COMMISSION NOTICE ON THE APPLICATION OF ARTICLES 3, 5 … · The BioIndustry Association (BIA) welcomes the opportunity to submit these comments and observations on the European Commission

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COMMISSION NOTICE ON THE APPLICATION OF ARTICLES 3, 5 AND 7

OF REGULATION (EC) NO 141/2000 ON ORPHAN MEDICINAL PRODUCTS

Comments from the BioIndustry Association

The BioIndustry Association (BIA) welcomes the opportunity to submit these comments and observations on the European Commission

consultation document - Commission Notice on the application of Articles 3, 5 and 7 of Regulation (EC) N° 141/2000 on orphan medicinal

products.

The BIA is the trade association for innovative enterprises involved in UK bioscience. Members include emerging and established bioscience

companies; pharmaceutical companies; academic, research and philanthropic organisations; and service providers to the bioscience sector. The

BIA represents the interests of its members to a broad section of stakeholders, from government and regulators to patient groups and the media.

Our goal is to secure the UK's position as a global hub and as the best location for innovative research and commercialisation, enabling our world-

leading research base to deliver healthcare solutions that can truly make a difference to people's lives.

The BIA has had sight of the response by the EFPIA-EuropaBio Joint Task Force on Orphan Medicinal Products and Rare Diseases, and supports

the comments submitted by EFPIA-EuropaBio. Please note the comments below are identical to those provided in the EFPIA-EuropaBio response.

Contact:

Dr Christiane Abouzeid

Head of Regulatory Affairs, BIA

Email: [email protected]

Ref. Ares(2016)815409 - 16/02/2016

mailto:[email protected]

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General Comments:

Maintain a favourable and predictable environment to stimulate research

The consultation document is a welcome step to clarify certain provisions of Regulation 141/2000 (the Orphan Regulation); however we caution

that certain provisions raise the regulatory burden for companies without clearly stated benefit for the patient; furthermore some evidence

requirements might be unattainable for some rare diseases. The Orphan Regulation and the accompanying Commission Regulation EC 847/2000

have successfully stimulated research and development of orphan medicinal products (OMPs). It is important to maintain this favourable

environment to continue to see progress in treating rare diseases.

Challenges of pharmaceutical research in rare diseases

The Joint Task Force recalls the Commission approach in Commission Regulation 847/2000 underlining that “Given the nature of the medicinal

products concerned, and the probability that the conditions to be treated are rare, it is not appropriate to lay down overly prescriptive requirements

to establish that the criteria are met” (recital 4). We are concerned that the draft Notice moves away from this understanding and seems more

concerned by completeness rather than appropriateness of data requirements. It is essential in these discussions to keep the reality of OMP

development in mind and in particular the specificities of rare diseases. Far from all OMP designated products will be successfully developed and

introduced into the market. Pharmaceutical development is characterised by high attrition; in the case of rare diseases, development can be

complicated by a lack of scientific knowledge on the disease and by small patient populations. It is important to consider the feasibility of some of

the data requirements. A designation provides a tool to access resources (such as scientific advice by the EMA) and incentives to try and increase

the possibility of developing successful treatments for rare diseases. A designation will not necessarily result in the development of a successful

treatment.

Coordination across EMA committees

The Joint Task Force considers that many of the perceived issues with the application of the Orphan Regulation could be addressed by better

coordination across EMA Committees (COMP, CHMP, PDCP, SAWP). Based on companies experience it would be helpful to foster early and

iterative interactions throughout the process between the sponsor, the COMP, the CHMP and the SAWP. This would reduce the administrative

burden for the EMA committees and increase the coherence of the process for the OMP developers

In this document, the Joint Task Force focuses on the specific questions raised by the Commission, including line-by-line comments and

suggestions for modification. We also refer to our general comments submitted to the European Commission in April 2015, attached in Annex.

