Feature article

Safety First: Making the Next Step Change

Team Capital’s International Director David Pierce Hallahan interviews Julie Barnes PhD, Chief Scientific Officer at BioWisdom on drug safety and making the next step change. Prior to joining Biowisdom in 2001, Barnes spent 15 years in Pharmaceutical R&D, mostly at GlaxoSmithKline and is trained in pharmacology and behavioural neuroscience.

DPH: With new safety regulations recently issued by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA), what burning issue does the healthcare sector face?

JB: Avoiding human harm from the inappropriate use of approved medicines is one of the most challenging and pressing issues currently facing the healthcare community. The cost of drug-induced adverse events is almost incalculable. Over 750,000 people in the US alone are injured or die each year in hospitals from adverse drug events. Hospital expenses to treat patients who suffer adverse reactions during hospitalization are estimated at between $1.5 and $5.6 billion annually. For the pharmaceutical industry, there have been $billion lost because of the impact of product withdrawals, delays in getting new medical entities approved and soaring litigation in response to human injury.

DPH: What specific challenges does this bring for drug safety leaders in pharmaceutical and biotechnology companies?

JB: Despite a continual series of reforms in R&D and regulatory process over the years, the challenges in ensuring the safe use of medicines seem to be getting greater. People are living longer. We are managing more complex disorders, and because of the tendency for multiple drug combinations, the potential for unexpected reactions is higher. The science of drug safety has revealed itself through research endeavour to be highly complex. Individual genetic variation has shown to contribute to idiosyncratic adverse events and the way chemicals interact with specific biomolecules to affect organ systems can be very diverse. We are also living in a world where peoples’ expectations are greater, exacerbated by the media, lawyers and a continual stream of publications that implicate (sometimes inaccurately) increased risk of drug-related life-threatening events. This has led to a very risk-averse regulatory environment, the ultimate impact of which is the delay in getting new medicines to the market. The environment is set to stay.

DPH: What progress are companies making to comply with drug safety regulations throughout the clinical development process?

JB: While progress in the assessment of drug risk is being made, the improvements are still incremental. While more stringent non-clinical testing means that we are able to capture many forms of toxicity relatively early, statistics show that new compounds still carry considerable risk as they move into clinical evaluation and beyond. We still have very limited means to predict drug-related adverse events. Insight into any potential liability remains dependent on the experience of individual scientists (and the inherent bias that that brings), rather than anything more systematic. Assessments are still too reactive, and often when liability is seen, it is too often late to do anything more than terminate the compound from further development. Time and energy is lost and huge expense incurred.

DPH: Where will the step change come from?

JB: I believe that the opportunity will come from the move to a fully electronic world. The availability of electronic literature and technological advances in search and semantic text mining is already enabling the wealth of historic information to be put to good use in generating new knowledge systems and predictive models. This means that we can now better apply learnings from the past, right at the start of the synthesis of a new molecular entity. Perhaps more significant is the establishment of computerised systems for all primary and secondary medical care. This is high on government agendas and the Obama administration has authorized $19 billion to be directed to the adoption and use of certified electronic health record technology during the next several years. Although drug safety is not the only driver, an early benefit of electronic patient management is a reduction in adverse events due to medication errors. In the longer term, we will undoubtedly see the use of the resulting collection of anonymised databases of electronic health records for mapping out the complex profiles of drugs according to their ability to induce various adverse events in a wide population. The ability to position those profiles next to genetic and phenotypic fingerprints of patients or patient groups will provide significant advance in bringing together the complexity of human subjects with the complexity of drug action.  Data mining techniques across databases of post-marketing spontaneous adverse event reports is already common, and the legal requirement for the regulatory reporting of serious adverse events will drive similar technologies to be applied to larger datasets generated through electronic medical management. There is a great opportunity to apply semantic technologies such as lexical and ontology-based text mining, and terminology mapping to extract relevant data from such resources so that early signals of risk can be detected across very broad populations. The validation of such signals will require the integration of collated literature and knowledge models so that scientific plausibility of an adverse event can be assessed.

DPH: So, what sort of changes might we see?

JB: At the end of 2007, Prexige (lumiracoxib), a novel treatment for rheumatoid arthritis was rapidly withdrawn from European and Canadian markets because of liver injury. Prior to approval, there was considerable debate about whether this drug was too structurally similar to ibufenac, which was withdrawn for the same reasons some 40 years earlier. The hope is that the so-needed step change in our approach to safety assessment will enable us to better harness past experience and assess risk in a much more informed way. The use of technology that allows the exploitation of our ever-growing collection of electronic resources, and the constant reappraisal of safety risk in the context of competing products, patient use and individual patient characteristics, must hold the key to the future.

DPH: Thank you very much.

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