The industry is closely watching the European Medicines Agency’s (EMA) experiment in adaptive licensing, which challenges the way new medicines are evaluated and approved—since a successful outcome could play an important role in moving the approach forward in the U.S. and other regions.

Adaptive licensing, also known as “staggered approval,” begins with early authorization of a drug candidate for a small, well-defined group of patients in which the drug’s benefits have been clearly shown to outweigh its risks. The approval is gradually expanded into new populations, in an adaptive fashion, as more safety and efficacy data is gathered through clinical trials and real-world outcomes in treated patients. Data about benefits and risks continues to be evaluated during the entire life span of the drug.

The approach could allow sponsors to make innovative medicines available to patients up to eight years earlier than possible under conventional drug development pathways, according to researchers at the Massachusetts Institute of Technology (MIT). It also enables drug developers to collect revenue and real market experience while they continue to gather clinical evidence about the medicine’s benefits and risks. Adaptive licensing also allows for earlier input from regulators and other stakeholders, including prescribers and payers, to inform development strategies that could help reduce costs as well as the risk of late-stage attrition.

“It is the most substantial paradigm shift in regulatory sciences we have seen for the last decade,” said Detlef Niese, M.D., an industry veteran who has been involved in discussing the emerging adaptive licensing model with regulators. After having worked for more than 20 years in development at Novartis, Niese now is an independent consultant with Germany-based Dr. Niese Health Science & Policy. “It is a very important effort, on one hand, to make drug development more efficient but, above all, to provide patients early access to new promising treatments as soon as it is responsibly possible.”

The outcome of the EMA’s pilot program, which began last March and is about to move into its second stage, could give other agencies important information regarding the benefits and limitations of the model and help determine whether it has the po­tential ultimately to replace the current de­velopment and authorization processes for many new products.

Already there have been calls for Congress and the FDA to consider a similar pilot proj­ect in the U.S., as industry supports alterna­tives to the traditional three-phase clinical trial model that could improve efficiency and lower the costs of drug development.

“Every regulatory agency around the world is constantly looking at how it can do its mandate better,” said Jeffrey Spaeder, M.D., chief medical and scientific officer at Quintiles. “This pilot project is going to pro­vide other regulators—not only in Europe, but elsewhere around the world—some in­sights. If it’s a success—and there is reason to believe it will be successful—it can’t help but impact their calculus in terms of how they follow their mandate in the future. Whether they decide to adopt everything the EMA does or parts of it, it’s likely that it will influ­ence the perspective of other regulators.”

Alternative pathway tested

The concept of accelerated approvals has been around for years under different names. The U.S. has Fast Track and Breakthrough Therapy designations, for example, while Europe has a conditional marketing approv­al program. Last March, the U.K. launched an Early Access to Medicines Scheme. The programs all have a similar aim of trying to speed up the development process, mostly in the area of serious, life-threatening diseases, to allow patients early access to innovative medicines while at the same time protecting safety and maintaining high scientific rigor.

The EMA’s pilot project, which builds on earlier work with MIT’s Center for Biomedi­cal Innovation, will explore the adaptive licensing approach with medicines in the early stages of clinical development and is particularly relevant for drugs with the po­tential to treat serious conditions for which there is an unmet medical need. The ap­proach isn’t suitable for all trials. Yet one aim of the pilot project is to help develop an un­derstanding of how future adaptive licens­ing pathways might be designed for different types of products and indications.

“The idea is to move this into the general drug development paradigm,” said Niese. “It’s no longer just about serious, life-threat­ening disease. It’s about the development process.”

As of late November, the EMA had re­ceived 34 applications and assessed 29 as part of its pilot project; nine projects have been selected to move forward to the second stage, which will begin in March with in-depth, face-to-face meetings with sponsors. Companies have until the end of February to submit applications.

The pilot program uses regulatory pro­cesses already in place within the existing European Union legal framework, but it requires a radically different approach from the current binary approved/unapproved designation for a drug. Adaptive licensing is based on the idea that knowledge of drugs continues to evolve over time; it allows some drugs to be approved initially for limited populations before being approved for wider use based on clinical evidence.

“The current standard pathway to mar­ket access is not optimized to enable timely, well-informed patient access to drugs in this kind of niche,” said Michael George, M.D., vice president, global therapeutic area head at Covance. “Drug development is very ex­pensive, it takes a long time and there are delays to market access—particularly in those areas where there is high unmet medi­cal need or alternative therapies that really aren’t very effective.”

Importantly, adaptive licensing requires early collaboration between the sponsor and a wide range of stakeholders who influence patient access to medicines. These groups include regulators, payers, patient and con­sumer groups, health technology assess­ment (HTA) bodies, organizations that issue treatment guidelines, healthcare providers and the research community. The process creates a mechanism, called safe harbor, which allows companies to seek early buy-in and guidance from these stakeholders to ad­vance the development of promising drugs. Relevant stakeholders agree on a compre­hensive development and licensing plan for each product before it receives an initial ap­proval for limited subpopulations.