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Consultation item n°1:

Clarification of the definition of "significant benefit"

The Orphan Regulation aims at facilitating the placing of innovative products with a significant benefit over existing products on the European

Union market. Experience over the past 15 years has shown that the ‘significant benefit’ is one of the key criteria for the application of the

Regulation. In light of the experience, it appears useful to clarify how the sponsors need to demonstrate a significant benefit over authorised

medicines. It is also important to justify in which cases a new pharmaceutical form represents a significant benefit. Furthermore, in view of the

development and further integration of the European pharmaceutical market, it seems appropriate to remove the possibility of claiming a

significant benefit based on a potential increased supply. Moreover, a medicinal product should have a significant benefit over authorised

products or other methods of treatment used in the EU. Some Member States suggest that the medicinal products prepared in a (hospital)

pharmacy should be considered in the assessment of the significant benefit.

Level of evidence to demonstrate a significant benefit over authorised medicines at time of designation

The Joint Task Force agrees it is useful to clarify how sponsors need to demonstrate a significant benefit (SB) over authorised medicines, however

we also believe that a cautious approach is warranted when defining the level of evidence/proof required from developers. Conclusive data may

not be available until very late in the development of a product, so that requesting such data already at the time of designation could result in the

delay of a request for designation until the development programme is almost complete. As a result, the use of protocol assistance (PA) and

scientific advice (SA) to ensure that the development programme will address the expectations for demonstrating SB may no longer be viable.

This would seem to go against the view of the European Commission (EC) that PA and SA should be used more extensively in the development

of OMPs.

Comparative evidence and use of indirect comparison methods

It is essential that the text contain language that recognises upfront the validity of methods other than direct comparative head-to-head studies to

demonstrate SB. These should include but not be limited to: historical comparison, indirect comparison and non-clinical endpoints. The draft

Notice should also explicitly mentions new adaptive trials designs or other innovative designs such as trials-of-one. Indeed:

It may not be possible to recruit sufficiently large numbers of patients and the conduct of randomised, reference-controlled studies is

challenging. The complexities of rare diseases, where evidence is generated from a small heterogeneous patient population, can make it

difficult to generate a sample size big enough to provide statistically strong evidence. As per the CHMP ‘Guideline on Clinical Trials in Small

Populations’ adopted in 2007, it is recognized 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 improve the interpretability of the study results”.

It is unreasonable to expect direct comparison studies when comparators are multiple and/or identified in a late stage development phase. The

time period between the orphan designation and the subsequent review of maintenance of the same orphan designation at the time of review

of the marketing authorisation has been found to range from several months to several years. With a larger time period between the orphan

designation and review of the marketing authorisation, there is an increased likelihood that the satisfactory method(s) of treatment of the

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condition that were used for the assumptions of SB at the time of the orphan designation may shift or change by the time of review of the

marketing authorisation.

Quantitative elements in SB assessment: The Draft Notice should specify which studies would require a “quantitative element” in SB

assessment (line 219). A “quantitative element” may prove impossible to consider for certain indirect or alternative methods. Additionally, it is

quite unrealistic to require a “quantitative element” in the comparison for all existing therapies. It should only be included in the comparison with

a key comparator(s) identified at the orphan designation and protocol assistance.

Comparator for the purpose of SB assessment:

Medicinal products prepared in a (hospital) pharmacy: The Joint Task Force disagrees that medicinal products prepared in a (hospital)

pharmacy should be considered in the assessment of the SB. Since products prepared in a hospital pharmacy are not authorized, they do not

require any quality, safety and efficacy data or marketing authorisation review (confirmed by the CJEU last summer in Joined Cases C-544/13

and 545/13) and therefore there exists no clear basis for assessment of SB in terms of efficacy and safety. There may be various products

prepared by (hospital) pharmacies for a particular orphan disease across Europe based upon medical cultural and historical practice. It will be

difficult, if not impossible, to track down what these products are across European hospitals. Please see our specific re-wording suggestion

for this point (lines 154-159) further down in this document.

Unauthorised products/Off-label use: the Joint Task Force agrees with lines 151-153 of the current Notice, which state that unauthorised

products/off-label use cannot be considered as a satisfactory method for the purposes of orphan designation.

