Reshaping Pharmacovigilance

Pharmacovigilance has undergone tremendous changes since the Vioxx story in 2004, which triggered the risk management approach worldwide. However, a much disruptive evolution is already on its way with the apparition of news concepts, new tools and new actors, reshaping the pharmacovigilance of tomorrow.

Pharmacovigilance as a Public Health Multidisciplinary Activity

As widely discussed in scientific events and literature, Pharmacovigilance has remained limited far too much to clinical pharmacologists and pharmacists. It is a common understanding in other high-risk industries, such as aeronautics and nuclear power that management of risks can only be efficient when applied by a multidisciplinary team and considered across the entire system.

Leading Health Policy makers advocate this vision. This is the case for Peter Pitts, President of Center for Medicine in Public Interest and past FDA Associate-Commissioner, and Prof. Herve Le Louet, President of CIOMS (WHO Council for International Organisations of Medical Sciences is advancing public health through guidance which are the basis of all regulations worldwide.) In their respective roles, they are both leading the evolution of Pharmacovigilance and propose redefinition of roles and responsibilities.

It is interesting to note that the Institute for Safe Medication Practices (ISMP) is focused on healthcare professionals, mostly in hospitals. ISMP is working, closely with the FDA for more than 30 years, to prevent medication errors. In addition to its extensive training activity, ISMP has designed several tools such as the ISMP Safe Practices Self-Assessment for high alert medications such as anti-thrombotics. This tool allows a hospital multidisciplinary team to screen all aspects and steps of a treatment and to identify weaknesses in the system. Following gap identification, corrective actions are implemented for safer practices.

Where is the industry’s role in this process? In the case of ISMP, the industry has supported and participated to the expert team which has written and is periodically updating the Self-Assessment tool. Another role could be to participate actively to its systematic implementation.

Pharmacovigilance should not and will not remain only the expert’s job but must integrate all stakeholders along the treatment process. The future of Pharmacovigilance lies in it becoming a truly multidisciplinary and integrated public health.

AI is Redefining Roles in Pharmacovigilance

The switch toward real world evidence led naturally to Big Data and AI. AI associated with machine learning means a sky-rocketing evolution of pharmacovigilance, through the new tools that are already present on the market.

Today, AI is able to screen, identify, retrieve, and analyse adverse events (AE) and safety signals, across multiple sources: the patients’ electronic medical records (eMR), the social media and forums, the structured and unstructured databases from the industry or from regulators, the English scientific literature and the local literature, in several languages. Sensors, as well, are already producing a huge amount of data that are (or will be) integrated into the eMR and therefore included in the AE screening.

AI is already used by numerous hospitals and Health Management Organisations (HMOs) to prevent medication errors in prescribing or monitoring patient’s adherence. Such evolution toward a systematisation of AI is unavoidable for the whole healthcare system: hospitals, the industry and regulators. The general implementation of eMRs systematic screening for potential AEs, in the entire health care system, is only a matter of time.

Will we need any more the Healthcare Professionals (HCP) and the patients to report an AE when we know that it could be systematically identified through the patient’s eMR? Are we assured that the direct contact with patients and healthcare professionals will provide a more accurate report? The causality assessment of Adverse Drug Reaction (ADR) will certainly remain the last bastion before being processed automatically by AI and deep learning. Certainly, a disturbing thought which is shaking the very foundations of our vision of pharmacovigilance; a disturbing thought, indeed, but one which must lead us to reshape our role.

The core work of screening, analysing, trends detection, near misses, will then be performed by the health care providers.

How and when will this Information reach Pharma Companies?

Looking at the European model, pharma companies are no longer receiving AEs from the authorities but must daily screen Eudravigilance, the EMA safety database, to retrieve AEs reported by local authorities, patients or HCPs. But how much of the safety information collected and analysed in hospitals will reach the authorities? Except for the most advanced regulatory authorities, are the regulators ready to receive such an amount of data and process them in a way to improve drug safety at national and international levels?

Another hot topic which demands a thorough thinking is the data hosting and ownership. This is political and ethical issue that must be addressed, now.

Patients’ Rights for Transparency

In the era of the internet, patients can have access to an increasing amount of information on their disease and treatment. How much is this information relevant and understandable when provided by ‘Dr Google’? As an answer to the new patient’s role, the EU regulation requires from the pharma industry, and the EMA and national authorities, to summarise in lay language all regulatory safety documents: risk management plans, aggregate data safety reports, alerts, the list of black triangle products, etc.

Answering to patient’s requests to be actively involved in their treatment, many organisations or companies are focused on patient education and are providing accurate and relevant information to support a patient’s understanding thus securing a better treatment adherence.

For instance, the organisation BeMedWise, funded by the US FDA, is providing many documents, videos, and pocket guides for patient education either directly, aimed at the patient, or toward the HCP to help him educate his patients. In addition, BeMedWise organises large campaigns, focused on specific issues such as the opioid crisis, or polypharmacy in elderly people.

New activities are developing, new actors are now strongly involved in Drug Safety , such as hospital multidisciplinary teams, Information Technology /AI engineers, patients .These changes are not led by authorities or the industry, thus illustrating the outreach of Drug Safety outside of the usual pharmacovigilance pathway ‘regulator-industry’.

The ISOP ISRAEL Experience

Adhering to these new concepts, ISOP ISRAEL, the Israeli Chapter of the International Society of Pharmacovigilance, is experimenting with a new strategy which combines several tools and methods, and integrates several disciplines in a continuum. Supported by key health policy leaders and strong partnerships with ISMP, BeMedWise and others, ISOP ISRAEL puts in practice this new vision.

