EUROPE The General Court Limits the Scope of Satisfactory Methods That Must Be Compared for Orphan Drug Designation – JD Supra

On 23 September 2020, in a landmark case, Medac v Commission, the trial-level General Court (GC) of the European Union (EU) annulled the decision of the European Commission (EU Commission) that had withdrawn the orphan drug status of Trecondi (Treosulfan). The EU Commission had concluded that Medac did not demonstrate significant benefit of Trecondi over medicinal products containing melphalan and cyclophosphamide. The GC determined that the latter products were not satisfactory methods against which Trecondi had to be compared under the Orphan Regulation, because the summaries of product characteristics (SmPC) evidenced different intended treatment conditions and populations.

This is the first time that a European Court has disagreed with the EU Commissions restrictive approach to finding a significant benefit in the orphan drug context. While the EU Commission will probably appeal the GCs current decision in Medac, the European Court of Justice should affirm the GCs decision because it accurately reflects the limits set by the Orphan Regulation, as well as its objective.

This alert briefly explains the European regime for orphan medicinal products and, in particular, the criterion of significant benefit. It then examines and comments on the case.

The Medac case considers what satisfactory methods may be used for assessing the significant benefit that a future orphan medicinal product will bring to patients suffering from the rare condition for which an orphan designation is sought. The GC decided that:

This ruling clearly excludes off-label use, and also compounding, from being considered satisfactory methods, and limits the comparison for significant benefit purposes to medicinal products authorized for the same indication(s), including target populations, as the future medicinal product.

More generally, the Medac case illustrates the importance of the condition chosen for orphan status purposes, but also highlights the confusion around that concept. The determination of the condition is all the more important given increasing global development of orphan products and mandatory pediatric testing. Companies, therefore, should think about the condition strategically and early in the product development.

In the European Union, the legal regime for orphan medicinal products is established in Regulation 141/2000 (Orphan Regulation)[i], elaborated by an implementing regulation and several guidelines from the EU Commission and the European Medicines Agency (EMA).

The Orphan Regulation sets out, first, the criteria and procedure for an orphan designation (OD) and, second, the incentives afforded in relation to the OD, in particular 10-year orphan exclusivity. In a nutshell, the OD is granted by the EU Commission following the opinion of the Committee for Orphan Medicinal Products (COMP), one of the scientific committees within the EMA, on whether the OD criteria are met. The OD is granted to an active substance for the treatment, prevention or diagnosis of a rare condition. The subsequent granting of an MA for a medicinal product that contains the active substance and is authorized for a therapeutic indication within the defined rare condition, automatically triggers orphan exclusivity.

The OD criteria are listed in Article 3 of the Orphan Regulation:

Since adoption of the Orphan Regulation, most discussions about OD concern the significant benefit and the evidence thereof. Significant benefit is the most used criterion to justify a refusal to grant or maintain an OD. Related discussions turn around two main topics:

Arguably, this two-step approach makes sense because, in practice, companies are unable to bring the scientific evidence of a significant benefit at the initial time of granting the OD.

Yet, this approach defeats the very purpose of the Orphan Regulation. If the EU Commission withdraws the OD before granting the MA, the medicinal product does not have orphan status and, thus, is not protected by orphan exclusivity. In other words, the company invested in the development of an orphan product believing that it would benefit from orphan exclusivity and be able to recoup its investment; however, that incentive disappears after the investment is made.[iv] This risk is not one that all companies and investors are willing to take, especially in the case of old active substances. Accordingly, first, this approach undercuts the objective of incentivizing the development of products for rare diseases.

Second, the two-step approach requires companies to submit comparative data in relation to the satisfactory methods existing at the time of granting the MA, i.e., in relation to medicinal products authorized between the granting of the OD and the granting of the MA. This may prove very challenging when either (i) the development of the orphan product took many years so that several new medicinal products have been authorized for the condition since the granting of the OD; or (ii) the new comparative products have only been authorized very recently so that very little data has been published thereon[v].