Evidence to assess SB compared to existing treatments:

Based on improved efficacy: The acceptability of alternative ways of demonstrating SB such as comparison to historical data should be

reinforced. The treatment of a distinct aspect of the disease, which is not impacted by approved treatments, also constitutes a SB for the

patient. In the determination of the appropriate comparators, it should be specified that approved treatments that do not have an effect on the

proposed disease aspect to be treated should not be considered in the evaluation of SB. Additional examples of acceptable comparative data

should be included and clearly defined in the text, as well as a better acknowledgement that not all SBs are linked to clinical endpoints or

outcomes. The Joint Task Force also recommends the draft Notice take into account new methods for obtaining patients feedback (Patient-

Reported Outcomes).

Based on improved safety profile: There are limited examples of SB that are justified on the basis of improved safety profile compared to

existing treatments. This is likely to be due to the limited extent of safety data that may be available at the time of authorisation. Comparative

clinical trials in orphan population are in fact challenging to conduct and unlikely to be able to be conclusive on safety endpoints

Based on a new mechanism of action: the Joint Task Force agrees that an alternative mechanism of action (MoA) needs to be translated into

a clinically relevant advantage or a major contribution to patient care to show SB. However we caution against the requirement to show this

translation already at the time of orphan designation, based on the assumption of SB. We believe it should be specified that it is acceptable to

grant a designation based on a new mechanism of action as long as the sponsors provide the supporting evidence of translation of the SB in

clinical outcomes at the time of MA. At time of designation, it might not be feasible to provide all conclusive data on the link between the

new MoA and a clinically relevant advantage or a major contribution to patient. We consider a new mechanism of action by itself can

represent a SB as it may work in patients that did not respond to the initial treatment or have become refractory to that treatment. We believe

this would allow for the best development of the product while utilising PA and SA to ensure that the outcomes used in the pivotal clinical

trials are appropriate to demonstrate the SB. When it comes to documenting difficulties with the existing pharmaceutical form, from the

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consultation text it is not clear who is responsible to demonstrate the documented difficulties. In the spirit of the guidance we believe the

sponsors need to demonstrate SB, not inadequacy of other products. See further below some re-wording suggestions relating to lines 184-187

and 195-197 in Section II.

Conditional marketing authorization (CMA) for orphan medicines

The CMA pathway is a vital European regulatory pathway and remains the one true, mature, expedited pathway for patient access to innovative

medicines in areas of unmet medical need. In order to obtain CMA, a number of conditions have to be met; in particular the product concerned

needs to fulfil an unmet medical need (art. 4.1 of Commission Regulation 507/2006). In light of the above, the Joint Task Force considers that data

provided should, in most cases, be sufficient to also show significant benefit. We agree with the EC that PA will be helpful in that respect. Overall,

we would suggest rewording the section on CMA to better reflect Commission Regulation 507/2006 and highlight the opportunities rather than the

challenges of this regulatory pathway for OMPs. To date approximately 27% of OMPs have been approved via the CMA or are approved under the

exceptional circumstances pathway based on the CHMP determination that the safety and efficacy of the product is not fully demonstrated due to

the limited patient exposure.

Possibility of claiming a significant benefit based on a potential increased supply: The Joint Task Force agrees with the proposal to apply a

stricter approach to the possibility of claiming a SB at time of orphan designation application based on a potential increased supply (lines 189-

191). However, the Joint Task Force would appreciate confirmation (and clarification in the text of the Notice) that the possibility continues for

orphan market exclusivity to be challenged and overcome by a second applicant for a similar medicinal product (whether orphan designated, or

not), where the holder of the MA for the original OMP is unable to supply sufficient quantities of the medicinal product (as currently in the text of

Orphan Regulation). We believe this may become increasingly important given the anticipated entry onto the market in the coming years of

advanced modalities, such as gene and cell therapies, at least some of which are likely to be inherently subject to significant manufacturing

limitations, meaning inadequate supply of these important new therapies to the EU market. In these circumstances, the ‘safety valve’ provided by

Article 8 3(b), enabling other manufacturers to supply the market, is critical.


