The European Medicines Agency’s (EMA) Executive Director Guido Rasi and senior medical officer Hans-Georg Eichler sent a letter on Thursday to clarify some assumptions called into question by a group of nine professors who are criticizing aspects of the agency’s adaptive pathways pilot program.

Background

First announced in March 2014, EMA’s pilot program seeks to accelerate patient access to drugs for patients with pressing medical needs and after approval for a narrow indication, additional clinical and real-world data are expected to be used to gauge if the treatment is actually as effective as expected. As of November 2015, EMA has selected 19 proposals to participate in the pilot.

As Rasi and Eichler describe it, the adaptive pathways pilot “seeks to maximize the positive effect of new medicines by balancing timely access for patients likely to benefit most from a new medicine with the need for adequate, evolving information on their benefits and risks.”

Three participating companies include Bluebird Bio, which said in May 2015 that it plans to seek conditional approval for its gene therapy LentiGlobin BB305 to treat beta-thalassemia major; the biotech company Immunocore said in September 2015 it also plans to seek conditional approval for its lead biologic IMCgp100 for the treatment of patients with metastatic uveal melanoma, a rare and fatal disease with few available treatment options; and in August 2015, Pluristem Therapeutics, said it's using EMA's guidance in the pilot to develop a cell-therapy product that targets a subgroup of patients with critical limb ischemia before looking to expand to other patient subgroups.

Assumptions

In May, nine professors from Oxford, Cambridge, the London School of Hygiene and Tropical Medicine, the French National Academy of Medicine, Royal College of Physicians, Toronto-based York University, as well as others from Barcelona, Italy and Copenhagen raised some serious questions with respect to the assumptions made by EMA in developing the adaptive pathways pilot.

“The evidence on which these assumptions is based does not seem very convincing to us and there seems to be a lot of uncertainty in their potential operational application,” the professors wrote, noting a list of eight general assumptions, including:

• That “new” or “innovative” drugs and biologics are more effective and safer than existing ones
• Current mechanisms for market and postmarket regulation stifle innovation and delay market entry for “innovative” and “new” drugs
• Early market entry is beneficial to society
• That patients will switch back to an older drug if the newer one ends up failing regulatory or postmarket hurdles and that physicians act on such postmarket warnings based on harms or use restrictions
• EU information systems can support the adaptive pathways process with unbiased (or minimally biased) up to date information such as observational data
• Surrogate outcomes are acceptable
• The idea that “something is better than nothing” is an acceptable principle

And though the professors said they think the idea of adaptive pathways has “great potential benefit for society,” they also argue that scientific terms “should be used correctly, as there is potential for misinterpretation. The term ‘real world evidence’ is a euphemism for observational evidence as it comes from observations which always precede experiment and production of empirical evidence.”

They also say that before the use of an adaptive pathway leads to a new drug’s authorization, “any subsequent plan to generate evidence must be agreed and legally binding on all parties, following an agreed protocol. This is because of the need to ensure accountability for the considerable sums of public money which have been invested and will be invested.”

EMA Response

In response to the letter, Rasi and Eichler offer a point-by-point rundown on whether they agree with the professors and try to offer more supporting information for how adaptive pathways works and will work moving forward.

For the assumption that “new” or “innovative” drugs might give the impression that these treatments are more effective or safer than existing ones, EMA says that the terms (new and innovative), which they say are synonymous, are “neutral” with respect to whether a given innovative or new product is more or less effective or safe than existing treatments.

“The aim of adaptive pathways is to bring potentially beneficial treatments to the right patient group as early as appropriate,” the officials wrote. “Therefore, an assessment of the likely benefit over existing treatment options, not of ‘newness’, has to precede a decision to follow adaptive pathways. Note that EMA received 60 applications from sponsors for its ongoing adaptive pathways pilot program, but selected only 20. We aim to ‘pick the winners’, in the interest of patients with unmet medical needs.”

And though the officials clarify that “Real-World Evidence” is used by EMA “to mean evidence coming from registries, electronic health records (EHRs), and insurance data either in specific observational studies or through continued monitoring of use, benefits and risks,” they also say they “are aware that observational studies have produced non-reproducible or contradictory results; however, so have other methodologies, including RCTs [randomized clinical trials. The adaptive pathways concept therefore emphasises the need for planned collection of observational data where evidence from trials may need to be complemented. This collection is based on expert methodological advice and multi-stakeholder input. Furthermore, repeat cycles of evidence generation are emphasized to quickly refine or correct past decisions where needed.”

And as far as being able to switch a patient back to an older drug when the newer one might prove to be less effective, EMA recognizes the difficulties of such a scenario.

“We are aware of disappointing experiences in the past; indeed, physicians have not always acted on post-marketing warnings on harms and restrictions of use,” Rasi and Eichler write. “However, recent experience with prospectively designed Risk Management Plans shows that, if appropriately managed, restrictions/warnings can be successful.”

For the assumption that “something is better than nothing,” the officials also make clear that it “would be unethical and incompatible with the role of regulators to ‘sell hope instead of help’ [Bianco & Sipp. Nature 2014; 510, 336–337]. This is why adaptive pathways places strong emphasis on sufficient early evidence of relevant patient benefit and close monitoring of patient benefit after launch.”

EMA Letter