The PVRMS19 was presented at the Omni Shoreham Hotel, Washington DC, January 2019. During the packed three-day event, we learned that many aspect governing the development and subsequent safe and effective use of medicines are in a state of flux… and so they should be. As we learn by our actions (triumphs and failures) we make adjustments to enhance the future investigations and create medicinal agents that are effective and safe, or more precisely, have a benefit that outweighs the risks.This evolving process would not be possible, and certainly not as successful, without input from regulatory authorities, the pharma industry and patients alike. Neither would it be possible if collectively the mind set of those involved had not shifted from one of simply safety to one of benefit over risk.

This year at PVRMS the 400+ delegation had the opportunity to attend 14 separate sessions chaired and presented by more than 30 experts. Throughout the sessions we learned how the regulatory authorities were “listening to industry” with regard to updating and implementing guidelines related to enhancing the availability of medicines to patients with the rarest diseases and those with unmet medical needs – this is a good thing.

Another good thing was the physical presence of a number of uniform-clad FDA personnel who were actually able to attend, with the US government shut-down being temporarily lifted just hours prior to the beginning of the short courses on Sunday.

Another “government intervention” that bubbled under in many sessions was the impact of BREXIT. In most cases we were told that the UK, or rather the MHRA (Medicines and Healthcare Products Regulatory Authority) is preparing for a hard BREXIT. With this in mind, industry would have a new reporting line to contend with … although a daunting thought, we must remember that Norway, Iceland and Liechtenstein already exist outside the EU.

Indeed, in a session relating to the EU updates, Vicki Edwards, VP Pharmacovigilance Excellence, AbbVie, explained that the Industry approach was one of maintaining as close a relationship between the UK and the EU as possible. She stated that it was imperative to “ensure there was no disruption of access to medicines, especially safe medicines.”

She stressed that removal of a single country from the EU would not fundamentally change how MAH’s would conduct PV activities. Safety information from the UK would be still available to the EU (but not non-serious cases) and conversely, EU data would be available to the MHRA (but not via Eudravigilance).

Of more immediate concern for the governance of PV activities is rather the “who” and the “where”. This relates to the legal requirements for the role of QPPV [Directive 2001/83/EC – Article 103]. In some cases it will mean that companies will require a UK-based QPPV in addition to the EU-based QPPV. This, she said, would feed in to the most important aspect: “potential for duplication and divergence”.

BREXIT is less than 2 months away, yet still, Vicki concluded, there were so many unanswered questions; she urged Industry to prepare for a hard BREXIT in terms of QPPV resource.

During the FDA Update session, Dr Gerald Dal Pan, Director, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research (CDER) shared the results of a large study investigating the activities surrounding label changes related to 278 NMEs approved between October 1, 2002 and December 31, 2014. For this set of drugs, more than 700 label changes were made; updates appear to peak three years after marketing, but continue for the lifetime of the product.

The need for continued long-term follow-up and potential label changes were highlighted in several unrelated presentations. This is not just the case for new “Advanced Therapies”, where the benefit of using these drugs in rare diseases and in those with unmet medical needs outweighs the risk (even though the risks are high). But also in “household drugs” such as paracetamol (acetaminophen) that has been available in some markets without prescription since 1959.

With regard to three Advanced Therapy products (i.e. Luxurna, Kymriah and Yescarter), each approved in 2018, we learned that consultation with the relative regulators and strict RMP/REMs were necessary to facilitate appropriate clinical investigation and to allow market authorisation. Without the opportunity for Industry to seek guidance from the regulators, and without the promise from Industry to execute strict post-marketing surveillance, it is likely that these products would have gone directly to jail, would not have passed go and most certainly would not have collected…… (you get the picture)

The audience learned that for each of these products, long-term follow-ups and Patient Registries have been planned, resulting in final reports stretching out to 2038. Additionally, there are strict conditions surrounding the administration of the agents, including restrictions in geographical centre availability and practitioner expertise. The RMPs for Kymriah and Yescarter, the CAR-T cell therapies, were described as “the most burdensome you could get…. And yet without them these effective agents may never have been approved”.

The long-term vigilance for this category of agents may not seem so harsh considering the revelations by Dr Rosa Piccirillo, Senior Director and Global Head, Medical Safety, IQVIA in her presentation about experience in performing Benefit-Risk assessments. She described the latent safety findings, and the subsequent actions relating to paracetamol. She explained the assessment for this well-established drug was initiated as a result of a MAH acquiring a number of medicinal agents via a company acquisition (a common occurrence in her experience). In a timeline slide, we learned that approximately 44 years after the drug was launched in the EU in the 1970’s, a new signal was detected: Use in pregnancy and child neurodevelopment and effect on the urogenital apparatus. And, almost 50 years after the EU launch, modified release-containing products were to be suspended from the EU market in 2018.

