Overcoming Delays in Europe's Advanced Therapies

It may seem paradoxical, but Europe's advanced therapies aren't advancing all that fast. The European Medicines Agency has received 18 marketing authorization applications since its regulation for Advanced Therapy Medicinal Products (ATMP) came into force in 2009, and only nine products have been approved. As concerns grow about the slow progress, drug developers are pushing for action from European authorities. The main lobby group for these products, European Biopharmaceutical Enterprises, speaks of the "growing urgency to understand which factors are associated with the advancement of ATMPs through the medicines life-cycle."

This autumn is seeing flurry of industry-backed European conferences on the subject. As the flyer for one upcoming meeting puts it, "ATMPs offer the promise of providing innovative treatments for patients. However and despite considerable development activity, few have received a marketing authorization in the EU." Or as Alberto Chiesi, CEO of Chiesi, said at a recent conference in the European Parliament, "we have proved products work. We have made great progress." But, he went on, "the market doesn't get the issue of patient access." Payers are not prepared to meet the cost, he complained, and the result is that products don't make it to market-or don't stay there. Nearly half of the few ATMPs that have been launched in Europe have since been withdrawn for commercial reasons, he said.

The authorities are making some attempts to make up for lost time, but industry still has many questions about whether the efforts go far enough or in the right direction. The European health commissioner Vytenis Andriukaitis shares the optimism about the opportunities."ATMPs have the clear potential to bring major benefits to patients," he said in a recent speech, accepting that with so few products yet on the market, "some would say that the outcome is disappointing."  But at the same time he issued a note of caution. "The risks of ATMPs and the detrimental consequences for patients when products are administered to patients without appropriate controls have been amply reported," he said. "A system ensuring independent review of the treatments used, and that experimental treatments are administered to patients only under the safeguards of the clinical trial framework is necessary for good science to develop."

The commissioner was keen to point out that Europe is fertile territory for ATMPs, listing 487 clinical trials hosted between 2009 and 2015, and 244 requests for scientific advice from the EMA until July 2017. This is, he said, "testimony of the promising pipeline of products to come." Guido Rasi, Executive Director of EMA, also believes that there is "a promising pipeline," with rapid advances and fast-changing targets that are also driving changes in therapy delivery.

But Andriukaitis insists that this remains "a very novel field, and many of the expectations of a decade ago have not been confirmed in clinical trials." That view is not universally shared. "Cell and gene therapies can deliver life-changing therapeutic effects as demonstrated by compelling clinical data," boldly states the publicity for another of the upcoming industry conferences.

The quality of the regulatory framework is at the heart of the discussions. Chiesi described the current legislation as a "nightmare for developers and regulators," but the EU has promised to improve it. In early October, EMA and the European Commission published an "action plan on advanced therapy medicinal products," accompanied by an admission that there are "shortcomings" and that action is needed "to help translate scientific progress into medicinal products available to patients." The plan was prefaced by the claim that "the EU is committed to support the development of these products and will keep monitoring developments in the field to ensure that the regulatory framework supports-and not hinders-the development of ATMPs."

The plan promises publication of a new guideline on manufacturing requirements before the end of this year, "to reduce administrative burden and adapt GMP to the specific characteristics of ATMPs." EMA will also train European inspectors to achieve more harmonization, and continue promoting exchanges among them on GMP inspections." To reduce discrepancies among national interpretations of EU rules on authorizing medicines and GMOs, the Commission "will initiate a dialogue with national competent authorities." EMA assessment procedures for ATMPs will also be reviewed before the end of the year "to reduce administrative burden, and avoid overlaps."

By the end of 2018, a draft of new EMA guidelines is promised on investigational ATMPs, "to avoid discrepancies across the EU regarding the requirements" in the clinical trial phase.  This "will help create common standards for the assessment of these novel products," says the plan. Over the next six months, new scientific guidelines on gene therapy and on genetically modified cells will "support developers of these novel therapies by clarifying regulatory expectations." And the current guideline on safety and efficacy and the risk management plans for ATMPs are scheduled to be revised in the first half of 2018.

Fixing the regulations governing safety and efficacy may go some way to easing the situation-but it is unlikely to be enough. Even Rasi, Europe's top regulator, observed recently that the relatively limited number of ATMP approvals was not the result of regulatory constraints, but arose from challenges in terms of pricing, health technology assessment, and infrastructure. As Chiesi complained, "we have to find different ways to evaluate these products." 

But it is in just those areas that the EU has little to say, and even less margin for maneuver, because they are matters that remain under national control. Andriukaitis recognized the "need to identify cost-effective ways to maintain access to these new therapies," but could realistically offer no more than report that he had asked the commission's expert panel on effective ways of investing in health for an opinion on "innovative payment models for high-cost innovative medicines." The Commission's plan envisions only a "training workshop planned in 2019" to  contribute to "health technology assessment, regulatory processes, and clinical added value of ATMPs." As a consolation prize, as it were, the plan also suggests "an improved regulatory framework will contribute to promoting innovation, investments, and competitiveness of the EU biotechnology sector."

Conspicuously, Andriukaitis offered virtually nothing to comfort drug industry executives who have been complaining about the commercial disadvantage they suffer from competing hospital-produced ATMPs. Hospitals enjoy an exemption from the EU authorization requirements for ATMPs that they prepare themselves, for which they can obtain a purely national approval, and there about 60 of these at present in Europe. This risks creating parallel paths to market access for ATMPs, argues EBE, expressing concerns over traceability, pharmacovigilance, and quality standards. The result is "uncertainty, barriers to patient access, lack of transparency on available therapies, and reduced incentives for developing ATMPs in the EU," the industry organization argues.

Far from accepting the industry's concerns, Andriukaitis defended the exemption on the grounds that "the development and manufacturing of an autologous product cannot be subject to the same requirements for a mass produced chemical substance… In this case, one size does not fit all." All he offered was the vague concept that the commission will "initiate a reflection process with the member states," and discuss "the current situation and address possible options."

The next few weeks will see numerous discussions of the changing global competitive landscape, and numerous reflections about how EU biotech can adapt and succeed. As always, the underlying question is whether Europe's authorities can move fast enough to keep up with progress in medicine.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.