Encouraging the development of orphan medicinal products for communicable diseases (e.g. Ebola)

According to the orphan Regulation, a medicinal product shall be designated as orphan if the sponsor establishes that the product is intended for

the treatment of a “condition affecting not more than 5 in 10000 persons in the EU when the application is made”. In the past, there has been

discussion whether this should be understood as meaning that the prevalence in the EU should be above zero. The European Commission for

example refused orphan designation for products that were intended for diseases that have been declared eradicated by the WHO. The outbreak of

Ebola has shown that an infectious disease with a very low prevalence in the EU can very rapidly become a serious threat to public health. It may

therefore be appropriate to apply a risk-based approach under which the prevalence equal to zero complies with the threshold of not more than 5 in

10000 people.

The Joint Task Force agrees with the inclusion into the scope of the Orphan Regulation of diseases which have zero prevalence in Europe.

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Simplifying the procedure for the reassessment of orphan criteria when two authorisation application procedures are pending in parallel

for two orphan medicinal products

The orphan criteria are assessed first at the time of designation and secondly at the time of the marketing authorisation. Any change in the

treatment landscape, including products recently authorised, may affect the evaluation of the ‘significant benefit’ criterion. When the scientific

assessment of two orphan medicinal products is being carried out in parallel, the applicants are unable to demonstrate the significant benefit over

another medicinal product assessed positively by the European Medicines Agency only one or two months before. The European Commission

therefore proposes to provide some flexibility in the assessment of orphan medicinal products in this case.

We welcome the European Commission’s recognition that issues may arise when assessing SB in case of simultaneous MA applications (MAA)

and, in particular, the difficulty for the second applicant to prove SB against products still being assessed. However, the Notice proposal to

exempt the sponsor from the requirement to provide more data to demonstrate SB when there is a distance of 1 month between two CHMP

opinions is arbitrary and could lead to unintended negative consequences, and should be revised.

According to the Orphan Regulation, it is necessary to demonstrate SB over other authorized methods; a positive CHMP opinion is not equivalent

to an approval and thus the first product will not be approved by the EC by the time the second sponsor is required to update its argumentation of

SB. 1 month seems unnecessarily restrictive, as the EPAR and therefore details necessary for the appraisal of the benefit risk of the first product

will not be available in this timeframe. Moreover, demonstration of SB over the first product will in most parallel cases only be claimed based on

indirect comparisons. Such analyses require researching the appropriate data, which is not always readily available, or generating additional data.

Performing indirect comparison and subsequently producing a report for submission takes several months and hence approval and patient access to

a second product with orphan designation would be pushed out by several months for purely procedural reasons.

We suggest acknowledging the following in lines 296-307: SB has to be shown over authorized treatments (in that case authorized OMPs)

available at the time of validation of the MAA. In other words, as long as the “first” product MA is not yet published in the Community Register

and the “second” product has had its MAA (or extension/modification application) validated, the sponsor for the second product should not be

required to show SB over the first product. This will ensure that the EPAR and approval information is in the public domain and that the second

sponsor is able to make appropriate comparisons in term of SB. This will ensure both procedural and legal predictability of the OMP approval

process.


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 authorisation

Based on the experience with the Orphan Regulation, there are indications which show the need to clarify the necessity for a reassessment of the

orphan criteria in cases where, based on new evidence, the marketing authorisation holder extends the use of its product to other therapeutic

indications within the same orphan condition. Although such extensions of the initial marketing authorisation are encouraged for the benefit of

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patients, it may be considered that the variation of the marketing authorisation should only be allowed after formal verification that the new

therapeutic indications are of significant benefit when compared to existing treatments. This proof of significant benefit would be required for any

other new orphan marketing authorisation holder seeking authorisation for a different therapeutic indication within the same orphan condition.

