Rasi At The EMA: Redefining Benefit/Risk As Staggered Approvals Rise

The Executive Director of the European Medicines Agency Guido Rasi’s dual goals of increasing safety and overall accountability undoubtedly will benefit patients and industry alike, but a grueling task lies ahead.

When Professor Guido Rasi finally was appointed officially to the post of Executive Director of the European Medicines Agency in October 2011, there was a sense that the EMA was entering a new era of openness and accountability. The introduction of new pharmacovigilance legislation and the increasing demands from an ever-more powerful European Parliament already are ratcheting up the pressure on Rasi to come up with innovative solutions and fast. The signs so far are encouraging, but there is still some way to go.

Against the backdrop of the scandal involving Servier SA’s diabetes drug Mediator (benfluorex), the concept of benefit/risk is undergoing a revolution (Also see "Mediator Is Tip Of EU Parliament's Probe Into EMA; Funding Held In Balance" - Pink Sheet, 19 May, 2011.). Indeed, only a few years ago the concept was termed as risk/benefit – the negative potential of a drug no longer come before the positive.

In a recent interview with “The Pink Sheet,” Rasi noted: “Many cases in the pharmaceutical sector have gone wrong and this raises the question of whether the regulatory system can be trusted.” He also points to the media’s ability to better inform the public about what once was regarded as the obscure world of regulatory affairs. Part of Rasi’s solution is to increase transparency surrounding the EMA’s actions and procedures, and he has made greater openness a primary goal for the agency.

CHMP Disclosures Are “Crucial Test” For Transparency

However, Rasi is clear that scientific debate must be shielded from external pressure. “If you are debating, for example, a ‘yes’ or ‘no’ for a particular product, there may be someone who is interested in promoting a positive or negative answer,” he explains.

But with the new pharmacovigilance legislation, bringing with it the mouthwatering prospect of public hearings at the EMA, transparency is going to be problematic to achieve even outside of scientific debates. “In Europe, for example, we have the problem of the 23 languages and then we have the issue of where to hold the meetings – because for some it will involve a lot of travel,” Rasi points out. Logistics and practicalities can only be addressed properly when the EMA has built up enough experience in this new area, he adds.

Rasi already has traveled far down the transparency road by publishing all applications to the EMA and, most recently, suspected side-effect reports for medicines authorized in the European Economic Area (EEA). But he is keen to go further, by offering restricted access to the public to sessions of the EMA’s senior scientific body, the committee for medicinal products for human use (CHMP).

But shielding commercially confidential information and ensuring the independence of the CHMP will prove to be a challenge (Also see "European Regulatory Round Up: While EMA Opens Up, European Pharma Battens Down For Tough Year" - Pink Sheet, 27 Feb, 2012.). Rasi stresses that much of the CHMP deliberations will have to be held behind closed doors, but once the committee takes a decision, this could then be open to public debate.

“Of course opening up the CHMP will be a crucial test, because before it reaches a decision, you cannot have any influence from the outside world,” Rasi stresses. Another possibility would be to hold a public discussion prior to the actual deliberations of the CHMP.

In a sense, the CHMP discussions are akin to the internal discussions that take place within the various offices and divisions within FDA and hence the need to restrict public access. Unlike FDA advisory committees, which are external to FDA, and provide advice for FDA to take into consideration when reaching its decision, the CHMP is an integral, internal part of EMA and is responsible for formulating the agency's opinions on medicines.

The new public hearings that will be introduced as part of the pharmacovigilance legislation on July 2, 2012, will be similar to those that take place in FDA advisory committees.

The increased transparency that will promoted as a result serves a dual purpose, says Rasi. For patients and the general public, it offers a vehicle for communication. “If you have perhaps a relative affected by a disease, then you should know that there is a way to get information from us,” Rasi said. Transparency in this case is aimed at raising consciousness, increasing the ability of the public to protect itself and reassuring it of the positive role of the agency in securing health.

The “self protection” element should be reinforced by the European Commission’s Information to Patients Directive – although many in industry are now suggesting that this will never get off the ground, mainly because the various stakeholders cannot agree on a way forward and some Member States still have concerns about the industry trying to introduce direct-to-consumer advertising (which is illegal in the EU), through the back door (Also see "Rx Websites Permitted By EU Court, But Does That Dim Hopes For Further Promotions?" - Pink Sheet, 20 May, 2011.).

Were life to be breathed once again into the Directive, however, Rasi foresees a role for the EMA, perhaps not as previously envisaged by many members of the European parliament as the gatekeeper for information flowing from manufacturers to patients, but more as a provider of supporting information for the final output.

