Licensing Approval in Europe: New Options for a New Era

Hans-Georg Eichler

Dr. Hans-Georg Eichler is an old hand at the business of being a regulator, having been senior medical officer at the European Medicines Agency (EMA) since 2007. Before that, he was a member of the scientific advice working party at the EMA. Over that time, much has changed, not least the public recognition of the need to revisit the approach to regulation in the 21st century, given the burgeoning knowledge of disease and how that is translating into increasingly specialized new drugs. Enhancing patient access to the best of this new science is behind the EMA’s signature pilot project on Adaptive Pathways (AP), now entering its second year. In a wide-ranging discussion at the EMA’s Canary Wharf headquarters in London, Eichler spoke to Pharm Exec about the pilot as well as other pending priorities. 

Guardians of public safety

Eichler is well aware that there is tremendous scrutiny of the work of the EMA and how well the agency is doing in protecting the public. After all, regulation as we know it today is the result of unfortunate events: from the death of over 100 people in the US in 1937 from diethylene glycol poisoning after using a sulfanilamide elixir-with no safety testing-to the over 10,000 babies born with deformities after their mothers took thalidomide in the late 1950s and early 1960s. 

Regulation hasn’t stood still either. For  example, additional requirements for a risk management plan (RMP) as part of the licensing approval submission dossier were introduced in EMA legislation in 2005. That speaks to the constant concern about guarding public safety. But in today’s world of medicine and drug development, there is also an equally intense  debate on drug innovation: why don’t we have more of it, what can we do to get more of it, and what is it anyway? 

The EMA, and Eichler as senior medical officer, has to “strike a balance between being guardians [of public safety], but also enablers of innovation,” Eichler says. He has a quick answer as to whether the EMA has struck the right balance: “the short answer is yes.” 

Eichler goes on to qualify that by acknowledging that, “it’s like beauty being in the eye of the beholder. People will ask if we always strike the right balance. Yes, we’re scrutinized and yes, we’re criticized. We are constantly and keenly aware that we have dual roles and there is a trade-off between the two.” 

The trade-off is perhaps best crystallized when it comes to access. EMA will be criticized if it’s too slow to license a drug that delivers on its early promise of patient benefits. But that will pale against the criticism if it’s too fast to license a drug that doesn’t deliver, but even worse, turns out to be harmful. Some 19 products have had their European Union (EU) marketing authorization withdrawn between 2002 and 2011, illustrating that it’s not always possible to get the right answer about the balance of risk and benefit at the time of initial licensing. 

“We’re constantly told that we’re not doing enough to enable fast access,” Eichler points out. Committees at EMA are “always aware of the trade-off [between risk and benefit and access and evidence],” he says. 

From a ‘magic moment’ to life-cycle approach

There’s been something of a quiet revolution at the EMA as it has refined its approach to regulation. Both benefits and risks are increasingly approached by taking a life-cycle perspective. RMPs were in part introduced to proactively manage risk over the life cycle. AP, introduced in March 2014, first as adaptive licensing and now renamed, is another lens on the same issue. But this time in looking also at how benefit is delivered over the product life cycle. That’s led EMA to introduce AP, which Eichler describes as “a safe harbor forum to discuss evidence standards and the timing for when the regulator, and others, need what type of evidence.” 

Eichler credits the idea for AP as coming from “a growing realization among many people that the world is changing. Society and the science has led us all to rethink how we can do the best job of balancing enabler and regulator.” These

social and scientific drivers are identified in some of Eichler’s work that’s been published to let people know about the idea of AP and why it needs to be piloted (see chart at right; click to enlarge).

Some of the discussions that have led to AP have come from the work of groups such as the New Drug Development Paradigms (NEWDIGs) program at Massachusetts Institute of Technology (MIT) in Cambridge, US. According to Eichler, “the discussions included all sorts of stakeholders-industry, patients, regulators, for example-and we had fruitful discussions. That has helped us [at the EMA] formulate ideas.” 

Other regulators took part, too: the FDA, Health Canada, and the UK’s Medicines and Healthcare Regulatory Products Agency (MHRA). The UK’s National Institute for Health and Care Excellence (NICE) joined NEWDIGS in November 2014, so it’s attracting some of the big-hitting health technology assessment (HTA) agencies, too. They are joined by EUnetHTA (a network of agencies partly funded by the European Commission that is exploring collaboration in HTA), France’s Haute Autorite de Sante (HAS), the Zorginstitutt Nederland (ZIN), as well as US payers Aetna and Kaiser. And not forgetting patients, too, they’ve been represented by the Genetic Alliance and the National Organization for Rare Disorders (NORD), as just two examples. On the industry side, Bristol-Myers Squibb, Bluebird Bio, Sanofi, and Pfizer are participants.

