After announcing the long anticipated adaptive licensing pilot programme would begin from the 19th March 2014, the central regulatory authority for medicines in the EU, the European Medicines Agency (EMA) says initial uptake has started encouragingly, with 20 applications so far made to the pilot. Interest in this pilot programme for adaptive licensing is being actively canvassed by the EMA with Dr. Hans-Georg Eichler, an EMA employee and advocate of the pilot, recently presenting at a BIA event in London to an audience of industry people who he hopes will apply to participate in the programme. He says; those sponsors with innovative medicines treating unmet medical needs are the suitable candidates for the adaptive licensing procedure, ideally assets in Phase I or Phase II before a confirmatory study.
What is adaptive licensing aimed to achieve and how?
Last year we published a report on the pathway for new medicines addressing unmet medical needs, such as those found with rare diseases. This report uncovered that people in the drug development industry, as well as patients, believe that the stages of regulatory approval and pricing reimbursement were impeding patient access to new medicines.
It is unconstructive to talk of the regulatory licensing process as a hurdle, because it is there to guarantee patient safety, something which must remain paramount with new medicines is citizens are to be safe-guarded. However, the regulatory application and licensing process has imposed time horizons which have frustrated the drug development industry, as well as many patients seeking new and innovative medicines they believe could help their disease. This risk / benefit proposition is at the heart of the debate over earlier access.
Adaptive Licensing is a response to this problem. The pilot offers a new and innovative approach to the approval of new medicines by the EMA. Earlier this month (6th June 2014), the agency announced it has initially selected 2 applications to go forward in the pilot process. This adaptive licensing pilot is actually taking advantage of the current freedom of the regulatory licensing framework and many of the features of the adaptive licensing process have previously been employed by the agency with particular medicines. It is also part of the adaptive clinical trial design now more frequently employed.
Sponsors will have an opportunity to discuss the adaptive licensing in a safe-harbour environment with the key stakeholders, including the Health Technology Assessment agencies, as well as the patient groups in some cases. The presence of this ‘safe harbour’ is very important to encourage multi-dimensional discussions which are both confidential and designed to optimise the pathway for the drug candidate through the stage-gates towards patient-access.
This adaptive licensing process seems particularly applicable in areas like rare diseases, gene or cell therapy, but could be applied in many different disease areas where innovation is at the heart of new therapeutic approaches and early patient access a highly desirable outcome. This enables new drugs, where there is no current treatment, to reach patients and to allow real-world data to inform regulators about the licensing of the drug thereafter.
As suggested earlier, this attempt to achieve earlier licensing of drugs is not entirely new and we have already seen initiatives like Compassionate Usage Licenses and Conditional Approval Licenses helping new therapeutic approaches. In recent weeks for example, we have seen a new drug for treating Duchenne Muscular Dystrophy, Translarna™, gaining CHMP conditional approval.
Regulatory Agencies shift perspective
This focus on early patient access for innovative new drugs has stimulated a number of initiatives. Adaptive Licensing is just one such initiative introduced by drug regulators and payers to create a more efficient pathway for access. Adaptive Licensing is now very much an attempt to embrace the possibilities of evidence generation once a drug is being used by patients. Regulators have grown in confidence about the ability to detect adverse events and are beginning to see opportunities to shift the paradigm towards one based on evidence generation rather than the historical prediction paradigm which emerged in the wake of drugs like Thalidomide. At least this adaptive licensing pathway might begin to show what is possible in this respect.
The EMA talks of a systems approach for adaptive development which comprises the entire life-span of a product, of which there are five key stages:
Achieving early clinical results which demonstrate some activity in the desired patient populations and achieving a license on this basis, is insufficient to achieve the access which adaptive approaches are designed to achieve. There is also a necessity to ensure that evidence generation plays a role in the HTA evaluation and that these critical stakeholders are aligned with the adaptive licensing decisions. This in itself is a challenge, particularly in Europe’s highly fragmented payer environment. While regulatory decisions have been able to be centralised, the payer decisions still reside with the healthcare systems of individual nations, and in some cases, even more localised authorities. Regulators are confident that HTAs will come to the table and be prepared to take part in this proactive coalition, something that patients and their representative groups will also be pleased to see.
