Best practice: solid risk management plan

27 June 2017



As highlighted by a fatal clinical trial in France in 2016, good pharmacovigilance is paramount for drug companies. That means a solid risk management plan, as Sini Eskola, director of regulatory affairs at the European Federation of Pharmaceutical Industries and Associations, tells Ross Davies.


Forming a central plank of the European Medicines Agency (EMA)’s new guidelines on pharmacovigilance protocol, a risk management plan (RMP) remains a vital document for stakeholders in the clinical trials sector.

The second revision of Module V Risk Management Systems of Good Pharmacovigilance Practice (GVP), which came into effect on 31 March 2017, signals a change of tack from the EMA on how RMP should be approached.

In a nutshell, the emphasis of the revamped Module V is on RMP being a concise, risk-proportionate document, strictly based on science. Lengthy passages of duplicated text and data from the previous RMP guidelines – universally bemoaned by stakeholders – have been cut.

All in all, it’s considerably easier on the eye and abates previous concerns from some that the initial Module V had little scope to be modified, despite the strong possibility of risks in an RMP increasing over time. The new revision states that safety concerns can be added at any point, while risks can also be removed or reclassified as seen fit.

Snip through the red tape and the overall aim of risk management in clinical trials is simple: to ensure that the benefits of a medicinal product exceed the risks. An RMP serves to provide appropriate risk management throughout a medicine’s life cycle, standing as an integral component of any clinical trial information submission.

Early planning, and effective and sustained communication with the regulators will enable an integrated post-marketing pharmacovigilance plan that takes forward the strengths of the clinical development programme into the real-life use of the medicine.

“The RMP is a very important document required for the marketing authorisation application,” explains Sini Eskola, director of regulatory affairs at the European Federation of Pharmaceutical Industries and Associations (EFPIA).

“An update to the RMP is also required when substantial changes, such as applying for a new indication, are being sought, which involves new evidence from additional clinical trials or literature.

“It builds on knowledge gained most commonly during the clinical trials conducted in the different phases of the medicine’s development,” she says.

This includes information such as the medicine’s safety profile; how risks will be prevented or minimised in patients; and plans for studies and other activities so as to “gain more knowledge about the safety and efficacy of the medicine, and on how to measure the effectiveness of risk minimisation measures”.

When it comes to forming a solid risk evaluation and mitigation strategy, preparation is essential, says a spokesperson from the EMA.

“Early planning, and effective and sustained communication with the regulators will enable an integrated post-marketing pharmacovigilance plan that takes forward the strengths of the clinical development programme into the real-life use of the medicine,” he says.

“Thus, clinical trials necessary for approval should be designed to not only maximise the safety information gathered before authorisation but also allow that the safety follow-up is seamlessly continued in post-marketing.”

As part of the European legal framework for conducting clinical trials as well as pharmacovigilance requirements, sponsors carrying out trials on a new potential product – in addition to marketing authorisation holders who have already authorised medicines on the market – are fully aware of what is warranted of them, says Eskola.

“There are no big secrets as such,” she continues. “Players know what is expected and can continuously manage the known or potential risks associated with medicines, and ensure the ongoing safe use throughout the life cycle of a medicine.”

Eskola cites the example of the EFPIA’s member companies, which are largely focused on the research and development of innovative medicines. They all have well-staffed clinical patient-safety departments so as to ensure that risks are “collected, evaluated, mitigated and reported appropriately, with patients’ safety and well-being in mind”.

The EMA has been praised for the aforementioned revision of Module V, as well as its guidelines on product or population-specific considerations, including vaccines and biological medicinal products.

The agency also has a team of risk management specialists on hand to provide specific advice on RMPs.

The EFPIA has been an active contributor in the dialogue with EMA over GVP, explains Eskola.

“We welcomed EMA’s thoughtful efforts to make the revised guidance and accompanying template a more user-friendly document,” she says.

“It more clearly outlines the EU requirements for the development of an RMP, and provides a more concise and clear description of risk management, and how safety risks evolve through a product’s life cycle, based on evidence from a variety of sources.”