We agree that extensions of the initial MA to e.g. further therapeutic indications or the different lines of treatment should be encouraged for the

benefit of patients (l. 372-373). This reflects the reality of pharmaceutical research. Indeed, it is common in drug development to initially target

populations or line therapy where the unmet need of patients may be the greatest, so expansion into populations where the disease might be less

severe or with existing treatment options is usually done in a second phase.

Whilst we agree that an extension of the initial MA should provide benefits to patients, we strongly oppose the provision of a formal verification of

significant benefit within an existing designation (l. 374-375) proposed in the draft Notice. Extensions of MA have proven to be important to

provide more treatment options to patients and this provision could create delays in registration of new indications or discourage meaningful

indications extensions because of the need to develop additional data.

We are particularly concerned that the current text is unclear as regards to the impact of the assessment of SB of the MA extension on the original

MA, and whether this could put into question the orphan designation as a whole. Such a perceived risk of loss of the orphan designation would

negatively impact companies’ investment decisions in rare disease research. We recall the Orphan Regulation which looks at the condition in

general as approved by the COMP, and not to a specific subset of patients or different indications within the same condition, at MA stage. The

proposal to seek a MA outside the scope of the Orphan Regulation for an orphan designated condition (l. 386-387) is unclear, and risks putting a

substantial regulatory burden on MA holders. We therefore question whether the provision foreseen in the draft Notice is in line with the Orphan

Regulation.

Since, as clarified in l. 360-361, a MA extension would not lead to an additional period of market exclusivity, a formal verification of SB for each

extension of the initial MA seems to be a disproportionate regulatory burden. This could have two negative consequences for patients:

Manufacturers might limit their development plans to only one subset of the population or to one line of treatment where the expected

benefit will be highest, and refrain from investment in further extensions where expected benefit exists, but is more difficult to

demonstrate. With this provision in place, improvements in Multiple Myeloma treatment may not have been achieved in Europe, whereas

they might have been achieved in other parts of the world, which could in turn have led to increased off-label use in Europe.

Manufacturers might wait until data for all subsets of patients or all lines of treatment are available before filing their MAA in order to

reduce subsequent regulatory burden. This would delay access for patients with the highest unmet need.

Additionally, it might be worth considering whether COMP would have the necessary resources to assess SB for each extension of MA.

We therefore suggest deleting lines 373-387.

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Clarifications on processing the transfer of orphan designations between sponsors

It is not possible to obtain an orphan designation for a new pharmaceutical form if the sponsor already has an orphan marketing authorisation for

the same active substance, for the same condition. These applications are generally refused as the orphan designation should be requested before

the marketing authorisation is granted (Article 5(1) of the Orphan Regulation). As a consequence, some companies have asked a third party to

apply for the desired orphan designation, which is subsequently transferred to the original applicant. This practice can be considered as an attempt

to circumvent the intention and the purpose of this provision. In addition, experience shows that this process has also delayed the placing on the

market of generic medicinal products. To provide fair conditions of competition among all the companies concerned, it may be envisaged to lay

down control mechanisms for the transfer of orphan designations between companies in that respect.

The Joint Task Force agrees with the proposal of laying down control mechanisms for the transfer of orphan designations between companies. We

however caution that a case-by-case assessment of transfer of orphan designation needs to be applied. Mergers and acquisitions are very common

among pharmaceutical companies, which may lead to a transfer of designation between companies. In such cases, the transfer of orphan

designation should not be considered a deliberate intent to circumvent provisions of the Orphan Regulation.

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LINE-BY-LINE COMMENTS

LINES COMMENTS

109 Comment:

Case study data should also be acceptable to support global development since case study data are already accepted by FDA.

Proposed change (if any):

In order to support the rationale for development of the product in the proposed condition, preclinical and / or preliminary clinical data

or case study data where justified are generally required.

154-159


Commonly used methods of diagnosis, prevention or treatment that are not subject to marketing authorisation (e.g. surgery,

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) for the safety, efficacy and quality of such method(s). The scientific

evidence should would refer to scientific and medical literature or any other relevant information e.g. clinical guidelines by

European medical societies.

