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1 Sobi’ s Response to the European Com
Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 1 Response on behalf of Sobi (Swedish Orphan Biovitrum AB) t o the European Commission’s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” Contact: Christina Rickhammar ( Christina.rickhammar@sobi.com ) Vice - President Global Regulatory Affairs Sobi (Swedish Orphan Biovitrum AB) Transparency Register Number: 050036210658 - 03 Tomtebodavägen 23A SE - 112 76 S tockholm Sweden BACKGROUND + GENERAL COMMENTS The legal and regulatory framework for Orphan Medicinal Products , as well as the incentives defined in the Regulation (EC) No 141/2000 of 16 December 1999 on Orphan Medicinal Products, have successfully stimulated investment in research and development of treatments in the f ield of rare Diseases. In fact, until this EU Regulation was put in place, research and development in the field of rare diseases was very limited, mostly given the inherent complexities of the rarity of such diseases, which often also added to the limited commercial attractiveness. The EU authorisation of more than 100 new treatments for rare and serious dis eases and conditions speaks to the success of the Regulation and its framework in the past 15+ years since its inception and implementation. The European Regulation and its framework of implementing legislation and guidance is, therefore, of crucial impor tance to continue supporting its stated intent to stimulate “ the research, development and bringing to the market of appropriate medications ” for Rare Disease patients in the European Union. The Regulation should be supported and maintained in its current form as basic primary legislation, because it is accomplishing what it seeks to accomplish. Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 2 A s important as it is to keep the Regulation, Sobi also acknowledges that , after 16 years since its enactment , a lot has been learned based on the experience to date , hence the importance of continuing to clarify important aspects of this Regulation so that the system continues to be robust, in line with the current experience and still delivering on its original intent – to “ stimulate the research, development and bringing to the market of appropriate medications ” to “ diagnose, prevent or

2 treat ” rare diseases or conditions.
treat ” rare diseases or conditions. Sobi therefore welcomes the European Commission’s initiative to provide further clarity and guidance on the Regulation, by means of the Commission Notice on the application of articles 3, 5, and 7 of the Regulation (EC) No 141/2000, as well as to seek the stakeholders’ vi ews via this public consultation. And it will be critically important that such clarificatio n and guidance further allows to focus on the Regulation’s original spirit and intent, while not raising the regulatory burden for companies when there is no clear benefit for the patient, as well as not to further restrict the ev idence requirements to a l evel which may not be attainable in the specific context of rare diseases. At the same time, we note that the “significant benefit” concept – a concept unique to the European legislation around orphan medicinal products, has created a strong perception of the value of being authorised as an orphan medicinal product , and the scientific and regulatory review which the products undergo, including the significant benefit judgement, is acknowledged and respected beyond its sole function regarding the gr anting o f a Marketing Authorisation as an Orphan Medicinal Product . Several Member States use the orphan designation and the positive judgement about “significant benefit” – if applicable – in their national decisions about Orphan Medicinal Products, therefore su pporting the Regulation’ s intent of supporting not only the research and development but also the “ bringing to the market ” of such products. The significant benefit criterion is, therefore, an important part of the EU’s legislative framework in this regard and should be regularly reviewed and – if necessary – refined, in order to secure that it continues to fulfil the function for which it was designed. One element to continue to underpin the Orphan legislation could be further communication about th e difference between designation and marketing authorisation; which might – in some cases – create a perception that the orphan system in Europe is somehow “failing”. It has generally been the case that sponsors are given possibility to apply for an Orph an designation early in the development process, indeed, as early as possible, in order for the compounds under investigation for development to benefit from the incentives created at the European Medicines Agency, amongst others. Early designation of a c ompound in a development programme means that many compounds under investigation will not make it through to full Marketing Authorisation – and this is the natural course of pharmaceutical research and development, where, even today, as many a