“They are looking for strengths and weaknesses of the options for development and the pathway for licensing,” said George.

Adaptive licensing could reduce the over­all cost of development by allowing better-informed decisions on product viability to be made earlier in the development process. In some cases, it could reduce the time to full-market approval. The concept allows sponsors to receive guidance from regula­tors and other stakeholders about designing studies that could not only help control cost, but also increase information and insight about the drug. Sharing risk between payers and developers by allowing patients early ac­cess to a drug candidate also gives sponsors an early source of revenue while they con­tinue to develop the product.

Requiring the alignment of stakeholders early on also could help prevent situations in which a drug completes all stages of review and receives market approval, yet payers are unwilling to cover it because they consider the evidence insufficient to justify the cost. Incorporating reimbursement and market access discussions as part of the adaptive li­censing process will be critical to the pilot project’s success.

“In the specific context of adaptive licens­ing, there definitely is emphasis on a col­laborative approach between EMA and the reimbursement authorities,” said Pinar Ak­pinar, Ph.D., senior director of pricing and market access at Icon. “There sometimes is a divide between what is appropriate for regulatory approval versus what some of the countries are looking for in how they define value of the product. In this particular case, it will very much depend on the disease area, the level of unmet need and the level of evi­dence to be generated.”

Questions about U.S. adoption

A number of other countries also are con­sidering the use of adaptive licensing strat­egies to address some of the challenges in­dustry faces. The Singapore Health Sciences Authority, for example, is looking to pilot an adaptive licensing model, and Health Can­ada has implemented modernization efforts that include key aspects of adaptive licens­ing, such as benefit-risk science.

In 2012, the President’s Council of Ad­visors on Science and Technology recom­mended the FDA run pilot projects using existing pathways to explore adaptive ap­proval mechanisms that could collect evi­dence across the life cycle of a drug. The approach was the subject of an FDA public hearing a year later. Quintiles, the world’s largest CRO, also has been at the forefront in calling for the FDA to adopt, on a pilot basis, an alternative development pathway similar to the EMA’s adaptive licensing program.

“Data required to determine the effi­cacy and safety and the benefit-risk profile of a drug can come from a variety of areas. There is value in data that not only comes out of clinical studies, but also is available from electronic medical records, registries and observational studies,” said Quintiles’ Spaeder. “There are many people in the in­dustry who look at the tools we have avail­able now and are interested in seeing if we can incorporate those tools into the approv­al process.”

Many challenges exist in implementing adaptive licensing as a common pathway for drug approval. Sufficient incentives must be in place to encourage sponsors to continue developing a drug candidate after initial approval. Mechanisms must be introduced to quickly withdraw the medicine if some­thing goes wrong in studies. Other obstacles include biomarker validation and adoption and the need for common data standards. There are questions about intellectual prop­erty protection and reimbursement path­ways during development. Some of the many other questions include how to limit early access to only the approved subpopu­lations and who should pay for the ongoing data collection after the initial approval.

Despite those difficulties, many indus­try leaders believe it’s inevitable regulatory models will evolve to include adaptive licens­ing approaches both in Europe and the U.S. Many researches, including those at MIT’s Center for Biomedical Innovation, believe the adaptive licensing model could help ad­dress some of the root causes of the overall high cost of drug development. It’s broadly acknowledged the cost, size and complexity of clinical trials required to obtain market­ing authorization are increasing, and the number of products reaching the market no longer supports R&D activities.

“The current approach simply is unsus­tainable,” said Niese. “It is clear that even with the increasing investments on the de­velopment of new medicines, the results are not getting better. In fact, we see a declin­ing number of approvals per billion dollars spent. That can’t continue, because at some point in time there will be no money left for development. At the same time, it is critical that the scientific rigor and the assessment of benefit-risk for new medicines is not re­duced so the public health is protected. I think the question is how to find the right balance.”

Cyril Clark, M.B., B.S. (equivalent to M.D.), vice president of translational medi­cine at Icon, believes other trends in devel­opment, including the move toward person­alized medicine and better understanding of the biology of common conditions such as asthma or rheumatoid arthritis—which will target specific treatments to smaller patient populations—also will help lead the indus­try toward an adaptive licensing model. In addition, while classical trial design for reg­istration has focused on efficacy, he said, payers and patients have become more fo­cused on the drug’s effectiveness.

“Effectiveness is how the product actu­ally works in the real world and the value it provides for the individual patient in the context of costs in an overall healthcare system where judgments have to be made. There is a clear requirement for trial design­ers to develop data sets that support both ef­ficacy and safety—the traditional regulato­ry endpoints. But for the last decade, those who have been doing this in an appropriate manner already have been thinking about the end game and reimbursement and ef­fectiveness endpoints and outcomes,” said Clark. “The regulatory environment realiz­es it needs to evolve, but this time it actually is proving to be in step, rather than being fully reactive or one step behind, certainly in Europe.”