The Rise Of The Staggered Approval

While transparency is one element of addressing the benefit/risk issue, the EMA also is set to adopt a more practical approach to approvals: the staggered authorization process. This system would allow a drug to be authorized in order to provide timely access for patients, balancing it with the need for the company to provide the agency with adequate evolving information on benefits and harms.

Two factors will likely drive the adoption of staggered approval: development of more innovative medicines and creation of stronger post-market safety systems. For the former, the more a medicine is focused on addressing an unmet medical need, the more pressing the need to ensure rapid access to the drug – although safety will remain of paramount importance. And for the latter, “the more robust the pharmacovigilance system becomes and the more it is in a position to guarantee greater confidence in post-marketing safety, the less we will hesitate about initiating staggered approval,” Rasi said.

But while Rasi certainly sees regulators focusing on this form of entry more often, he also emphasized that the onus is on industry as well to adapt its business model in order for a recognizable staggered entry system to succeed. “The development of the post-marketing strategy is crucial to allow for staggered entry,” he stressed.

The new model would not be a “one-size-fits-all” approach, however, and is more likely to apply to new, more complex molecules, rather than “me-too” drugs.

The staggered approval approach is not a new concept and was in development before Rasi’s appointment to the EMA. In November 2010, the EMA and the Massachusetts Institute of Technology’s Center for Biomedical Innovation and Center for International Studies launched a collaborative research project with a focus on enhancing regulatory science in pharmaceuticals. Among other things, this addressed the issues of “staggered” and “adaptive” approaches to drug approval. Some of the conclusions reached during this collaboration were published in Clinical Pharmacology and Therapeutics in early 2012 (Also see "“Adaptive Licensing” Proposals View REMS As Answer To Limited Evidence" - Pink Sheet, 12 Mar, 2012.).

But much will rest on the willingness to accept risk itself, which Rasi acknowledges is extremely difficult to define. For instance, the risk of a drug affecting erectile function as a side-effect is perhaps less likely to be acceptable to patients within the 30-50-year-old age range, whereas patients aged between 70 and 90 may be more ready to take this on board. Other factors may include religious and social backgrounds as well as disease severity. “So the acceptability of risk for a patient could help to define a more appropriate indication for medicine,” Rasi suggests. In a nutshell: the risk tolerance per age cohort could determine the appropriate use for a medicine.

It is not necessarily a case of requiring patients to take on board more risk, but more a question of defining risk more effectively so that patients are able to make an educated choice as to the level of risk that they are willing to accept. “A one-size-fits-all approach to risk is over,” Rasi says. The EMA already has hosted patients in specific committees and has relied on their input to help assess what level of risk they are willing to accept.

An Integrated Approach To Regulation And HTA

But improved benefit/risk assessment is only one issue that Europe needs to address in order to improve access to medicines. It is becoming more evident that the EMA itself can no longer exist in the splendid isolation that is regulatory affairs – increased cooperation with health technology assessment processes already is on the rise.

The agency has gained some experience to date with this type of collaboration and is now building on two successful experiments to date: the offering of parallel scientific advice with HTA bodies; and input from HTA bodies into the format of a European Public Assessment Report – a full scientific assessment of an authorized medicine. “My idea is that the earlier we start to cooperate during the drug-development stage, the smoother all the processes will be,” Rasi stressed.

In fact, EMA and representatives from the European network for Health Technology Assessment (EUnetHTA) Joint Action met in London on Feb. 11, 2010, which marked the beginning of a collaboration in which the sides examined how the EPAR could make a better contribution to the assessment of relative effectiveness by health technology assessment bodies in the EU Member States.

The EMA also took part in a pilot process testing multi-stakeholder consultations in early-stage drug development in 2010. The aim of the pilot was to clarify what constitutes a medicine’s value and the evidence required to demonstrate that value most effectively. It was initiated by the European Healthcare Innovation Leadership Network, was led by Tapestry Networks and was supported by AstraZeneca PLC, GlaxoSmithKline Inc. and Johnson & Johnson.

Rasi added that while credit must be given to other bodies for establishing this interaction, companies are now coming independently to the EMA to seek joint scientific advice with HTA bodies. “The rising number of requests simply reflects the needs of the collaboration,” he said (Also see "Europe’s Two-headed Monster: Divergent Demands For Comparators Squeeze Rx Trials" - Pink Sheet, 3 Apr, 2012.).

But Rasi stresses that, while HTA cooperation is a must, the EMA has neither the mandate nor the intention to stray into the realms of pricing. “On pricing, we will remain completely out of the process, but on value – in terms of efficacy or effectiveness – we could not be neutral, even if we wanted to be,” Rasi said.