175-176


For example, “a clinically relevant advantage” may be considered based on:

- An improved efficacy of the entire population suffering from this condition, for a particular population sub-set or for a sub-set

of the population which is resistant to the existing treatments. The claim should be based on clinical experience; clinical

experience may include indirect comparison, historical data, or patient reported outcomes on a case-by-case basis

where justified.

178-180

Comment:

There are limited examples of SB that are justified on the basis of improved safety profile compared to existing treatments. This is

likely to be due to the limited extent of safety data that may be available at the time of authorisation.

Comparative clinical trials in orphan population are challenging to conduct and unlikely to be able to be conclusive on safety

endpoints.


- A better safety profile or a better tolerability for the entire population suffering from the condition or a particular patient sub-

set. The claim should be based on clinical experience; clinical experience may include indirect comparison, historical data

or patient reported outcome on a case-by-case basis where justified, acknowledging that a limited clinical safety

dataset may be available at the time of authorisation.

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182-183

Comment:

Quality of life of patients and caregivers should also be considered.


“- Ease of self-administration e.g. if the new treatment allows ambulatory treatment instead of treatment in a hospital only or if the

new treatment has a significant impact on convenience of use and decrease treatment burden”

184-187


Important improvement in adherence to treatment by changing the pharmaceutical form (e.g. Modified released formulation) only if

there are documented difficulties meaning as documented in peer reviewed publications, patients registries or therapeutic

guidelines with the existing form and or if there are data showing better clinical outcome with the new form. In addition to better

clinical outcome other evidence such as e.g. better quality of life or ease of use are also considered as a valid criterion, e.g.

development of an oral formulation to substitute an infusion or a subcutaneous formulation to substitute an intravenous one.

195-197


An alternative mechanism of action or more favourable pharmacokinetic properties per se, to be sufficient for the assumption of

significant benefit. It needs to which can be translated into a clinically relevant advantage or a major contribution to patient care at

the time of marketing authorization should be sufficient for the confirmation of significant benefit.

229-231


Where protocol assistance for the justification of SB has been received in accordance with Article 6 of the Orphan Regulation, the

review will also comprise the assessment on how the sponsor has taken into account the advice given. Deviations from protocol

assistance, for example because circumstances have changed, should be duly justified by the applicant.

219-228


“The significant benefit should consider ntitative element(s) that allow(s) the Committee on Orphan Medicinal Products to

determine the magnitude of the effect based on direct or, when not possible, indirect comparative clinical trials with already

authorised medicinal products. 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 possible. In

exceptional cases, If it is not possible to generate a sample size big enough to provide statistically comparative evidence, or, due to

the heterogeneous patients’ population, it would be possible to employ adapted clinical trials designs and or use alternative methods

(such as surrogate endpoints, trials of one, adaptive design)

232-237 Proposed change (if any):

Granting 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

considered 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.

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238-248


“To meet unmet medical need and ensure early patient access, it may be appropriate to grant marketing authorisations to orphan

medicinal products on the basis of a less complete package of data. In such cases, applicants may seek a conditional marketing

authorisation for orphan medicinal products. 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. 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 committees 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”.

279 Comment:

This draft Notice does not mention the possibility of the removal of an orphan designation from the registry to be done at the request

of the sponsor. Since this is expressly provided for under article 5(12) of the Orphan Regulation, it should remain in the text of the

Notice. Therefore, the recommendation is to revert to the text of the 2003 Communication.

282-289

Comment:

The provisions of Article 8 (2) (Review of Marketing Exclusivity at 5 Years) are applicable to all marketing authorisations, which

includes conditional marketing authorisations. The text below relating to conditional marketing authorisation does not present any

new information beyond that Stated in Article 8 (2).

