A Faster Finish May Depend On A Better Start – EMA's PRIME Program

Improving drug development programs in their early stages may be a key way Europe's new PRIME priority review program will help bring important drugs to market more efficiently, European Medicines Agency officials suggested at a March 7 brief to kick off the program.

While PRIME's centerpiece is earlier identification of drugs with potential to address significant unmet medical needs and accelerated review, EMA officials shied away from any approval goals and timelines. PRIME would help to increase the chances for such drug candidates to reach the approval stage, but it is difficult to predict just many products would be submitted to and accepted into the program or how much PRIME might speed up approval times, they said. But they emphasized the impact of helping companies better target resources and starting out with more promising research plans.

EMA Executive Director Guido Rasi painted a somewhat bleak picture of the current drug development scenario, claiming that a scheme like PRIME was needed because "two out of three" development plans were "inadequate" in terms of producing the data needed for drug approval, and many of the trials conducted to support such programs were therefore "useless."

He went on to say that many of these "very promising medicines" fail to reach patients, resources for medicines are wasted, R&D costs increase, "and more importantly, patients are enrolled in useless clinical trials." This is "particularly true of those developers with less regulatory experience and capacity, such as academia and SMEs." PRIME's benefits for small and medium-sized enterprises have been emphasized by EMA officials and those entities are favored in some provisions of the new program (Also see "PRIME Time: Smaller Companies In Focus As EMA Launches Priority Medicines Scheme" - Pink Sheet, 7 Mar, 2016.).

PRIME, Rasi said, could make a difference here by fostering better planning of resources and drug development in order to "enable the high level of data we need to assess medicines and enable innovation to reach the patients."

EMA officials drew some questioning about Rasi's claim that two out of three development plans are inadequate, but since the executive director left the briefing immediate after his presentation for a business trip, the attempts at answers were left to others. Tomas Salmonson, chair of the EMA's Committee for Medicinal Products for Human Use (CHMP), said he did not know exactly where the figure quoted by Rasi had come from, but he was "sure it is derived from scientific advice, and that it is correct."

Hans-Georg Eichler, the EMA's senior medical officer, said it was up to the regulator to decide whether a protocol was inadequate or not, "and if the regulator says the design of the study is inadequate, by definition it is a suboptimal design." He continued: "A couple of years ago we looked at what comes in and what was deemed by the CHMP and the scientific advice working party members as adequate versus inadequate." The result, he said, was "a rather large figure, but whether that is because some companies try to push the envelope or there are other reasons we can only speculate."

Speeding Up Approval?

So how much more quickly might new drugs might be approved under the PRIME scheme?

Zaide Frias, head of the EMA's human medicines research & development support division, said that "overall we are confident that there will be earlier access but at present is difficult to predict how much faster this will be." The agency would need to see what the uptake was, and how the scheme developed, but "it will bring medicines earlier to patients in different ways, through optimizing drug development but also through acceleration of the evaluation itself."

She added that "we have also received confirmation from the European Commission that they will be willing to take the decision-making step in a faster way." Asked how much faster, she said the standing committee phase would be shortened from 22 days to 10 days for any drug given a CHMP opinion following development under the PRIME scheme.

Salmonson was not concerned so much about the actual time saved, but more about the benefits in terms of optimizing drug development and the collaboration with other stakeholders that PRIME would engender.

"We all know that we have had accelerated assessment for quite some time – it lets us prioritize individual applications and shorten the timetable, and there will be also a shorter decision-making phase. Cutting a month here or there is valuable but is not a big gain – the big wins, we are convinced, will happen in the development phase, the adequate design of clinical trials, and the involvement of other stakeholders in part of the decision-making before the product reaches the patient. So it is a way of recognizing where we can get the big gains… it depends very much on the individual product, but just preparing for accelerated procedure will be of value."

As to how many requests for PRIME eligibility might be received in any given year, Frias hazarded a guess at round 100, although Salmonson said in his opinion it would probably be fewer because "unfortunately there are not that many developments that meet both the unmet need [criterion] and [have] very strong potential to fulfil that need."

He said that "obviously there is an impact on workload here, we have not defined a number saying we can take 20 or 30 a year… so we have not locked ourselves into certain numbers," but "we have to be prepared for a lot of applications for eligibility we will turn down. This is my expectation because I expect there will be quite a number of applications that will not meet the requirements, but time will tell whether I am right or wrong."

EMA reiterated earlier warnings that the criteria for eligibility for PRIME review will be tough, and that it is prepared to turn down "a lot of applications" that don't meet the scheme's requirements (Also see "EMA Advice On PRIME: 'If You Don't Meet The Criteria, Don't Apply'" - Pink Sheet, 23 Nov, 2015.).

Might PRIME bring about a rise in drug approval rates? Perhaps, said Eichler. "There is nothing PRIME can do to rescue a molecule that is not beneficial. If a molecule doesn’t engage the target it is meant to, and so has no efficacy, or it has a nasty adverse event, PRIME will not rescue it. But can we raise the approval rate? Possibly yes, because what we avoid is avoidable errors on the part of the company."

There was some basis for this assertion, he said, based on previous experience with the EMA's scientific advice process: "We looked at approval rate of compounds that came for and followed scientific advice, and we compared it with those that did not, and it showed there was an increase in the approval rate."

Frias added that the EMA would be publishing monthly statistics on the uptake of PRIME and on its progress, including details of the products granted PRIME eligibility.

As a regulatory tool, PRIME should be viewed in the context of other initiatives such as parallel scientific advice with health technology assessment (HTA) bodies, and talks with payers and patients, Salmonson said (Also see "EU Faster Review Path Should PRIME New Links With HTAs, Payers – Industry" - Pink Sheet, 26 Oct, 2015.). In addition to strengthened scientific advice on trial design and drug development, PRIME will include early appointment of a rapporteur who would not only be a link to the drug development program but also to the other EMA committees involved in the product's evaluation.

Eichler said that in his view PRIME was "the last piece of the jigsaw, and we have set it up in a way to ensure that in terms of synergies it is most complementary with the other tools and initiatives that we have ongoing." Its role would be to bring medicines to patients as quickly as possible, but other tools would then come into play to understand whether the new drug is being used appropriately, or where there might be the potential to expand its use to other populations over time (for example via adaptive pathways).