3 s 50% of Phas e III compounds do not su
s 50% of Phas e III compounds do not succeed in proving sufficient quality, safety and efficacy in order to receive a marketing authorisation. Early designat ion of compounds as orphans might create the perception that there is a higher - than - acceptable “failure” rate in the field of orphan medicinal products and that, somehow, the orphan system is failing. Pushing designation later in the development cycle will – potentially – reduce the perceived “failure” rates; at the same time, we believe that having the possibilit y to gain an orphan designation as early as possible is important and should be maintained. We would suggest that probably t he orphan community could communicate better about the realities of research and development and, consequently, better explain t he “failure” rates, rather than let this perception of the system affect the time at which designation should be possible. Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 3 In this document Sobi provides a response to the specific Consultation Items raised by the European Commission, including lin e - by - line comments and suggestions on the Notice text. Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 4 SPECIFIC COMMENTS Consultation item n°1: Clarification of the defi nition of “significant benefit” Sobi appreciates the efforts made by the European Commission to streamline the available guidance and to provide clarity on the definitions of significant benefit and other items as indicated. Sobi agrees that there is a need to clarify what is required from sponsors to demonstr ate a significant benefit over authorised medicines, given that the evidence requ irements have evolved over time, along with the experience gained in the past 16 years of the Regulation. Sobi is also of the opinion that caution needs to be exercised when defining the level of evidence requirements to document significant benefit, give n that – particularly in the case of rare diseases – conclusive data may only be available at the very last stages of the development or even in a post - authorisation setting. Because of the intrinsic uncertainties of rare disease research and development, caused by a variety of factors, including the lack of data, the heterogeneity of many rare conditions, and the inherent rarity of such conditions, which will often result in limited data sets for orphan medicinal p

4 roducts, it is crucial that the Commis
roducts, it is crucial that the Commission Notice acknowledges the need and possibility to accept other methods than only direct comparative studies when demonstrating significant benefit, particularly at the time of designation, but also continuing through the developme nt programme. LINES COMMENTS + PROPOSED CHANGES (if applicable) 154 - 156 COMMENT: Regarding medicinal products prepared in a hospital pharmacy, Sobi is of the opinion that such products cannot be considered in the ass essment of significant benefit. Not only these are non - authorised products – which is clearly stated in the current Commission Notice as precluded from being a valid comparator for the purposes of demonstrating significant benefit – but also these do not undergo EMA/competent authority a ssessment of quality, safety, or efficacy that could be a basis for assessment of significant benefit. The Regulation 141/2000 states that “ patients suffering from rare conditions should be entitled to the same quality of treatment as other patients ” and, as such, should benefit from treatments that have been reviewed for quality, safety and efficacy by the EU regulatory system, where these are available. A product having been reviewed by this system should be the standard where it is availabl e, not hospi tal - based products that have not undergone this review. PROPOSED CHANGES: “Commonly used methods of diagnosis, prevention or treatment that are not subject to marketing authorisation (e.g. , surgery, Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 5 radiotherapy, medical devices, medicinal products prepared in a (hospital) pharmacy) may be considered satisfactory methods if there is scientific evidence as to the value of such method(s).” 174 - 180 / 198 - 204 COMMENT: Sobi supports the European Commission’s statement that “ the criteria for a finding of a significant benefit are strict”, because this underpins the respect and acknowledgement by third parties of the scientific judgement of the significant benefit, which an Orphan Medicinal Product may be judged to have. However, Sobi’s understanding of proposed text as it currently stands in lines 174 - 180, where the claims are required to be “ based on clinical experience ”, is that there would now be an additional requirement to provide clinical evidence already when applying for an orpha n designation, instead of the current requirement of an assumption at the time of designation application, which then needs t o be demonstrated at the time of Marketin

5 g Authorisation Application and the revi
g Authorisation Application and the review and eventual confirmation of Orphan designation . Should this interpretation be correct, we caution to the fact that comparative clinical studies in rare disease populations a re not only challenging to conduct, but may be associated with bias and have the potential to be inconclusive due to the heterog eneity and sample size limitation . One important incentive for designated Orphan Medicinal Products is the possibility to apply for Protocol Assistance to agree on the clinical development plan at an early stage. Consequently, the perceived requirement t o have clinical evidence available already at the time of Orphan designation could limit this possibility. PROPOSED CHANGES – Clarification requested between 174 - 180 and 198 - 204, with preference for the interpretation in 198 - 204 It is not clear from the document whether clinical data to establish Significant Benefit is needed or not, because it is still stated in lines 198 - 204 that Significant Benefit may be based on assumptions, to which Sobi agrees. 181 - 187 COMMENT: “Major contribution to patient care” is an important concept and one that may not be immediately obvious to a sponsor or, indeed, other bodies outside the patient community for the condition in question. The text refers to some important elements, such as “ease of self - administration” and “important adherence to improvement in treatment”. We would recommend that patient reported outcomes and other patient contributions from the condition in question be highlighted in the text. PROPOSED CHANGES: Add after line 187: “ Patient reported ou tcomes and real world evidence or experience gained by the patient community for the disease or condition in Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 6 question shall be included in this evaluation”. 219 - 228 COMMENT: In the CHMP’s “ Guideline on Clinical Trials in Small Populations ”, adopted in 2007, it is recognised that “in conditions with small and very small populations, less conventional and/or less commonly seen methodological approaches may be acceptable if they help to im prove the interpretability of the study results”. Suc h guidance is particularly relevant in the context of rare diseases, where evidence is generated from a small, heterogeneous patient population that, in turn, makes it challenging to generate statistically strong evidence. Bearing in mind that this Notice ’s scope is for medicinal products used for the treatment of rare disease, Sobi suggests that such flexib

