A letter to a patient representative on Adaptive Licensing / pathways

by Yannis Natsis, 13 May 2015

(Views do not necessarily represent TACD positions)

Dear Bettina,

Many thanks for taking the time to comment on my analysis on adaptive licensing/pathways entitled “Adapting medicines to the market or to patients’ needs”. Interventions like yours are necessary and certainly help the debate move forward. Let me start by expressing my firm belief that we share the same goals as we both strive to ensure access to the right treatments for all those who need them. At the end of day, we are all potential patients who are entitled to enjoy the highest quality the healthcare system has to offer.

To this end, I am glad we agree on an additional imperative that of denouncing the immorality of exorbitant drug prices which in fact deprive tens of thousands of people in Europe today of their treatments. As you rightly underline, the profiteering character of the current business-driven pharmaceutical model results in medicines whose primary adverse effect is “financial toxicity”.

As regards adaptive licensing (henceforth AL), there is a series of serious questions that remain unanswered. I am confident that we agree that when it comes to such complex topics, a comprehensive and unbiased debate is mandatory. AL puts patient advocates in the spotlight and with that comes increased responsibility and higher expectations for accountability. In the words of the EMA’s Guido Rasi “patients will play an even bigger part in the drug development process but need to be distanced from the emotional involvement in the product under evaluation”.

Unmet need” is supposed to be the defining criterion of the scope of application of adaptive licensing…but wait, we do not even know what falls under unmet medical need

Theoretically, AL aspires to address the needs of patients that fall under this category. This is of pivotal significance in the course of the debate because “unmet medical need” not only constitutes the starting point but more notably defines the scope of application of AL. In other words, the candidate drug must present a real advance for patients in areas of unmet need. However, European countries have always had a very hard time reaching a consensus on a definition. The current stalemate in the respective negotiations at the recently established European Commission Expert Working Group on Safe and Timely Access to Medicines for Patients (STAMP) confirms the difficulties. This is hardly surprising as apart from the scientific criteria used to delimitate unmet need, numerous political, economic and societal aspects come into play and thus vary considerably between member states. This is a profoundly important point, as pricing & reimbursement decisions depend on this definition. It is remarkable that the European Commission as well as the European Medicines Agency (EMA) are quick to dismiss any fears that AL will apply to all medicines and are eager to stress that it covers unmet need only. But how can we rest assured that the exception will not become the rule when unmet need is so controversial and vaguely defined? It is totally unclear to me how it will be established and I am not the only one to find this puzzling.

Real world clinical trial data collection sounds good but how, who, what, when?

Another key component and insurmountable “If” in the case of AL, is the collection of real-world clinical trial data (hereafter RWD). As you acknowledge in your response, AL’s success and credibility depend on this. In fact, the roots of the AL debate are not about improving access but about redesigning the clinical trials model and promoting the adaptive trials narrative. The current randomized controlled trials (RCT) model usually requires lengthy trials, a significant cost for industry and most importantly a numerous products fail after a lot of money has been spent. AL entails instead a well-defined subpopulation implying very limited initial clinical trials where efficacy will be demonstrated quickly (contrary to patient safety) and that will lead to a gradual expansion. It is common ground that AL shifts the paradigm prioritizing efficacy over safety which in the case of certain categories of patients makes absolute sense. But again, this can only be the exception and not the rule. This means that industry gets to save a lot of money while managing to place its expensive products on the market much earlier than ever before. Moreover, it is not sure that a novel trial design will facilitate the AL, nor how the additional data will be collected, what type of data will be collected, who will collect it, who will pay for this and over what period. Needless to mention, that how this data will be evaluated scientifically and by whom are crucial questions in relation to their reliability and objectivity.

We need the products on the market”. Great, but at what price?

Let’s talk about money. Another challenging and pretty tangible problem is the question of pricing and reimbursement of these drugs. They rely on much fewer clinical trial data, their efficacy looks good (the benefit-risk analysis is positive since theoretically at least, we should be talking about patients with a higher risk profile) and they cover the needs of a small group of patients. Industry claims that since the volume is small, the price should be high, whereas countries fearful about their health budgets argue that since the volume is small, the price should be small as well. As a consumer and potential patient, I wonder how these products will be reimbursed especially during the initial authorization. There is considerable concern about this in the Council too. Another critical question often asked is on what grounds the price will be reviewed.

What if it goes wrong?

