of the world developing these linkages with genetic biobanks and registries, so we could use the availability of information technology infrastructure to identify the signals and then evaluate them further.”
While the interconnectivity of electronic patient data and analysis of those data can lead the charge in tackling some of the challenges on the horizon, there is another key technology that can also play a key, or perhaps even central, role. Of course, it’s the industry’s darling: AI.
“AI is emerging in biomedical science. A definition of AI is really to make a computer replicate the human intelligence; I think that is a limited definition,” Professor Shakir remarks. “AI is enhanced intelligence, doing things that the human brain cannot do – complex computations. The human brain may be able to do it in three months, while artificial intelligence may do it in two seconds.”
“The point of artificial intelligence in this context is to put together multiple data and then use that to predict something. A lot of work is happening where people are trying to put clinical laboratory data – whether it be haematological, biochemical, imaging, genetic – together and predicting whether a certain person will get an adverse reaction and stratify them into low/medium/high likelihood and so on and so forth. So, AI at the moment is being studied in an experimental way. I predict that in the next five to ten years that there will be applications of AI and ML into actual pharmacovigilance.
“It’s happening in other fields: in oncology, for example, not all tumours are the same, so people are linking imaging and the computer may not look at the image of the MRI scan in the same way that the radiologist looks; it may look at the numbers of pixels and then relate that to physiological findings, to the patient’s characteristics, to the family history, to the genetics, and then come up with predictions and suitability for treatment. We in pharmacovigilance are, to a certain extent, followers in these areas,” he continued. “At the moment that prediction from AI and ML is at an experimental stage and there are a lot of players working on it, and it will circulate through the system.
“And there are people whose job would be to introduce new developments into our system. For example, in the UK, huge amounts of money are being invested to incorporate pharmacogenetics into healthcare, and there will be a move to incorporate these new developments – AI, ML, genetics and so on – into pharmacovigilance. First there is the development, then there will be the other stage of incorporating it into day-to-day practice. Who is going to be the developer and the winner for this? Are they going to be the Googles and Apples and Amazons? Are they going to be biomedical providers? Is it going to be the megacorporations, or is it going to be small, active, nimble players? That’s beyond me; I can’t say who, but it may end up being a combination of both.”
Left in the dark
Of course, while the natural progression of scientific development would have always manifested these challenges for the pharmacovigilance space regardless of any societal or regulatory shifts, it could never have prepared for the seismic shift facilitated by Brexit. It’s the biggest and most all-encompassing issue facing British and European industry across all sectors, not just life sciences and pharmaceuticals, with the almost perpetual uncertainty placing a stranglehold on any potential decision-making. With the official departure having been triggered on 31 January this year, one would hope this had put an end to the second guessing, but is this really the case?
“I’ll give you a short answer,” Professor Shakir muses. “Will Brexit impact on pharmacovigilance in the UK? The answer is yes. The second question is: how will it impact? Anyone who tells you that they know is telling you a lie; no one knows. We know one thing: we know that during this transitional period, between now and the 31[st] of December this year, there will be no change. Things will continue as they are. Another thing that we know is that, from the first of March, there will be negotiations. Now, what will be the results of the negotiations? No one knows. There is a wish list by the UK Government to keep alignment and keep collaboration. And I think that in the EU27 there is mutual respect. I think everybody is going to put the patient and their safety first, but when negotiations haven’t even started, how do we know how it’s going to end up, other than knowing what is publicly being stated as their intentions?”
It’s not a reassuring take, but the industry has been left with little option; with negotiations between the two parties yet to begin, pharmacovigilance functions across the region are stuck waiting to know what direction the wind is blowing. However, Professor Shakir offered what little advice he could for those in the space:
“I think that people would be wise to prepare for three possibilities,” he noted. “A possibility of having a special relationship where there will be little change. The second possibility is the UK will be a third member state, as we are now, but we’re going through the transition stage with close collaboration and exchange of information and so on. And the third possibility, which the government is not hiding, is no deal, and we will be a third member state; our relationship with the EU would be similar to that of Canada or Australia or Japan with the EU. We are being told by the MHRA that they are prepared for all eventualities.”
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