An evolution, not a revolution

Eichler is keen to point out that AP operates within the existing legislation that underpins EMAs work. “We recognize that we have a legislative framework [we have to work within], but it’s relatively wide, and wide enough to try to bring drugs to market in many different ways,” Eichler says.  

The EMA’s materials on AP point out that the program builds on scientific advice, compassionate use, conditional approval, patient registries, and pharmacovigilance tools, as well as RMPs. 

AP could mean more uptake of scientific advice from the EMA, because AP is not formal, unlike scientific advice. Eichler says the uptake of scientific advice is already increasing, although “it’s hard to tell if there’s a direct link to AP,” he notes. 

Scientific advice was given  438 times in 2014, up from 365 in the previous year. Eichler also notes that, “We envision that as  the AP pilots are informal, that if we [EMA and the company] can find a constructive way

forward, then this would segway into parallel scientific advice.” The parallel scientific advice he refers to includes HTA agencies, such as the early scientific advice service from NICE. By 2014, parallel advice from EMA and a HTA agency has been taken up 35 times, a third of these in 2014 alone.  

AP won’t mean a new formal procedure, according to Eichler. He says, “we [at EMA] have always said that this can happen within the existing regulatory framework. We believe that we have the legal tools in place. This is about evidence standards, what evidence we need for what patient group, at what time. We don’t see a need for a new formal marketing authorization procedure.”

Myths of AP

Eichler is aware of some of the debate surrounding the AP pilot project, particularly the concern about lowering standards in drug evaluation. 

“I can say it’s absolutely not the idea to lower standards,” Eichler says. “The whole idea is to increase evidence, but in a staggered way, with continuous learning over the lifespan of a product.” 

Mark Trusheim from MIT has been myth busting, too. He believes that instead of evidence standards being lower, an adaptive approach actually increases evidence over time. Companies get earlier access but must monitor use and accept label changes over time, based on that. 

An opportunity for all companies

When pressed on why a company should take part in the pilot-after all it’s still new, untested, and bound to take up in-house time and effort-Eichler is straightforward. “[Taking part in the AP pilot] is a unique opportunity for any company, big or small, to sit down with the regulator and other stakeholders and discuss, in a totally open way, without strings attached, their ideas on developing their product and getting it on the market place,” Eicher says. That [the pilot] is a safe harbor is a great asset.”

Not all companies are keeping their involvement in the pilot under wraps. Pluristem Therapeutics, for example, has made public its discussion on AP on their PLacental eXpanded (PLX) cells in critical limb ischemia (CLI). The discussion so far is focusing on Pluristem’s Phase II protocol. It received guidance on the design of a Phase II trial in a subgroup of patients with severe CLI. Pluristem is hopeful that this could, in time, help them secure conditional approval and achieve faster access for patients in Europe. The discussion hasn’t stopped there, though; Pluristem has also been talking to the EMA about other indications, ranging from ischemic stroke, muscle wasting, and hip fracture. 

Bluebird Bio-which is also  a member of NEWDIGS-is taking part in the AP pilot program as well. The company is pursuing conditional and accelerated registration strategies in the EU and the US for LentiGlobin BB305, an experimental treatment for beta-thalassemia, a rare and

potentially debilitating blood disorder. Bluebird met with EMA in May and is hopeful that it’s ongoing Northstar Study, a global Phase I/II study, and HGB-205 study, a single- center study in France, will help it achieve faster, conditional approval in Europe. The full approval could follow, subject to completion of HGB-207 and HGB 208 clinical trials-both of which include 15 patients-with additional long-term follow-up and real-life monitoring data after licensing. Bluebird’s vice president of regulatory science,  Anne-Virginie Eggimann, is positive about the engagement with EMA under AP so far, reportedly saying that the agency has demonstrated its ability to be innovative and creative. 

Eggiman also credits the EMA for challenging Bluebird to think about the earliest the company could file LentiGlobin BB305 for marketing authorization and how to justify it-and also how to build adaptive elements into the development plan. 

That confidentiality that Eichler speaks to could hamper engagement, too. Some companies may be simply watching and waiting before coming to a view on the merits of AP. Eichler reflects that one of his worries about AP before the program initiated was that “it would be like a dinner party, with the risk that no one turned up,” he says. “A big question was would the companies come?”

Eichler goes on to say that, under AP, companies “get all the decision-makers in one room. I thought companies would jump at the opportunity,” he says.  

All indications thus far appear that  Eichler was right, with life sciences companies coming forward with 58 drugs for EMA to consider for inclusion in the pilot. Of those, 19 were selected for stage 1. Eichler describes this first stage as “a preliminary horizon scanning.” Thirteen products have now gone on to stage 2. Under stage 2, companies can expect an in-depth discussion with EMA to take place, according to Eichler. 

“That can be a whole afternoon, with a follow-up of a second, or even third afternoon to discuss all the options about what could be an adaptive plan,” he says. 

