By Ludwig Burger
FRANKFURT (Reuters) - A push by the European Medicines Agency to speed up the approval of new drugs that show promise is running into resistance from some of the national agencies that will ultimately decide whether the medicines are worth buying.
Pharmaceutical companies, patient advocacy groups and lawmakers around the world are pushing regulators to cut through what they see as red tape and adopt more streamlined approval processes for new drugs.
Europe has been looking at new approaches to drug testing for several years and the issue came to the fore again in January after U.S. President Donald Trump vowed to accelerate approvals to get new drugs to patients faster.
However, critics of new approaches, such as lowering the requirements for lengthy clinical trials, worry that selling drugs with relatively little testing data, even if the go-ahead comes with strict limits, will expose patients to greater risks.
The independent authority in Germany (IQWiG) that evaluates new drugs and plays a key role in what price health services pay for them has been one of the most vocal opponents of such new approaches within Europe.
Given Germany is Europe's biggest drugs market and the fourth in the world, its misgivings risk hurting a broader drive to bring new treatments to patients faster, not least because drug companies may conclude that dealing with price-setting authorities country-by-country ends up being too costly.
"Accelerated approval on the basis of reduced data should be limited to special situations. But there is reasonable concern that it is intended to become the norm," said Stefan Lange, the deputy director of Germany's Institute for Quality and Efficiency in Health Care (IQWiG).
The agency has in the past rejected pivotal studies that had convinced the EMA to approve a drug, saying they were not statistically valid. This has resulted in some drugs not getting launched in Germany, or being withdrawn soon after their launch.
The push to adapt the approval process is partly the result of advances in genetics that are yielding previously unknown treatments for serious conditions and new tools that can forecast better which patients can be helped, and which cannot.
Europe's drug licensing authority, the European Medicines Agency (EMA), has been pursuing a new approach to testing known as "adaptive pathways" for experimental drugs against serious, hard-to-treat conditions. It picked six drugs under development for a pilot scheme that ran from March 2014 to August 2016.
Two of the drugs were for rare cancers, two for hereditary blood diseases, one for a fungal infection and one for heart problems. The companies included U.S. biotech firm Bluebird Bio Inc <BLUE.O>, Israel's Pluristem Therapeutics Inc <PSTI.O> and unlisted British firms Immunocore Ltd and F2G Ltd.
One of the most contested methods advocated by the adaptive pathways approach is to bring the launch of a promising drug forward on a provisional basis, and then gather some of the evidence about its effectiveness and side effects in an everyday medical setting, known as the use of "real-world evidence".
Under established randomized controlled trials (RCT), new drugs are given to some participants while a standard treatment or placebo is given to a randomly assigned control group, with the results determining whether the medicine gets approved.
Typically, neither group in the trial knows whether it is getting the new treatment or not.
The new approach is to gather data from patients being treated, using new medical sensors, smartphone apps and data processing tools. Depending on the outcome of the real-world trial phase, the group of patients eligible for the drug could be narrowed down or widened for permanent approval.
This approach appeals to patient advocacy groups such as Eurordis for rare diseases, or the European Cancer Patient Coalition, which has called for more faith in real-world data and letting patients decide whether they want to take the risk.
"BOUND TO FAIL"
Germany's IQWiG argues that reducing the role of randomized trials goes against the scientific principles that are needed to get clear results on the risks and benefits of a new treatment.
IQWiG's Lange said relying on real-world evidence would mean experimental research, with all its risks of side effects, would be moving into the "uncontrolled environment" of everyday medical care - and that could only be justified if the early signs of a drug's therapeutic benefits were truly dramatic.
Linked to this is the problem that once a treatment gets even a provisional green light, it would be hard to conduct a randomized trial simply because it would be unethical to arbitrarily deny some patients an approved treatment.
Attempts to preserve comparison benchmarks for real-world evidence projects include drawing on data from patients still taking older treatments elsewhere.
IQWiG argues that any factors playing a role in the composition of study groups would skew the findings. "Any attempt to statistically eliminate the distortions from these selection mechanisms afterwards is bound to fail," said Lange.
France is another country to voice scepticism about the EMA's new approach and some smaller countries have expressed misgivings privately. France's Haute Autorite de Sante, for example, says it has "mixed feelings" about expanding existing conditional marketing approval rules, according to Chantal Belorgey, its director in charge of medical assessment.
But Britain's National Institute for Health and Care Excellence (NICE) said it supported the adaptive pathways concept and was exploring how different sources of evidence could supplement data from randomized trials.
The EMA's Senior Medical Officer Hans-Georg Eichler also says the advent of precision drugs which would only be used by small groups of patients has added urgency to the quest for new sources of evidence to complement the established trial route.
Researchers are splitting medical conditions such as cancer or neurodegenerative diseases into ever smaller sub-groups as they learn to parse through the multitude of genetic traits that fuel a disease. But that is leading to smaller drug trials, making it difficult to produce statistically reliable results.
The EMA is now taking stock of the conflicting views about its pilot scheme from the national cost-effectiveness watchdogs, patients and organizations that pay for healthcare.
In the meantime, the companies involved in the pilot are continuing to receive scientific advice from the EMA and the scheme is open to new applicants, a spokeswoman said.
(Additional reporting by Matthias Blamont in Paris; editing by David Clarke)