Over the last years, the EU Commission and the COMP have become more restrictive regarding the concept of significant benefit and more demanding regarding the evidence of significant benefit, which has resulted in more OD not being maintained or being voluntarily withdrawn by companies.

Facts. On 23 February 2004, the European Commission granted Medac an OD for Treosulfan (active substance) for conditioning treatment prior to haematopoietic progenitor cell transplantation (rare condition).

On 13 October 2017, at the time of MA, Medac submitted an orphan maintenance report.

On 19 December 2018, the COMP adopted an opinion on the maintenance of the OD for Treosulfan and concluded that Medac did not demonstrate significant benefit in comparison with medicinal products containing melphalan and cyclophosphamide (because the indirect, literature-based comparisons provided by Medac were insufficient to substantiate a clinically relevant advantage of Trecondi). Medac requested a re-examination of the opinion and submitted new analyses comparing Trecondi with melphalan- and cyclophosphamide-based products. The COMP, however, confirmed its initial opinion.

On June 20, 2019, the EU Commission granted an MA for Trecondi but decided not to classify this medicinal product as an orphan medicinal product and withdrew the OD for Treosulfan.

Medac filed an application for annulment of the EU Commissions decision on the OD.

Court Decision. In essence, Medac claimed that medicinal products containing melphalan and cyclophosphamide were not satisfactory methods for the condition treated by Trecondi (and therefore should not be used to judge significant benefit). Five main arguments were raised, but the General Court only examined the first two arguments, as it concluded that they had merits.

The first two arguments simply alleged wrongful interpretation of the concept of satisfactory method under Article 3 of the Orphan Regulation and the 2016 Commission Notice. The General Court ruled in Medacs favor on the following grounds:

The exclusion of a potential medicinal product from the benefits of the Orphan Regulation on the ground that satisfactory methods exist only for a portion of the rare conditions covered by the future medicinal product is contrary to the intended purpose of the Orphan Regulation.

Concept of satisfactory methods. The Medac ruling is important because:

Concept of condition. The Medac case illustrates the importance of the condition chosen for orphan status purposes, but also the confusion around that concept.

The Guideline on Orphan Designation specifies that, when applicable, companies should refer to the condition according to International disease classification systems such as the WHOs International Classification System (ICD) or other well recognised systems. The WHO ICD classifies diseases based on symptoms and thus is a medical/clinical classification of diseases. The next version of the WHO ICD ICD 11, which will enter into force in 2022 contains a definition of disease: [ a set of dysfunction(s) in any of the body systems defined by: 1. symptomatology - manifestations: known pattern of signs, symptoms and related findings, 2. etiology: an underlying explanatory mechanism, 3. course and outcome: a distinct pattern of development over time, 4. treatment response: a known pattern of response to interventions, 5. linkage to genetic factors: e.g., genotypes, patterns of gene expression, 6. linkage to interacting environmental factors.

Haematopoietic progenitor (or stem) cell transplantation (HSCT) is a procedure that infuses (autologous or allogenic) stem cells to re-establish haematopoietic function in patients with damaged or defective bone marrow or immune system. Before certain HSCT, cells that may react against the stem cells have to be eliminated this is a conditioning treatment prior to HSCT.

In its orphan maintenance assessment report of 20 June 2019, the COMP indicated that (i) it recognizes HSCT as a treatment modality for the delineation of an orphan condition, which is only used in exceptional cases; (ii) in light of this exception, the initial orphan indication Conditioning treatment prior to [HSCT] remains acceptable; and (iii) now and for future OD, the COMP generally designates the slightly reworded orphan condition treatment in HSCT. The COMP refers to the Guideline on Orphan Designation according to which [e]xceptionally, a particular treatment modality could be considered to define a distinct condition. This could apply to products needed in medicinal procedures, but regardless of the specific underlying condition.

