First published in our Biotech Review of the Year publication (Issue 10).

It’s been clear since the NHS’s right to produce Avastin to treat macular degeneration was upheld by the Court of Appeal[1] (Avastin decision) that market rules do not restrict clinical practice. Once a product such as Avastin is placed on the market, it’s up to practitioners whether or not to use it for the indication it was approved for. Indeed, the fact that there is already an authorised medicinal product for the target indication cannot fetter a clinical decision to use a different licensed product off label. Where, as in the NHS Darlington case[2], clinicians instruct a pharmacy to divide the licensed medicinal product into aliquot doses for use in treating individual patients for an off-label indication (e.g. WAMD), the person dividing doses into individual syringes (Compounder) will not be placing anything on the market, provided the compounder does not modify the authorised product.

The Avastin decision, which builds upon an earlier decision of the CJEU[3], is a signal indicator of the importance of clinical choice, but it’s not the only one.

When the Advanced Therapy Medicinal Product (ATMP) Regulation emerged in 2007, many applauded its scheme for assisting SMEs. Others, however, argued that the incentives were misplaced. More important than encouraging small businesses, they claimed, was helping academics and clinicians.

At first blush, worrying about individual academics and clinicians makes no sense. But ATMPs are different. They require a denser dossier of manufacturing and clinical data than a biological medicinal product to stand a chance of receiving a marketing authorisation (MA). Very few small businesses can approach this level of funding. ATMPs tend to target rare diseases, a quality which, notwithstanding the possibility of securing orphan market exclusivity, rather blunts the financial appetite. But while businesses are chary about curing rare and supposedly incurable diseases, clinical academics are curious. They play a more significant role in developing and translating advanced gene and cell therapies than small businesses, so why wasn’t the ATMP Regulation helping them?

Perhaps it is. Could the ATMP-specific “hospital use exemption” (HE)[4] provide a helping hand? The exemption applies where the cell or gene therapy product “is prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.” It’s tailor-made for academic hospitals, isn’t it?

In practice, academic hospitals in the EU and UK already have recourse to another exemption to the MA rule: one not restricted to fancy ATMPs, but available, in the right circumstances, to any medicinal product. The “specials exemption”, which in the UK has been used in every instance where the HE might have been attempted. This excludes products supplied “to fulfil special needs” in response to a bona fide unsolicited order, where the product is “formulated in accordance with the specifications of an authorised health-care professional” for use by an individual patient under his direct personal responsibility. It’s good enough, perhaps, and note the difference between “formulated in accordance with the specifications of an authorised health-care professional” and its more demanding HE equivalent: “prepared on a non-routine basis according to specific quality standards” and the associated manufacturing requirements. Who needs the hospital exemption? But not all Member States are quite so dismissive. Some, like Germany and Spain, consider the HE to be useful tool to encourage innovation.

In February 2021, Spain’s regulator, Agencia Española del Medicamento y Productos Sanitarios (AEMPS), became the first medicines agency in Europe to formally authorise a complex ATMP under the HE[5]. ARI-0001 is a preparation of autologous CAR-T cells customised for the relief of relapsed/ refractory acute lymphoblastic leukaemia (ALL) in adults younger than 25. ALL is not only a rare disease[6], but a divided one, originating in either T or B cells. 85% of cases are B-ALL, for which the prognosis is poor despite breakthrough monoclonal antibody products. ARI-0001 was developed at Hospital Clínic de Barcelona. Preclinical and preliminary clinical data were obtained in an academic environment, which demonstrated robust and reproducible lentivirus and ARI-0001 cell production. The safety and efficacy of ARI-0001 were then assessed in a study conducted together with the paediatric hospital Sant Joan de Déu in Barcelona. To ensure compliance with strict manufacturing criteria, the CAR-T cell products are supplied to the hospital by a pharmaceutical company producing them under a manufacturing licence.

There are several striking aspects to AEMPS’ scheme. First, there is the national regulatory framework to facilitate the HE. This not only complies strictly with the EU ATMP Regulation, but makes the exemption conditional upon satisfactory data on clinical efficacy and safety, and limits it to a three year “conditional licence”.

The Spanish legislation also seems to consciously anticipate how emerging EU policy on “substances of human origin” (SoHO)[7] might help to overcome a key limitation of the HE: that patients in hospitals other than the one that developed an HE-ATMP may not access the product. The SoHO proposal aims “to provide representative technical expertise to the European decision-making organisations in the field of SoHO”, essentially enabling a fluid and transparent environment for transferring SoHO technology and know-how. Could AEMPS use this as a lever to expand access to HE-ATMPs? It’s certainly notable that the Spanish regulation describes the hospital developing an HE-ATMP as a “reference hospital”[8].

The clinicians who developed ARI-0001 clearly think Spain is on to something[9]. Even so, they consider that the “the Spanish legislation is not agile enough to allow the development of new CAR-T therapies with the speed needed by patients with potentially life-threatening diseases for whom treatment alternatives are lacking.” Why? Because, primarily “any change (either minimal or substantial) in the product is seen as a ‘new product’ in the eyes of the legislation, which means starting the development process (including generation of evidence) from scratch, with limited possibilities of bridging data between dossiers.” In other words, it’s adopting the same standards as for ATMPs that are not exempt from having an MA. Given the autologous origin of the product, they ask why the approach shouldn’t be less rigid where proposed improvements do not involve substantial changes of the core product. It would certainly remove a significant barrier to product improvement.

The second striking aspect of AEMPS approach is economic. It is reported that ARI-0001 costs a mere third of commercial CAR-T cell products available in Spain (although some have questioned the basis for calculation). Put another way, the prospects for a return on an ATMP investment have tripled, paradoxically, by not commercialising the product or following the conventional regulatory pathway (which is both demanding and expensive). The return on investment comes instead from the manufacturing and therapeutic delivery. So, should the HE now become the rule? When we contemplate that, since the inception of the ATMP Regulation 15 years ago, only 12 ATMP MAs have been granted in Europe of which only 8 have not been abandoned, we might well wonder.

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[1] R. (on the application of Bayer Plc) v NHS Darlington Clinical Commissioning Group, R. (on the application of Novartis Pharmaceuticals UK Ltd) v NHS Darlington Clinical Commissioning Group [2020] EWCA Civ 449. The Supreme Court refused an application to appeal the decision

[2] R. (on the application of Bayer Plc) v NHS Darlington CCG, R. (on the application of Novartis Pharmaceuticals UK Ltd) v NHS Darlington CCG [2018] EWHC 2465 (Admin)

[3] Case C 535/11 (Apozyte)

[4] Article 3(7) of the Medicinal Products Directive, inserted by the ATMP Regulation

[5] AEMPS authorises Hospital Clínic’s CAR-T ARI-0001 for patients with acute lymphoblastic leukaemia

[6] 1.28 in every 100,000 adults in Europe

[7] The UK government has stated, sotto voce, that it will follow future EU SoHo regulation

[8] Terapias avanzadas

[9] Bone Marrow Transplantation (2022)