I must say that I am a bit surprised with your stance towards safety. In my opinion, society should aim to safeguard the maximum degree of both safety and efficacy. Furthermore, I strongly disagree with the view that patient safety regulations stifle access. Of course, the system as I indicate in my original analysis already foresees the necessity to live with increased uncertainty for very specific groups of patients and accommodates this through the current fast track mechanisms (conditional marketing authorization-CMA, accelerated procedure, compassionate use schemes and others). One of the fundamental questions that AL fails to effectively resolve is what will happen if the advertised benefits of candidate drugs are not confirmed in the populations targeted. I am particularly concerned about this as we are fully aware that most member states neither have the administrative capacity nor the political will to withdraw products once they are on the market. This issue cannot be pushed aside as the liability for whatever goes wrong does not fall on the companies but on public authorities. AL relies heavily on enhanced post-marketing safety and efficacy surveillance to manage this increased uncertainty. It is erroneous to believe that the EU Pharmacovigilance system –seen as excessively demanding, disproportionate and counter-productive by industry, hailed as a success by public health advocates- can or should carry the burden of this monitoring. It was not set up for this reason in the first place.

Why not work with what we already have?

Pharmaceutical companies must reconsider their negative view about the present fast track instruments and commit themselves to enhance them. They prefer full marketing authorization over CMA mostly because they are not 100% certain that they will obtain reimbursement when complete data are not available. As you probably know, STAMP is conducting a review. It is collecting experiences and best practices from member states via concrete questionnaires on how they implement these schemes, what the various criteria and obstacles are etc. This mapping exercise is significant as its findings will feed into ongoing discussions and will define the need or not to redesign the EU market access system. At the same time, the EMA’s Committee for Medicinal Products for Human Use (CHMP) is revising the draft Guideline on the CMA. There is no doubt that today’s options can be improved. Patient groups have an obligation to actively and constructively contribute to the ongoing evaluations (on the member state level too) and to work on improving the inadequacies. I hope that the findings of these reviews will be unbiased and will genuinely aim to develop the current system, tailor it better to the needs of patients and make it more efficient.

What is the big picture about AL? Is it only about access to medicines?

No, its scope and impact are much broader. This is the so-called life-cycle approach to drug development with far-reaching implications across the entire regulatory framework. In a nutshell, industry is not happy with the fact that high prices have become a political issue on an EU level. It is thus trying to shift attention away from the subject and to reshape the agenda by putting fast & early access on top of it. Their long-term strategic goal is to restructure the EU medicines regulatory framework. They conveniently describe it as too rigid and accuse it of hindering patients’ access to “innovative” treatments. That is why; they showcase AL as the future and reiterate that efficacy -as it costs them far less to demonstrate- should be the key focus. A more “flexible” and “predictable” market access and pricing and reimbursement environment as envisaged and guaranteed by AL opens the doors for their expensive treatments. Here lies one of the keys to better understand AL and its place in the overall debate about medicines in Europe. Industry does not appreciate the polyphony that exists with the different evidence requirements and standards put forward by the various national regulatory authorities. AL offers a way out, as it tries to a) “tie the hands” of Health Technology Assessment (HTA) bodies, payers and national competent authorities by limiting their independence and b) force them to accept greater uncertainty (for more information, please read “Pharma is moving fast: What is coming up in pharmaceuticals in Europe”). Additionally, it touches the sensitive and emotionally charged notion of unmet need and emphasizes the mantra of early and fast access over everything else. It thus leaves no space for discussion around the quality of innovation (access to what?) and eventually prevents an open, healthy and impartial debate on the genuine needs of patients across the spectrum. We cannot afford not to have such a conversation as a lot of the areas where there is unmet medical need today are due to the current market and not public health-driven model of medical innovation. We need to work together to demand real innovation based on public health needs and proven therapeutic advance in comparison to existing medicines.

AL is a highly complex and delicate issue. Let us not forget that up until recently even the Commission’s DG SANCO (now DG SANTE) was very skeptical towards it. There are voices within industry that still express similar doubts. Nevertheless, EFPIA along with the EMA promote it as a flagship initiative. DG SANTE has the oversight of the CHMP/EMA’s decisions and a duty to carefully balance all positions as public health is at stake. As I have previously noted, a shorter time to the market would possibly be beneficial both for the industry as well as for particular categories of patients only as long as sufficient safeguards are in place.