HSCT is a rare (0,67 in 10,000) and serious (risk of severe infections and of graft vs host disease) procedure designed to treat conditions, some of which are rare but it is not a condition. Granting an OD for a procedure is questionable under the Orphan Regulation that expressly refers to condition. Logically, the OD should be granted for each condition to be treated by the HSCT since the future medicinal product will treat those conditions, be it indirectly. Regulators however disfavor this approach because it would lead to many more OD.

Granting an OD for a procedure also raises practical issues when applying the OD criteria and, in particular, identifying the satisfactory methods as the Medac case illustrates. One may also wonder about orphan exclusivity. Does the OD for treatment of HSCT prevent, for the same active substance, a second OD for one of the conditions that could be treated by HSCT?

Yet, such interpretation may be necessary for the orphan regime to support the scientific and technological development in life sciences. Indeed, a search on the EMA website shows that, since 2016, more than 10 OD have been granted for treatment in HSCT, mainly to biological substances to be used in cell and gene therapy medicinal products.

Given the overlap between orphan and pediatric conditions/diseases, it is key to align the two legal regimes with regard to the determination of the relevant condition.

Yet, comparable definitions and references should be used in the EU and the U.S. in order to support the granting of OD for the same conditions and thereby global development of orphan drugs.

Like the EMA, FDA has granted more than a dozen OD for treatment of patients receiving HSCT and several OD for conditioning treatment prior to hematopoietic progenitor cell transplantation. Interestingly, with regard to Treosulfan, FDA also granted an OD for conditioning treatment prior to haematopoietic progenitor cell transplantation but added in malignant and non-malignant diseases in adult and pediatric patients. Moreover, the most of the OD granted in relation to HSCT, are for enhancement of cell engraftment or prevent of morbidity and mortality associated to HSCT.

Joint Evaluation of the Paediatric and Orphan Regulation. The recent EU Commissions Joint Evaluation of the Paediatric and Orphan Regulations (Joint Evaluation) (see previous alert) does not discuss the issue of significant benefit and does not suggest any legislative or other modification to the current system. Yet, this is the most disputed aspect of the Orphan Regulation by the pharmaceutical industry as shown, inter alia, by the number of cases before the European Courts of Justice. On the other hand, the Joint Evaluation clearly indicates that the basic concepts have to be redefined for purposes of both the Orphan Regulation and the Paediatric Regulation, and those basic concepts include condition.

The Medac ruling provides arguments for companies to oppose the choice of satisfactory methods imposed by the COMP and reduce the comparisons mandated with their future orphan medicinal products.

It also shows the importance of the condition at issue for future orphan medicinal products. Choosing the condition is a strategy exercise because that choice will impact the satisfactory methods and, thus, the orphan status, orphan exclusivity, and pediatric development.

Coming out of this decision, companies should define the condition in light of the COMPs current practice, but also keep in mind both the future adult and pediatric development and, of course, global development (i.e. the approaches adopted by FDA and other regulators). In practice, companies should identify the best condition, develop scientific arguments to justify their choice, identify the satisfactory methods of that condition, and then request scientific advice for significant benefit so that they can discuss and confirm their choice and selection in advance with the EMA and other regulators.

King & Spalding is regularly working with companies to help make the best decisions early on in the process to ease the path for orphan medicinal products.

[i] Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products.

[ii] GC, 16 May 2019, GMP-Orphan v Commission, T-733/17 and ECJ, 11 June 2020, C-575/19 P.

[iii] EU Commission Notice of 18 November 2016 on the application of Articles 3, 5 and 7 of Regulation No 141/2000. See G. Michaux and L. Salernitano, How drug preparations undermine Europes regulatory system, Scrip. 30 Nov. 2018.

[iv] On this issue, see G. Michaux, Demonstrating significant benefit for orphan medicines is it time for a drastic change, Scrip. 8 June 2016.

[v] GC, 5 Dec. 2018, BMS v Commission, T-329/16.

[vi] EU Commission, Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another, 27 March 2014.

[vii] EU Commission, Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies, 27 Sept. 2014.

Excerpt from:

EUROPE The General Court Limits the Scope of Satisfactory Methods That Must Be Compared for Orphan Drug Designation - JD Supra