Proposed Change (if any):

Deletions of lines 282-289:

“For the orphan medicinal products approved under the conditional marketing authorisation, further data will be generated

post authorisation as part of the specific obligations and are reviewed on an annual basis in the context of the review of the

benefit risk balance by the Committee for human medicinal products. In the light of the updated data at the end of the fifth

year as provided in Article 8.2 of Regulation 141/2000, a Member State may inform that the criterion on the basis of which

market exclusivity was granted may not be met and the agency shall then initiative the procedure laid down in Article 5.”

296-307


Irrespective of the stage of evaluation, when 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

be difficult for the second product to show significant benefit over the first authorised product. It follows from article 3(1)(b) of

Regulation 141/2000 that significant benefit has to be shown over authorised treatments available at the time of validation of

the marketing authorisation application. Therefore, the requirements for demonstrating significant benefit over existing

therapies only apply up to the time of validation of filing of the marketing authorisation application, in relation to existing

medicinal products which have already been granted a marketing authorisation (Commission Decision). If Provided the two

applications are validated and the first authorised product is not yet published in the Community Register, and assessed by the

CHMP at the same time, the sponsor for the second product should not be required to show significant benefit over the first product.

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On other hand, when the procedures for the simultaneous marketing authorisation applications do not remain in parallel and

the 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, the significant benefit may be based on indirect comparison.

323-324

Comment:

Sponsors often have more than one orphan designation for a single medicinal product, where different conditions are being

investigated. The current wording can be misinterpreted to mean that Sponsors are only allowed one orphan designation per medicinal

product and are not allowed to investigate several conditions.

Proposed Change (if any):

“Based on a combined reading of those two provisions, the Commission considers that, for any given medicinal product, a sponsor

can only receive one orphan designation per medicinal product and per condition. However one medicinal products can be

investigated in several separate orphan and non-orphan conditions

357-363 Comment:

The proposed changes to the text make it less clear than the 2003 Communication, without changing the content of guidance. It is

recommended that the previous text is restore for these lines:

Proposed change (if any): Text of 2003 Communication

In cases in which the therapeutic indication approved through the marketing authorisation procedure is a subset of the designated

orphan condition, the marketing authorisation holder will benefit from market exclusivity for this product, for this indication.

If the same sponsor applies subsequently for a marketing authorisation for a second subset of the designated orphan condition, the

product will not benefit from any additional period of market exclusivity, for that second authorised indication, i.e. the second

authorised indication will be covered by the market exclusivity granted on initial authorisation.

373-387


While such extensions of the initial marketing authorisation are encouraged for the benefit of patients, the significant benefit of this

extension compared to existing treatments should be subject to a formal verification. This will align the requirements for the

marketing authorisation holder, who will enjoy the benefits of the orphan regulation, especially in terms of market exclusivity,

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 onset.

Consequently, if a sponsor varies its marketing authorisation to a new subset of the condition, the variation will entail a review

of the orphan criteria as far as this new subset is concerned to ascertain that the orphan marketing authorisation complies

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 of 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 legislation.

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After

line 397

Comment:

It is possible that two different products with different indications cover the same population, for example, a product which is given as

treatment until progression in a first line indication versus a product given as maintenance following 1st line induction. In both cases,

it is the same population which is treated (1st line patients), however, the indication is very different. We believe that in such cases,

these two indications are clinically different, and therefore demonstration of significant benefit should not be required.

Proposed new text:

D. SCOPE OF UNION MARKETING AUTHORIZATION – ARTICLE 7(3)

2. Same population but different indications:

“If an orphan medicinal product has been granted a marketing authorisation for an indication which is a subset of the

designated condition, an application for marketing authorisation of a second product, which claims to cover a different

therapeutic indication, and thus another subset of the same designated orphan condition, will have to establish that the

difference between the two subsets is clinically meaningful. In such situations, the marketing authorization of the second

product would not need to justify significant benefit over the first one.

In case of an overlap of the target populations of two allegedly different therapeutic indications, the second applicant would

have to demonstrate that the difference between the two indications is clinically meaningful. The extent of the overlap will be a

relevant factor for the authority to establish whether the claim for two different therapeutic indications can be upheld. In such

situations, the marketing authorization of the second product would not need to justify significant benefit over the first one”.

