Federica Santoro 0:02

Welcome to Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. This episode is part of the Uppsala Reports Long Reads series, where we select the most topical stories from our magazine, Uppsala Reports, and bring them to you in audio format. Our pick for today is the article Philosophy of Science Meets Patient Safety, which appeared in issue 82 of Uppsala Reports in April 2020. If pressed, most of us would probably say we want our healthcare to be both patient-centric and evidence-based. We want it to be tailored to our unique circumstances, but also based on sound scientific evidence, which often derives from average measurements in big populations. So, how do we reconcile these two seemingly incompatible goals? That's where the philosophy of science comes in. Emerging ideas are challenging a rigid reliance on evidence-based medicine and offering a more nuanced understanding of patient safety. Elena Rocca is co-director of the Center for Applied Philosophy of Science at the Norwegian University of Life Sciences. She's also one of the principal researchers of the Cause Health Risk and Safety Project. In her article for Uppsala Reports, Elena explored the nature of evidence and so-called dispositions. Here's the full story read for us today by Lee Bennett.

SPEAKER_00 1:44

Philosophy of science meets patient safety. What are causes and how can we find them? What's the value of outliers and unexpected observations for scientific inquiry of causes and effects? How do scientific discoveries happen? And how do social structures and communities help or hinder the process of discovery? Most practitioners would agree that these questions lie at the very core of pharmacovigilance and patient safety. And the same questions are continuously discussed by philosophers of science. Unfortunately, however, there is not much dialogue or exchange across these two disciplines. Our project, Cause Health Risk and Safety, Causation, Probability and Complexity in Pharmacovigilance, exists to develop that dialogue. Cause health works at the interface between philosophy of science and patient safety. Our aim is to contribute to a more self-reflexive and self-critical practice of pharmacovigilance and medicine. But at the same time to get philosophy of science closer to the specific day-to-day challenges of improving patient safety. Bridging two disciplines, one applied and one conceptual, is a challenge, even when they are grappling with many of the same issues. Embracing such challenge, however, has led us to new and exciting perspectives, and further challenges. In medical science, there is a general resistance against taking action or expanding knowledge based on evidence that does not include statistical correlations in a reasonably large and reasonably representative sample of the population. After all, the thinking goes, to be based on scientific evidence means to be backed by observation. The question is, what kind of observation? The current evidence-based paradigm has a clear and exclusive answer to this question. The best evidence of causality comes from controlled clinical trials, and the second best from controlled observational studies. However, a global movement of philosophers of medicine is emerging in opposition to that paradigm. Although starting from slightly different conceptual foundations, these scholars have independently reached the common conclusion that, for the purpose of making causal claims in medicine, evidence from causal mechanisms and patient-produced evidence are at least important as evidence from population trials. An early cause health initiative was an open letter published in the BMJ Evidence-based medicine journal, in which 42 clinicians and philosophers jointly urged that statistical approaches, in particular randomized control trials and systematic reviews, cannot uncover all causally relevant information contrary to their widespread assumed status as the universal gold standards of evidence-based medicine. For pharmacovigilance, this means that hypotheses of harm can be considered as scientifically justifiable and, therefore, worth pursuing even if they are not backed by big numbers and repeated observations. Reports of a specific symptom for a certain medicine might be few, there may be only one, but if they are qualitatively rich and point to a hypothesis for the underlying mechanism, they should be taken seriously. Further work on this front was done in a meeting in Erice, Italy, where eighteen experts from different medical fields, together with philosophers and patients, met to discuss the challenge of using patient experiences to improve causal understanding in medicine. A report of the meeting, the Eric Call for Change, is available as an open access article in the journal Drug Safety. Sometimes we observe that an intervention tends to make a difference in a regular way. For instance, ibuprofen causes gastrointestinal symptoms in many patients. This observation is useful because it points to an intrinsic property of ibuprofen. Intrinsic properties, which philosophers sometimes call dispositions or capacities, or causal powers, are what pharmacovigilance and medicine in general is after. We see correlations all the time, but not all of them point to intrinsic properties. From correlations alone, then it is hard to derive intrinsic dispositions. Paracetamol is correlated with childhood asthma, for instance, but is it because