I think this justifies the need for such long-term commitment in safety monitoring of new and old drugs.

Throughout the conference, it was evident that the Regulatory Authorities were committed to expediting the availability of effective and beneficial medicines to patients. This approach is perhaps even more evident in “emerging regions”. Dr Han Ma, APAC Site Head, Safety Risk Management, Roche Pharma Product Development, described the “vicious evolution in China”. She explained that this was the result of the “Healthy China 2030 Plan” that was being driven majorly by the ageing population, urbanisation, and healthcare spend and infrastructure. Starting in 2015, there appears to have been a seismic shift away from “made in China”. This is evident from the fact that Chinese Pharma companies are not expected to also be manufacturers, this has resulted in an increase in the number of small start-up companies. In 2017 the alignment with the Western world was strengthened when China joined the ICH, and in 2018 Drugs departed from Cosmetics in terms of pharmacovigilance regulatory oversight.

These milestones have encouraged innovation and regulatory convergence. Dr Ma explained that drug accessibility and drug affordability were key goals. To this end the Chinese regulators are now accepting of clinical trial data performed outside of the country; she was very excited to tell us that Roche had three agents (Alecensa, Hemlibra and Perjeta), approved in China in 2018, all within a year of the FDA approval for the same indications, each supported by ex-China clinical data. In terms of affordability, Dr Ma also explained that in addition to the regulatory reforms for novel agents, there was an overhaul in the quality control measures for generic agents.

Collectively, the transformation in the regulatory approach to pharmacovigilance in China is positive. Dr Ma concluded by explaining that implementation of ICH E2A to E2F guidelines was expected in the very near future.

Continuing with the theme of encouraging safe practices in emerging parts of the globe, the last session of the conference presented by Mick Foy and Raj Long, revealed the current status of 3S – Smart Safety Surveillance.

This initiative is being headed by Mick Foy (MHRA) and the tag line says it all….

Every person has the right to safe medical products.

The basic concept of 3S is to introduce pharmacovigilance practices into low-middle income countries (LMICs). To set the scene Mick asked, “…should safety be different to patients taking a product in Paris versus Ethiopia?” Clearly from the murmurs of the audience we think not…. But clearly from the information that followed, currently it is.

The reduced safety, we learned was the result of a number of issues including the source of the drugs (often they are donations from the UN), the large number and widespread location of patients being treated based on diseases of focus (e.g. Malaria and HIV) , the lack of expertise and resource for PV activities.

The latter, has resulted in the fact that reporting of safety issues is almost non-existent, the capacity to analyse what data are collected is very low, and the capabilities to take action against any alert signals received are even lower.

The initiative started two years ago, and includes Industry engagement from Abbvie, J&J, GSK and Pfizer. The aims are to select pilot countries and products to focus on, to develop action plans to build capacity for PV activities and further the regulatory systems to support on-going activities, and lastly, to develop outcomes targets to measure against.

In 2017, courtesy of the Web RADR project, the SAV app was introduced to Burkina Faso and Zambia, which allows direct reporting to Vigibase, without complicated form filling and with instant access to safety information. It is hoped this will increase the quantity and quality of safety reporting.  We learned that there are 8 more pilot countries that have been identified (including Armenia) for roll-out during 2019.

The presenters explained that while guidelines and regulations are necessary in these LMIC’s, they cannot be as stringent or complicated as those under the governance of the FDA and EMA for example, this is simply because there is not the immediate resource or expertise available. Mick explained that he was working with the MHRA to develop a short version of the GVP that was relevant for the pilot countries and the compounds selected for surveillance. Raj echoed this sentiment, explaining that “freedom to function, but not like the FDA or EMA” would be one of her dream milestones, particularly for a single product with a high disease burden, integrated across three continents…” a huge step!

However, she ended the session by qualifying the need for baby steps first …“with 3S we need to get the basics right in monitoring the adverse events and then we can build on it”.

In conclusion, this fast-paced conference was full of interesting updates presented by passionate people; this was interspersed with many opportunities for Industry representatives to seek information from the 60+ exhibitors with regard to a variety of solutions for fulfilling mandatory PV-related activities. First-hand experience at the ADIS Pharmacogivilance booth revealed the need for literature monitoring not only for mainstream ICSR reporting but also on-going safety monitoring pre- and post-marketing; of particular interest was the local literature monitoring service we have on offer. As a service provider, we act as a global vendor that offers a consistent and scalable approach, while ensuring high quality standards. We pride ourselves on keeping abreast with the changes to regulations and the technical requirements needed to deliver reliable, bespoke solutions for all our customers, large and small.

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