The ‘access v evidence’ conundrum is central to the adaptive approach. The health authorities describe this as the magic moment, when approval provides the green light for commercialisation. The notion that licensing decisions move beyond the definitive ‘go’ or ‘no-go’ regulatory decision and instead become a sequence of repeat licensing decisions based on evidence and learnings, creates a distinctively more advantageous drug access environment, at least from a regulatory perspective. Patients also view new drugs with varying degrees of risk and ongoing evidence generation will inform those patient decisions. Their participation in this more ‘observational’ approach will also enable all stakeholders to make better decisions about a drug, bringing forward options which might not be possible under more traditional randomised control studies.
Drug access is not just about regulatory approval
As with the more conventional drug approval process, there remain considerable complexities for pricing of new drugs. These complexities are in no way lessened for drugs which endure the phases of an evidence generating adaptive development pathway, a process which will inevitably determine the real value of a product. Early questions will need to be answered about what price can be reached for early approved products via the adaptive license and how this price might adjust with evidence gathering, further licenses or expanded populations of patients. The inclusion of key HTA bodies in these early discussions, long before a scientific advice is provided, is hopefully going to create a clear alignment across the stakeholders about these issues of pricing.
Of course providing earlier access in this way needs controls too. This is why utilisation is part of the systems approach. The regulatory authority will need to use all of its tools available to ensure that these new drugs are reaching the patients for which they’re intended and that use of the drugs in other clinical settings, such as off-label, is restricted. Of course tools such as risk-management plans can be applied but perhaps even stricter mechanisms might need to be introduced to control prescribing if this evidence based approach is to take hold. A new drug which becomes wildly adopted has the potential to threaten an innovative approach like adaptive licensing.
Industry business models changing too
The adaptive licensing pathway, and the more broadly applied adaptive development approach, has many applications for a pharmaceutical market which is changing dramatically. Despite the arrival of new blockbuster drugs therapies like Sovaldi from Gilead which has addressed disease in a global population of Hepatitis C patients, the industry is now heavily oriented towards targeting smaller populations. The pharma industry is switching away from focusing on targets, moving towards a focus on pathways, understanding the molecular basis for the disease. This means there is a need to deeply understand diseases, giving way to this idea of starting in small, well understood diseases. These diseases can be specifically targeted by a novel drug, then that drug can be developed into other populations of patients.
In fact, it is part of the business model of many companies to look into small populations and then develop towards broader indications; look at Novartis and their Anti-IL1 antibody as an example. This was originally developed in cryopyrin-associated periodic syndrome (CAPS) with a patient population <0.020m. The company then developed it in systemic juvenile idiopathic arthritis (SJIA) with patients <0.075m (FDA and EMA), then Gout with around 20m patients (EU approval) and now the company is trialing the product in atheroscleronis (130m patients).
A future regulatory landscape with patients in mind
In truth, the adaptive licensing pilot has been in the offing for some time, so industry and patients will be pleased to see it finally begin. The initial application of live assets entering the pilot will hopefully begin to contribute immediate learning opportunities for all the stakeholders. There are still many unanswered questions about the practicalities of a system like this, especially one which involves the drug industry to play its hand very early in the development process. If the questions about confidentiality, data exclusivity and the impact of developing a drug in an evidence generating real-world environment can be overcome, then so might some of sceptics. However, bringing more opportunities for patients to access new drugs earlier, and to have them more involved in the development of those drugs, seems to be a good start. After all, patient groups have been intimately involved in funding research, as well as providing access to patients in clinical studies or important disease history through registries, for a range of diseases where new therapies have been given approval. They are an important voice and one the regulatory bodies are trying to include where possible or appropriate. Whatever lessons are taken from the pilot will need to be applied effectively to embed adaptive licensing and encourage an evolving regulatory system which can be based on the concepts of earlier access.