6 ility in the acceptability of methodolo
ility in the acceptability of methodological approaches, including qualitative elements, shall be also reflected in the final Notic e. PROPOSED CHANGE S: “The significant benefit should consider a (n) quantitative element(s) that allow(s) the Committee on Orphan Medicinal Products to determine the magnitude of the effect based on direct or, when not practically feasible possible , indirect comparative clinical trials with already authorised medicinal products, unless it can be shown that the nature of the disease does not allow for this type of approach. Any advantage of the designated orphan medicinal product will be considered in the context of experience with authorised products in the orphan condition even if comparative clinical studies are not always feasible possible . In exceptional cases , If it is not realistic possible to generate a sample size big enough to provide stati stically comparative evidence, or, due to the heterogeneous patients’ population, it would be possible to adapt clinical trials designs and alternative methods (such as indirect comparative clini cal data, historical clinical data, modelling). 232 - 237 COM MENT: Granting an orphan marketing authorisation for a new pharmaceutical form could facilitate patient - centric thinking and what is important for the patient in her/his daily life. As with the comment and suggestion above on Line 181, the patient community in question should be considered in giving input for this element of the evaluation. PROPOSED CHANGES: G ranting an orphan marketing authorisation for a new pharmaceutical form of an existing medicinal product might be considered if could prevent the entry of generics of this existing authorised medicinal product on grounds that such generics would be cons idered similar to the orphan medicinal product. Consequently, the major contribution to patients care of the new pharmaceutical form should be justified in all cases is demonstrated with relevant data showing meaningful benefits for the patients as mentioned above . Patient reported outcomes and real world evidence or experience gained by the patient community fo r the disease or condition in question shall be included in this evaluation . Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 7 238 - 248 COMMENT: As described in the Commission Regulation (EC) No 507/2006 of March 2006 on the conditional marketing authorisation for medic inal products for human use, “in the case of certain categories of medicinal products (…) in order to meet unmet medical needs of p atientâ

7 €™s and in the interests of public heal
€™s and in the interests of public health, it may be necessary to grant marketing authorisations on the basis of less complete data than is normally the case and subject to specific obligations, hereinafter “conditional marketing authorisations.” Sin ce, according to this Regulation, a conditional approval is made on a limited data package due to the seriousness of the disease and an identified unmet need, a conditional approval is only made when the potential of the product to the patient outweighs th e risk of approving the product with a limited data package. Thus, the criteria for conditional approval should be sufficient to fulfil the criteria of significant benefit if an alternative treatment exists which apparently is not sufficient to treat the concerned patients. The way the draft Notice is currently written suggests that it would be required to demonstrate significant benefit at a time of conditional marketing authorisation, that is, on the basis of less complete data than is normally the case . Sobi is of the opinion that it is unreasonable to be required to demonstrate significant benefit – in fact a form of “ relative efficacy ” – when there is not even enough data to demonstrate full efficacy sufficient to grant a full marketing authorisation . A suggestion could be to allow for confirming the maintained orphan designation based on the clinical evidence allowing condi tional approval (unmet medical need). This would then be reassessed at the time of lifting the conditional aspect of the Market ing Authorisation, in order to maintain a consequent regulatory framework for orphan medicinal products and rare diseases. However, it is acknowledged that there may be situation where – if applicable – significant benefit m ay be possible to determine at conditional marketing authorisation and, therefore, we suggest that significant benefit requirements should be evaluated on a case by case basis dependent on indication. PROPOSED CHANGES: “To meet unmet medical need and ensure early patient access, it may be appropriate to grant marketing authorisations to orpha n medicinal products on the basis of a less complete package of data. In such cases, applicants may seek a conditional marketing a uthorisation. Nevertheless, the limited package of data may not be sufficient to confirm the significant benefit and the orphan designation may not be confirmed at the time of marketing authorisation. In such cases the reassessment of the significant benef it criteria has to respect the objectives of Regulation (EC) No. 507/2006, namely to facilitate access to medicines for patients with unmet medical needs. In addition, it should be in line with the objectiv e of Regulation