the drug has an intrinsic disposition to cause asthma, or do asthma and paracetamol have a common cause, for instance, chronic airway infections? From such simple examples, the connection between the practice of pharmacovigilance and the philosophy of causal dispositions seems almost trivial. Clearly, hypotheses of harm must be hypotheses of intrinsic dispositions and must be evidenced accordingly. This is, however, not so simple. In fact, harm detection is increasingly based on the recording of external relations rather than intrinsic dispositions. Causes and effects are mainly searched for as factors that correlate in populations. In our project, we have seen this by examining risk assessment methodologies in general. We also specifically analyze different approaches to evaluate the toxicity of petroleum residues in the environment. From this work, we have seen that thinking dispositionally requires a much more holistic or ecological approach than the traditional procedures for risk assessment allow. Pharmacovigilance, as a type of risk assessment, is no exception. There is, however, another point to make. Looking for causal dispositions is demanding. It brings us into the uncertain territory of mechanistic knowledge, and at the same time, it demands that we understand not only one phenomenon, but also its broader context. This is not always possible. Moreover, while all methods are useful to evidence causal dispositions, none of them is perfect. We can see a correlation, but we will never be able to see a disposition. We can only collect some symptoms of it. For medicine and pharmacovigilance, this means that causality assessment is a complex effort, which needs a plurality of evidence. How, however, should such causal evidence be evaluated for the purpose of looking for a causal disposition of a drug to harm a certain patient, what counts more? In our recent article, Causal Evidence and Dispositions in Medicine and Public Health, we consider systematically the different methods used in medicine as evidence of causality. All have advantages and disadvantages for the purpose of evidencing causal dispositions, which we describe. Ultimately, we propose the approach that we consider to be the best if we want to have good evidence of causal dispositions. This work applies to medicine and public health in general, and we are now in the process of working out what a dispositional approach to pharmacovigilance would look like. Pharmacovigilance is an explorative enterprise, and it is sometimes compared to serendipity. Untargeted effects of drugs are first observed when one is not looking for them. As is the case with serendipity, for harm detection, one also needs chance and a prepared mind, the clinicians or the causality assessors. But does that mean that in order to improve pharmacovigilance, we must promote discoveries by chance? How can this possibly be done? For an answer, we started by looking at how serendipitous discoveries happen and how they can be promoted. The latest developments in philosophy of science point out that serendipity in science needs chance and a prepared mind, but not only these things. It also needs a responsive network of scientists and stakeholders able to take up the unexpected observations and make use of them. We argue that isolated measures within the narrow boundaries of pharmacovigilance can be useful but not sufficient to improve the detection of the unexpected. More groundwork at the very structure of the medical community is still needed to create a flexible transdisciplinary network in pharmacovigilance. According to our reasoning, there is a need for institutional changes in medical training and research, so that clinicians, decision makers, causality assessors, patients, and manufacturers can create a common culture and be critical of their own premises and assumptions. Pharmacovigilance is an explorative science which starts by detecting unexpected and significant observations. To promote such serendipitous observations, it is not sufficient to make changes within the narrow boundaries of pharmacovigilance. Instead, the whole medical community must make an effort to promote transdisciplinary approaches to medical inquiry. Here are some summarized examples of the changes we suggest. In research institutions, quit the traditional organization as research groups divided by discipline. Ensure that research activities involve several disciplines throughout. In medical journals, include a section dedicated to conceptual deepening about the foundations, motivations, and blind spots of current methodologies for collecting evidence. In PhD training, include experimental work from at least two disciplines, one main, one complementary. For instance, toxicology and epidemiology, require a conceptual non-empirical manuscript for PhD training to promote critical reflection. And in conferences and societies, center around a task rather than a discipline, for example, a society for evidence evaluation, for causality assessment, for risk analysis, rather than for epidemiology, toxicology, etc. And collect experts from different disciplines. Building on this work, cause health risk and safety will continue using a dispositional understanding of causality and a transdisciplinary approach to advance pharmacovigilance and patient safety.org for more pharmacovigilance stories.

Federica Santoro 12:04

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