Eskola is also appreciative of the EMA’s attempts to revisit the principles originally set out by ICH E2E, the pharmacovigilance planning guideline from 2004.

“These principles are still relevant and facilitate a document that focuses on what really matters in terms of promoting public health and optimising benefit-risk,” she says.

“This guideline also describes concisely the principles and thought processes involved in risk management, which, in turn, helps companies to align their thinking and processes with what is expected by the regulators.”

A delicate balance

And what of human clinical trials? Negative scrutiny has abounded in recent months in light of a clinical trial in France, held by Portuguese pharmaceutical company Bial in 2016, that left one participant dead and four with long-term neurological symptoms.

Bial, it emerged, did not refer to data before deciding to administer a higher dose of the drug BIA 10-2474 – designed to offer pain relief by acting on cannabinoid receptors.

“EFPIA member companies conducting clinical trials have traditionally placed volunteer and patient safety at the forefront in their drug development programmes,” says Eskola.

“We look at what internal practices, procedures or processes can be adjusted to improve patient safety, especially in light of tragedies such as the one that happened last year in France.”

With Bial’s bungled trial still fresh in their memory, “stakeholders are sensitive to the issue”, according to an EMA spokesperson. Guidance for first-in-human clinical trials is set to be updated later this year.

But is there a danger of pharmacovigilance erring too much on the side of caution to the detriment of progression? It’s a tricky balancing act, according to Eskola.

“There is not a one-size-fits-all application to all first-in-human trials. A risk-based approach is the direction to take when considering application of additional safeguards to first human doses,” she says.

“There are situations in which a slow progression of dose escalation and application of sentinel dosing, and capping a maximum dose, for example, may indeed be necessary to safeguard the volunteers taking part in the trial.

“On the other hand, there are many other situations in which these approaches would be unnecessary, stifle drug development, provide a false sense of security and not serve patients or healthy volunteers well.”

EFPIA member companies conducting clinical trials have traditionally placed volunteer and patient safety at the forefront in their drug development programmes.

Next year sees the introduction of the Clinical Trial Regulation, which will replace the existing EU Clinical Trial Directive and drastically alter the way trials are conducted on the continent.

As part of the new regulation, the EMA – in collaboration with member states and the European Commission – is in the process of setting up an EU portal and database with the view to establish higher safety standards and greater transparency of trial information. To help companies adjust to the new rule, the agency holds regular demonstrations; it is also set to offer training in due course.

“The Clinical Trials Regulation opens up a new era in the conduct of clinical trials in the EU, ensuring that Europe remains an attractive centre for clinical research,” says the EMA spokesperson.

“It aims to create an environment that is favourable to conducting clinical trials in the EU while maintaining the highest standards of safety for participants, and providing unprecedented levels of transparency on clinical trials and their outcomes.”

EFPIA member companies, says Eskola, are already mapping their processes and updating their internal guidelines. They are also taking part in pilots, testing how the new requirements can be fulfilled in practice, including shortened timelines, and collaboration between ethics committees and competent authorities.

They are also looking to gauge how the industry itself can organise responsibilities between company headquarters and local affiliates, for example.

“We encourage all pharma companies to stay up to date on the contents of multiple implementation guidelines,” says Eskola.

“They are made available in a step-wise approach – usually following a consultation in which the industry can take part – as this gives additional information supporting the text in the regulation on what the expectations are.”

Adapting to new rules is seldom an easy undertaking. But pharma companies, on the whole, appear to be on board with the guiding theme of the incoming regulation – safer clinical trials in which all risks are covered. This can only be a good thing for patients and companies alike.

Sini Eskola has been director of regulatory affairs at the European Federation of Pharmaceutical Industries and Associations (EFPIA) sinceFebruary 2014. Prior to joining EFPIA, she worked at AstraZeneca’s R&D global regulatory affairs division.
Risk management is necessary in clinical trials to protect patients.
A good RMP should maximise patient safety without stymieing drug development.


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