8 141/2000 that “orphan medicinal p rod
141/2000 that “orphan medicinal p roducts eligible for incentives should be easily and unequivocally identified” (recital 4) and ensure practical effect to the market exclusivity, which is intended to be the main incentive (recital 8) and only functi ons when Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 8 there is sufficient stability o f the designation. Before considering a conditional marketing authorisation for an orphan medicinal product, it is therefore highly recommended to seek protocol assistance. The European Medicines Agency is fostering collaboration between the scientific co mmittees to ensure consistency between the confirmation of the 'unmet medical need' for the conditional marketing authorisation and the 'significant benefit' of the purpose of the orphan designation”. 267 - 270 COMMENT: Sobi has experienced that the criterion for significant benefit, based on assumptions, that was accepted at the time of designation, was not accepted at the time of M arketing Authorisation Application and review. This means that it may not always be enoug h to show maintenance of what was deci ded at the time of designation. It is not clear from the current text whether the criteria for significant benefit at designation can change over time and , thus , the when the assumption of significant benefit made at the time of designation is not valid at Marketing Authorisation Application and review . Guidance on the latest time point for Protocol Assistance regarding fulfilment of the significant benefit criteria would be h elpful. Consultation item n°2: Encouraging the development of orphan medicinal products for communicable diseases (e.g. , Ebola) Sobi welcomes the European Commission ’s initiative to encourage the development of OMPs for communicable diseases. We believe that the prevalence in the EU co uld indeed also be used to support developments elsewhere, as part of a broader public health framework. Consultation item n°3: Simplifying the procedure for the reassessment of orphan criteria when two authoris ation application procedures are pending in parallel for two orphan medicinal products Sobi welcomes the European Commission’s proposal to provide more flexibility in the assessment of OMPs when two authorisation application procedures are pending in parallel, and we would support that the sponsor is exempted from demonstrating significant benefit when there is a time difference even greater than the proposed 1 m onth between two CHMP opinions. We would like to suggest

9 that significant benefit needs to be dem
that significant benefit needs to be demon strated over authorised OMP treatments that are available at the time of validation of the Marke ting Authorisation Application. This will ensure that the EPAR and the Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 9 approval information is in the public domain and that the second sponsor is able to make appropriate comparisons with the first product for the purpose of demonstrating significant benefit. LINES COMMENTS + PROPOSED CHANGES (if applicable) 296 - 307 COMMENT: As above, Sobi welcomes the European Commission’s proposal to provide more flexibility in the assessment of OMPs when two authorisation application procedures are pending in parallel, and we would support that the sponsor is exempted from demonstr ating significant benefit when there is a time difference even greater than the prop osed 1 m onth between two CHMP opinions. We would like to suggest that significant benefit needs to be demonstrated over authorised OMP treatments that are available at the time of validation of the Marketing Authorisation Application. This will ensure th at the EPAR and the approval information is in the public domain and that the second sponsor is able to make appropriate comparisons with the first product for the purpose of demonstrating significan t benefit. We would also respectfully suggest that indir ect comparisons should not be limited to this specific circumstance, but should be available as a method for orphan medicinal products wherever the situation warrants it, due to the nature of the disease or condition a nd/or the ability to make a direct com parison, which might not always be possible. This we suggest be evaluated on a case - by - case basis, and – again – Protocol Assistance will be a vital tool in supporting a tailored development approach that balances the legitimate desire fo r data on which t o take evidence - based decisions; against the feasibility of generating such data in a given situation or rare disease indication. PROPOSED CHANGES: “Irrespective of the stage of evaluation, w hen two procedures for granting marketing authorisations for the same condition are pending in parallel before the European Medicines Agency, they might not be concluded at the same time. In such a situation, it may b e difficult for the second product to s how significant benefit over the first authorised product. If Provided the two applications are validated and assessed by the CHMP at the same time, the sponsor for the second product should not be required to show sig