Industry experts believe necessary pieces, such as tools and data required to identify and monitor patients, already are available in order for the FDA to pilot alternative pathways for drug evaluation and approval. Yet one of the biggest challenges remains getting the public and politicians to under­stand and accept the idea that drug testing involves a measure of risk.

The current framework for drug licens­ing relies on the perception that regulators should require sponsors to fully establish safety and efficacy before licensing a drug; to many patients, this implies the drug is 100% safe and effective. Adaptive licensing, however, acknowledges there always will be levels of uncertainty with innovative treat­ments. Regulators worry this idea might lead to the perception that they are lowering standards, putting the needs of industry be­fore the public and allowing untested drugs on the market. Yet, in reality, no licensing system can guarantee a drug is 100% safe and effective.

“Acceptance from the public at large and the politicians is one of the biggest hurdles to overcome. If regulators approve a product and they have to pull it, which is inevitable, they will be accused of bending over back­wards for big pharma,” said Beat Widler, Ph.D., managing partner and co-founder of Widler & Schiemann, who worked at Roche for more than 25 years. “We have a risk-adverse society. We enjoy the benefits. But if something goes wrong, we start pointing fingers.”

One of the main purposes of adaptive li­censing, however, is to gather stronger and more relevant data earlier and throughout the product’s life cycle to maximize the benefit-risk profiles of drugs.

In addition, research sponsored by Quintiles found patients are willing to use therapies developed under an accelerated pathway, particularly if they suffer from conditions or diseases with unmet need. A 2012 survey of patients living with chronic disease suggested they want access to new medicines sooner and those in greatest need are willing to accept more uncertainty about taking a new therapy; 72% of patients sur­veyed in the U.S., and 81% in the U.K. said they should be able to take potentially risky medications, even those not approved for use, if they feel it is their only chance to im­prove their health.

“Patients who suffer terrible diseases are willing to take therapies and undergo treat­ments even if there is risk to it, as long as they understand they have a high degree or high likelihood of deriving potential benefit from it,” said Quintiles’ Spaeder. “We want to maximize the benefit-risk profile. We are aiming to define the patient population that will most benefit or has the greatest benefit-risk profile.”

The FDA acknowledges the need for ac­celerated approvals, especially in therapies with unmet needs, and regulators have writ­ten in peer-reviewed journals they believe it likely new regulatory paradigms will evolve during the next few decades. But whether the FDA follows an adaptive licensing path or expands its own accelerated access pro­grams to include elements of this approach will rely on outcome of the EMA’s pilot pro­gram and other forces, such as whether in­dustry, patient organizations, reimbursers and payers become vocal in their support of the model. While these groups all have different objectives, they share a desire for making decisions based on good evidence.

“The FDA will want to see results of the pilot project. It will want to hear from the regulators in Europe, pharma and biotech companies and patient populations. If there is a demonstrably better and faster way to bring therapies forward, they will be open to incorporating the best of those ideas, just as the EMA will be looking at the break­through therapy initiative at the FDA and how that accelerates development,” said Spaeder. “I don’t think this a matter of one agency is right and one is wrong. They are looking at the same problems and diligently trying to address them. They are focusing on some different approaches. But the data and the evidence will be compelling to all regulators.”

Looking ahead

The EMA’s pilot program will gather real-world evidence to understand the advantag­es and drawbacks of adaptive licensing. The experiment’s outcome will allow regulators and the industry to understand the techni­cal questions associated with implementa­tion of adaptive licensing and appreciate the perceptions and needs of various stakehold­ers. With this information, regulators can evaluate whether adaptive licensing ulti­mately can provide a better alternative to the current licensing paradigm.

While there are many challenges to im­plementing adaptive licensing as a pathway for drug approval, many see the pilot pro­gram as a chance to test an alternative way to evaluate and approve new medicines and move toward a process that allows for better use of data from a variety of sources to assess the risk-benefit profile of a drug.

“The EMA is doing what good scien­tists do—coming up with a hypothesis and then performing a pilot test to see how this works,” said Quintiles’ Spaeder. “It may be a wonderful success which they can point to and say, ‘Our suppositions were proven cor­rect. And this is something we want to do more.’ Or they may come back and say there were unintended consequences or things they never anticipated, some of which may be good, others that may not have been the direction in which they wanted to go.”

“It gives them an opportunity to say, ‘Maybe we have to recalibrate what we do, expand this, or potentially stop it or wait to see what happens,’” he said. “This is a re­ally interesting way to roll this out in a pilot project.”

Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master’s of Science degree from the Columbia Univer­sity Graduate School of Journalism. Email karyn.korieth@centerwatch.com.

This article was reprinted from Volume 22, Issue 01, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>