Relying on a practical approach, where one learns while doing, the first projects are built around a case study — the anticoagulants — and in pilot centres — hospitals and a chain of community-pharmacies.

A medium-size hospital, Maayanei Hayeshualocated in Bnei Braq, Israel, has translated into Hebrew and implemented the ISMP Self-Assessment for anti-thrombotics, which has led to a wide corrective and preventive actions plan (CAPA). Other tools are also under implementation including a mobile application, MyeReport, which is focused on the patient, to report in a few minutes an adverse event. The mobile app is linked to a campaign of information for patients taking anti-thrombotics, using both BeMedWise documents and Educational material of the Risk Management Plans of DOACS (Direct Oral Anti-Coagulants), provided by the industry.

SuperPharm, a private chain of community pharmacies, launched a national campaign on anticoagulants. After extensive training, the pharmacists, when dispensing anticoagulants to patients, must check the dose, the indications, the renal function, and the interactions; they have intercepted several medication errors, have corrected the dosage, advised the patient and were able to show for each specific drug what kind of actions they have taken.

One-year experience in the pilot centers has shown the feasibility and sustainability as presented in the first ISOP ISRAEL International, Multidisciplinary and solutions-oriented symposium: 360⁰ of DRUG SAFETY, which was held in June 2019 in Tel Aviv. Chaired by Prof le Louet, president of CIOMS, the symposium illustrated the new trends in Pharmacovigilance and has given a glimpse on what is in front of us.

Israel, as the startup nation, is a leader in digital health and, therefore, has several solutions to offer to screen AEs (Data2Life), to prevent prescription errors (Medaware), to promote smart adherence (Water-io and Vaica), and to educate patients (Medivizor). Their results were presented during a full session dedicated to AI and Information technology solutions.

Some hospitals are leading the way, such as Sheba-Tel HaShomer Hospital, Israel, ranked by Newsweek the 10th top hospital in the world. Sheba Hospital has implemented several IT and AI tools such as the Institute for Health Improvement Trigger Tool. The Trigger tool screens eMRs to detect and identify potential AEs through markers such as a sudden drop in haemoglobin in a patient with anticoagulant which could mean occult haemorrhage. Medaware is now fully displayed in the hospital for all prescribers: its AI and machine-learning solution allows, through the access to the eMR, the prevention of medication errors and to fine tune the prescription according to both best guidelines and personalisation.

All presentations are now accessible through ISOP ISRAEL website.

The role of the Pharma industry

The pharma industry, especially the Marketing Authorization Holders (MAH), has to redefine its role, while relying on its many assets, that should be more focused on multidisciplinary projects.

During the design of such projects, the industry can constructively bring to the table its knowledge on regulation and international standards which can frame the links with authorities. Industry should also train the hospital teams on the organisation of their pharmacovigilance and quality systems.

Experience in risk management and risk minimisation actions will be precious for both sides: for MAHs, risk management plans will be integrated in the projects and, therefore, will be more efficient. For hospitals, at the CAPA time, corrective actions could be inspired by the risk prevention/minimisation actions as proposed in international regulations.

Industry expertise on the products and its use can support the design of new tools as is the case of the ISMP Self-Assessment tool.

The long experience in risk communication can be used to promote national campaigns and provide educational material. BeMedWise is largely supported by the industry in its campaigns of patients’ education, both with expertise and sponsoring. Certainly, also, in promoting and spreading the use of these tools.

Thanks to its long experience in scientific event organisation, the industry will be efficient in enrolling more stakeholders, or more hospitals, spreading the information about campaigns or projects within the healthcare system, through conferences, congresses and workshops.

Over the past decade, patient advocacy became a key strategy for companies with high risk products where the patients’ and healthcare professionals’ training is paramount for a better benefit/risk. This activity will increase in the future.

With the development of real-world evidence, big data and AI, the industry will have to focus its creativity in establishing strong partnerships with multiple stakeholders, proposing new tools and designing new projects throughout the whole healthcare system.

And the Regulator?

For the industry to change its paradigms, it will mean a parallel evolution for the regulators. The pharmacovigilance regulations today are mainly ruling the relationship with the industry. Even if the HCP and the patient have now more weight and at least receive a more transparent information thanks to the regulation, they are still more like observers than really involved.

Multidisciplinarity for regulatory authorities will start with collaboration between several departments in the Ministry of Health, which should be involved in multidisciplinary projects and national campaigns.

Will we have to wait for another Vioxx affair for proposing regulations which will be a profound change of paradigm or will the regulators accompany and support this evolution on real-time?.

By 2004, risk management was already a known concept and even an ICH draft guideline. However, it was only after Vioxx that the authorities issued the new requirements for risk management plans. This new breakthrough milestone will require much deeper changes, but let’s hope that lessons have been learned and that regulators will be proactive.

In Conclusion

ISOPISRAEL’s ambitionis to be at the forefront of this sky-rocketing evolution, as a link between all stakeholders, providing a platform for experience sharing, identifying new tools and implementing innovative multidisciplinary projects.

We believe that the pharma industry will have the opportunity to play a major role in bringing its experience and knowledge in pharmacovigilance; staying on track or even ahead of the tremendous evolution of drug safety.

The regulators will have the difficult task to redefine roles and responsibilities in the pharmacovigilance of tomorrow, to address and confront this staggering technologic and organisational evolution.

--PFA Issue37--