10 nificant benefit over the first autho
nificant benefit over the first autho rised product. On other hand, when the procedures for the simultaneous marketing authorisation applications do not remain in parallel and th e positive opinion for the second product compared to the first product is delivered by the CHMP with a difference in time of two CHMP meetings or more, the second sponsor should show data supporting the significant benefit over the first product. Moreover, th e significant benefit may be based on indirect comparison. Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 10 Consultation item n°4: Introducing the reassessment of the orphan criteria for a new subset of the condition when a sponsor extends the use of its product after marketing aut h orisation Sobi welcomes the fact that the European Commission encourages extensions of the initial Marketing Authorisat ion to other indications within the same orphan condition, for the benefit of patients. LINES COMMENTS + PROPOSED CHANGES (if applicable) 369 - 38 7 COMMENT: While we fully agree that the system needs to continue to be robust, needs to continue to focus reward and to avoid circumventing the Regulation, we recommend caution when suggesting in the Notice that a sponsor should formally re - demonstrate significant benefit compared to existing treatments if it extends its initial marketing auth orisation for a n ew indication, for instance (1) a sub - population in the same condition ; or (2) an extension to 3 rd , 2 nd or 1 st line treatment). Such additional requirement risks dissuading research into valuable new indications for the benefit of patients, as well as to delay authorisation of such new indications and this delay patients access on the grounds of having to generate additional data. Another consideration to make is that such approach would not be in line with the current concept on “adaptive pathways”, whe re sponsors are encouraged to target a first approval in the population with the highest unmet medical need and to further pursu e additional important sub - sets when the data set evolves. Finally, Sobi is also of the opinion that such additional requiremen t s may contradict the rules of orphan designation , which look at the condition in general as approved by the COMP, and not to a specific sub - set of patients or different indications within the same condition, for the use of an orphan medicinal product at t he point of Marketing Authorisation. Indeed, Article 5(12) is clear that there can be no involuntary removal of the orphan designation before the market ex

11 clusivity expires, once the (initial) ma
clusivity expires, once the (initial) marketing authorisati on is granted. This principle shall take precedence over Article 7(3), which in our view applies to indications that fall outside an existing orphan designation. PROPOSED CHANGES: Sobi’ s Response to the European Commission’ s Public Consultation on a “Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No. 141/2000 on Orphan Medicinal Products” 11 However, once approved, the marketing authorisation holder may wish to extend the use of the product to further therapeutic indications within the same orphan condition or to vary the indication as a first line treatment based on new evidence . While such extensions of theinitial marketing authorisation are encouraged for the benefit of patients, the significant bene fit of this extension compared to existing treatments should be subject to a formal verification. This will align the requirements for the marketin g authorisation holder, who will enjoy the benefits of the orphan regulation, especially in terms of market e xclusivity, for an extended marketing authorisation, with those required set under the orphan Regulation for another applicant seeking authorisation for a different subset of patients within the same orphan condition or a first line treatment from the onse t. Consequently, if a sponsor varies its marketing authorisation to a new subset of the condition, the variation will entail a review of the orphan criteri a as far as this new subset is concerned to ascertain that the orphan marketing authorisation complie s with Article 7.3. It is understood that the reviews from the Committee on Orphan Medicinal Products include whether these new therapeutic indications have a significant benefit over existing treatments and that the applicant therefore merits its status o f orphan for another sub - set of the condition. If that is not the case, the applicant may have to seek a separate marketing authorisation outside the scope of the orphan legis lation Consultation item n°5: Clarifications on processing the transfer of orphan designations between sponsors Sobi supports the proposal of laying down control mechanisms for the transfer of orphan designations between companies when these are condu cted as described, i.e., conducted in an attempt to circumvent the legislation. Where the transfer of orphan designation is considered a deliberate attempt to circumvent the legislation, this should be able to be documented. Probably further work needs to be done to understand h ow this would be accomp lished. -- Comments end here -- We would like to thank the European Commission for this important document and for the opportunity to comment and contri