From October 7 to 9, 2019, Re-Check’s Catherine Riva participated in the 4Es Forum Improving the detection, analysis and reporting of harms in medicines, a three-day workshop organized by the Centre for Evidence-Based Medicine (CEBM Oxford) and Uppsala Monitoring Center, the WHO Collaborating Centre for International Drug Monitoring. The meeting was held at the Ettore Majorana Foundation and Center for Scientific Culture in Erice (I), and brought together around thirty participants from different countries and very diverse professional horizons: researchers, clinicians, public health specialists, pharmacovigilance program managers, investigative journalists and representatives of patient and consumer advocacy initiatives.
Based on the observation that the current approval procedures have shortcomings, that many available medical products are ineffective and that post-marketing surveillance regularly fails to detect the adverse effects such products can induce before people are harmed, the workshop aimed at exploring for three days avenues of analysis and potential solutions.
Each day was devoted to a specific theme: the first to the pre-marketing phase, the second to post-marketing and the third to communication about the potential adverse effects of medical products. Each morning and each afternoon were structured around three presentations, the contents of which aimed at raising questions to be developed in plenary and group working sessions.
During the session “Potential solutions to the problems of pre-marketing approvals”, Catherine Riva presented the results of Re-Check investigation on the ghost-management and the capturing forces that were at work during the approval process of the first HPV vaccine, as well as Re-Check on-going research project GhoMan – Chasing the Ghosts.
The organizers had at the outset announced they expect the speakers to bring provocative content to launch and fuel the debate. And it happened: discussions were lively and passionate.
The participants quickly agreed on a first observation: the situation is extremely serious and bears all the features of a crisis. The adverse effects of medical products are a major and growing cause of illness, disability and death, and in some industrialized countries possibly even of reduced life expectancy. Much of this burden is due to over-medicalization, which increases the risks associated with common conditions rather than improving them. And the problem seems set to worsen with the acceleration of new drug approval procedures. Moreover, the current system too often fails to account for the harms caused by inadequate prescriptions, ineffective treatments and polypharmacy.
Another finding shared by all participants was that monitoring for adverse drug reactions largely depends on observational studies sponsored by the companies that market the medical products and are in charge of their risk management programs. Such studies are generally too small, bear significant methodological weaknesses and their results are too often not public, although the main regulatory agencies (FDA, EMA) rely on them to monitor medical products’ safety. Finally, if spontaneous notifications might identify previously unknown undesirable effects, it does not allow estimating their incidence and the problem of under-reporting remains unresolved.
This issues’ overview quickly brought up another key problem: how to establish with a high degree of certainty that there is a cause and effect relationship between a medical product and reported harms. The issue of establishing causality highlights the methodological limits of the current pharmacovigilance system, and it is complicated by the influence of players whose agendas conflict with patients’ interests. A theoretical problem that brings relevant real life consequences: even when studies suggest that a drug can cause an adverse event, how to assess the case of a single patient and how to conclude on the causality in any single case? Issues still unresolved, whereas the alleged victims are often left alone facing harms and uncertainties. Many participants agreed on the urgent need for a system reform that also can give the space they deserve to the stories of patients, and the necessity to find other ways to communicate on this subject.
Significant disagreements emerged during discussions concerning some fundamental aspects: the analysis of the causes and the main drivers of the current situation, the role of Evidence-Based Medicine (EBM) – in particular the pyramid of evidence and the value of randomized controlled trials (RCT) – as well as the degree of radicalism to be adopted in the positions taken and the consequences to be drawn. Even though the attendees were almost all personalities known for their critical positioning in relation to the current system and favorable to far-reaching reforms, apparently at the moment they can’t agree on some fundamental points and the direction to be adopted. In view of these differences, the three days of meeting at Erice can be surely seen as a first step in a process that promises to be long and complex.
Beyond that, Erice workshop was very productive. Several documents (positions and roadmaps) were notably put together and give a basis to be further developed. The first available is Erice’s Statement, which includes ten recommendations.
Improving the detection, analysis, and reporting of harms in medicines and devices – Statement from the 2019 4Es Forum (Exploring, Enhancing, and Empoweringin Erice) (PDF)
Serious global challenges exist in recognizing and minimizing harms from medicines and devices
Harms from medicines and devices are increasingly recognized as important causes of morbidity and mortality worldwide. Given the current and future levels of their use in clinical practice, the total burden from harms of medicines and devices is a serious and growing global public health problem.
Examining the benefit-harm profile of medicines and devices is the collective responsibility of multiple stakeholders, including industry, regulators, policymakers, healthcare systems, healthcare professionals, patients, and their carers. However, the current states of development, approval processes, surveillance, and use of medical products limit the abilities of all parties to fulfil their respective responsibilities. The competitive environment of research and development in industry and the shift towards rapid access by regulators have resulted in a growing number of new medicines and devices with marginal effectiveness and unknown harms receiving marketing authorization. Decisions by regulators are based on data of benefits and harms that are chosen by the sponsor and may be incomplete. Furthermore, estimates of benefit-harm at the time of marketing authorization are made using pre-selected populations which may fail to reflect the heterogeneity of users in clinical practice.