Fees aren’t putting anyone off at the moment, as AP is currently free for companies to take part. That’s in contrast to paid-for scientific advice from EMA. The reason that the agency isn’t charging “is because AP is informal,” Eichler says. That contrasts to the formal scientific advice service. 

However, there is recognition that an adaptive approach is not completely good news for companies. Trusheim points out that development won’t necessarily be fast and at lower cost overall; that is just for the first decision. Companies may have to pay more for monitoring, for example. Also, not all patients will get unfettered access.

Not just for orphan and cancer drugs

Candidates for AP are in the areas you’d expect, given the focus on drugs to treat serious conditions with unmet medical need. Of the original 58 applications, there were 11 advanced therapy medicinal products (ATMPs), 15 orphan drugs, and 20 anti-cancer medicines, according to Eichler.

“We have said all along that AP is for areas of unmet need; this was a given from day one,” he says. “For a lot of people, unmet need is synonymous with cancer and orphans, but, of course, there are other areas with unmet need. Forty-percent of applications came from non-cancer and non-orphans.”

Big Pharma interest: It’s a resource issue

Eichler acknowledges that the a majority of applications to the AP pilot program are from big Pharma. He attributes that to the need to prepare,

which requires resources on the company side. However, Eichler says: “We are trying to lower the angst barrier and the admin barrier.” That has helped small- and medium-sized companies take part in the AP program as well and “submit interesting proposals,” according to Eichler.  

Progress so far

When asked if there had been any surprises so far with the AP pilot, Eichler says that “companies have been conservative.” Despite the intention, according to Eichler, to “challenge companies to be more creative; their plans [submitted under the AP program] have been pretty standard. We’ve had to ask what’s new.”  Eichler believes that AP offers the chance “to test the waters about what is possible and what is not,” he says. “We hope for creativity.”

Come early-and get creative

Eichler singled out some tips for drugmakers to get the most from AP. He says they need to “please come early.” 

“We’ve rejected proposals on the grounds that they are simply too late [in development]” Eichler says. “If you’re planning to file [for marketing authorization] in three months, you’re too late.”

To generate the creativity that EMA wants to see, Eichler stresses, “there are no stupid questions. [AP] allows a brainstorm.” He also points out that “access is not just the upstream but what will happen downstream. Companies need to consider HTA questions and future payer arrangements.” It seems that so far at least, organizations are conservative and focusing on the point up to licensing. “[Discussing what happens after licensing] is where the AP discussions can run out of steam,” Eichler says. 

Real-world evidence should be part of the conversation, according to Eichler. “AP recognizes that different patient groups have different needs,” he says. “This translates to different types of evidence that will be relevant at different times. We can explore going beyond the venerable randomized controlled trial and look at how real-world evidence can contribute.”

Thomas Salmonson, senior scientific advisor at Medical Products Agency (MPA) in Sweden-another group involved in NEWDIGS-as well as chair of the Committee for Medicinal Products for Human Use (CHMP) at the EMA, also sees a key role for real-world data, particularly patient registries. These can provide answers to regulatory questions and support “managed introduction” of new drugs, he says.

More to do to speed up regulation

The EMA is ramping up efforts to speed access, and not just through AP. The regulator opened up a consultation on changing its guidelines for both accelerated assessment and conditional marketing authorization at the end of July, running until the end of September. One of the changes is to provide CHMP opinion within 150 days, instead of the usual 210 days under the traditional route. 

What’s next?

Eichler swiftly points out that “the regulator has no say about price and economic considerations,” when asked if we might see pricing formally included alongside adaptive pathways. He softens a little though, and acknowledges: “The goal [of AP] is to bring drug candidates as early as is reasonable to patients, and there are others who come [after the regulator]. If only one of the decision-makers says yes, and then downstream they say no, we will not achieve our goal.” 

Eichler sees AP as “the other side of the coin” to some form of managed-entry agreement. “Indeed, shared risk and managed access proposals have been put forward in some of the AP pilots,” he says.

HTA agencies are actively taking part in the pilot. In December 2014, EMA held a teleconference with 13 HTA agencies to discuss general issues about AP. Meetings like this are expected to continue. 

“We would love to have all HTA agencies [take part in AP],” Eichler says. So far we have agencies from the UK, Netherlands, Sweden, Germany, and France. We are trying to broaden that, but we know the resource constraints [facing HTA agencies]; it will take time.” 

Time will tell

There is a great deal of enthusiasm about AP. The uncomfortable truth is that it may take years to prove the concept can deliver. With the real test being faster access to patients-and that often requires HTA and payer approval, too-believing that they will be willing and able to find the money to pay for the AP drugs will stretch even the most optimistic perspective. But with Eichler championing the adaptive approach, there’s every chance it will have staying power.

Leela Barham is an independent health economist based in the UK. She can be reached at leels@btinternet.com.