Harms caused by medical products not only depend on the intrinsic properties of the product and on the susceptibility of the individual patient, but also on how they are prescribed and used within and outside of healthcare systems. Post-authorization surveillance of the adverse effects of medical products predominately relies on company-sponsored studies, as part of their regulatory commitments, and case reports collected by regulators from industry or directly from health professionals and patients. The results of post-authorization studies contained within risk management plans are often not completed and their results are often not published, while serious harms experienced in clinical practice are often under-reported. Furthermore, case reports are currently under-appreciated in the hierarchies of evidence used for the development of guidelines for clinical practice.
The 4Es Forum on Improving the detection, analysis, and reporting of harms in medicines and devices was held in Erice, Italy between 7-9 October 2019. It provided an opportunity to build a foundation for future collaboration between two disciplines – evidence-based medicine and pharmacovigilance – which share common concerns regarding harms from medicines and devices. This statement represents the common ground of agreement established at the conclusion of three days of intensive discussion and debate.
Our recommendations for improving patient safety
To improve the detection, analysis, and reporting of harms in the interests of patient safety, we recommend the following:
- Raise public and professional awareness of the harms from medicines and devices.
- Shift the culture within regulatory and health care management systems from one of secrecy to one of transparency.
- Enforce existing effective regulations, revise ineffective ones, and implement effective regulations in those areas lacking appropriate regulatory infrastructure.
- Transfer from industry to healthcare systems the responsibility for providing information and support to healthcare providers on the use of medicines and devices.
- Encourage and enable prescription and use of medicines and devices that are appropriate and tailored to the needs of individual patients.
- Facilitate access to all relevant data.
- Recognize case reports, including those written by patients, as a valid and important form of evidence of harms.
- Improve baseline and continuing education of all stakeholders, including healthcare professionals, policymakers, and the public.
- Recognize the importance of patients and carers, as well as healthcare professionals, in studying all aspects of therapy.
- Establish and continuously develop effective communication with patients and other relevant stakeholders about the potential benefits and harms of interventions to improve the basis for shared decision making about treatments.Mechanisms of change We believe that patient safety requires constant vigilance of safety systems, structures, organizations, and processes. Therefore, we encourage the formation of open, inclusive, and collaborative efforts to identify challenges and develop practical, implementable solutions that improve patient safety worldwide.
About this statement
This statement was created at the 4Es Forum on Improving the detection, analysis, and reporting of harms in medicines and devices in Erice, Italy, 7-9 October 2019. The 4Es Forum was co-organized by the International School of Pharmacology Giampaolo Velo, Verona, Italy; the Centre for Evidence-Based Medicine, Oxford, UK; and Uppsala Monitoring Centre, Uppsala, Sweden. The Steering Committee included Georgia Richards (Chair), Dr Rebecca Chandler, Professor Carl Heneghan, Dr Marie Lindquist and Ruth Davis. It was hosted by the Ettore Majorana Foundation and Centre for Scientific Culture, Erice, Italy and was attended by health professionals, researchers, academics, journalists, patient advocates, and consumers.
- Rebecca E Chandler, MD, Uppsala Monitoring Centre, Sweden
- Anthony Cox, BSc PhD FHEA FRPharmS Clin Dip Pharm, University of Birmingham, UK
- Nicholas J. DeVito, MPH, DPhil Candidate, University of Oxford, UK
- Kay Dickersin, PhD, Professor Emerita, Johns Hopkins University, USA
- I Ralph Edwards, Professor, Editor-in-chief International Journal of Risk and Safety in Medicine, Sweden
- Su Golder, BSc MSc PhD FRSA, University of York, UK
- Peter C Gøtzsche, MD Institute for Scientific Freedom, Denmark
- Carl Heneghan, BM, BCH, MA, MRCGP, DPhil, Professor, University of Oxford, UK
- Bruce Hugman, Communications consultant, Oxford, UK
- Florence van Hunsel, PharmD-epidemiologist, Lareb, Netherlands
- Tom Jefferson, MD MSc FFPHM MRCGP, CEBM University of Oxford, UK
- Lars Jørgensen, MD PhD GP-fellow, Nordic Cochrane Centre, Denmark
- Joan-Ramon Laporte, Professor Emèrit de Farmacologia, UAB; Fundació Institut Català de Farmacologia, Spain
- Tianjing Li, MD MHS PhD, University of Colorado Denver, USA
- Marie Lindquist, Director, CEO, Uppsala Monitoring Centre, Sweden
- Helen Macdonald, MD BA MSc, BMJ, UK
- Gilles Mignot, MD, Founder, Prescrire, France
- Asger Sand Paludan-Müller, MSc, Nordic Cochrane Centre, Denmark
- Georgia Richards, BSc (Hons I), DPhil Candidate, University of Oxford, UK
- Catherine Riva, Investigative journalist, Re-Check, Switzerland
- Gerard Ross, Uppsala Monitoring Centre, Sweden
- Kath Sansom, Journalist, Founder of Sling the Mesh Advocacy Campaign, UK
- Kim Witczak, Drug safety advocate and public speaker, consumer representative on FDA Psychopharmacologic Drugs Advisory Committee, USA