3. Separate marketing Authorization

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ANNEX

Industry recommendations to the European Commission on significant benefit guidelines revision1:

The purpose of this paper is to share industry´s concrete ideas and experience for preliminary input to the EC´s current initiative to revise several guidelines implementing the Orphan Medicinal Product Regulation (EC) 141/2000 and specifically the 2003 Communication from the European Commission on the OMP Regulation (“2003 Communication”) which provide interpretations of the legislation on criterion like “significant benefit” or market exclusivity. In particular, we would like to share: 1/ Our vision of the current 2003 Communication 2/ Proposals on areas for clarification 1/ Our vision of the current 2003 Communication: The regulatory framework and incentives defined in the Orphan Medicinal Product Regulation (EC) 141/2000 have stimulated the research and development of medicinal products to treat rare conditions and successfully led to an increase in research investment in this field. Until then, research in the rare disease space was limited given the complexities linked to limited number of patients and limited commercial attractiveness. As a positive result of the Regulation, today more than 110 orphan medicinal products (OMP) are approved in Europe, providing patients with continuous treatment improvements in various disease areas. The 2003 Communication is an important document providing interpretation on several key aspects of the Regulation, including the definition of criteria for significant benefit and a number of clarifying points for market exclusivity. These elements of the Regulation are key to ensure continued improvement of rare disease treatments, as well as to secure adequate protection offered by market exclusivity of orphan medicines which are already on the market. The heterogeneity of rare conditions and the small patient populations call for a regulatory framework which will be able to take into account the diversity of clinical data. Considering the above, the revision of the 2003 Communication should be driven by the need to accelerate development and approval of new therapies for rare disease patients. In this view, the revision of the 2003 Communication should be approached with caution and limited to areas where clear issues have been identified. It should be particularly mindful to continue stimulating research in disease areas where there is unmet need, including the development of alternative therapies in disease areas with existing treatments. Flexibility when it comes to requirements put on sponsors is key to maintain such an environment conducive of innovation.

1 EC Communication (2003/C 178/02 JO 29.7.2003)

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Industry would welcome a discussion with the relevant Commission services to address the rationale and scope of the proposed revision and exchange views on the suggested solutions. This would also be the opportunity for industry to better understand the Commission’s plans regarding revision of other important guidelines, including the guideline on similarity2. 2/ Proposals on areas for clarification of the 2003 Communication: • Flexibility for clinical trial designs and clinical development program Article 3(1)b of Orphan Medicine Regulation (EC) 141/2000 states that where a “satisfactory method of diagnosis, prevention or treatment of the condition exists”, the sponsor has to establish “that the medicinal product will be of significant benefit to those affected by that condition”. It would be helpful if a revised 2003 Communication explicitly enable adaptive and flexible clinical trial designs and development programs. Sponsors would indeed benefit from the acceptance of alternative methods (such as indirect comparative data, historical data and adaptive designs) to generate the required level of evidence allowing for proper assessment of the significant benefit of an investigational orphan medicine versus an existing alternative treatment in the same condition. This is particularly important given the complexities in rare diseases, where evidence is generated from a small heterogeneous non-expandable patient population, which can make it difficult to generate a sample size big enough to provide statistically strong comparative evidence.

Alignment between COMP, CHMP and SAWG on standard of care and level of evidence required

Industry welcomes the protocol assistance process and the flexibility of this mechanism, which helps better plan development and provide relevant data to demonstrate significant benefit. Significant benefit is reviewed at different time points by the COMP (assumption at time of designation, with confirmation prior to MA3), and is confirmed at time of marketing authorisation by the CHMP. In order to avoid discrepancies between the COMP review and CHMP assessment as regards to significant benefit, it would be helpful if the 2003 Communication could foster earlier and iterative interactions throughout the process between the sponsor, the COMP, the CHMP and the SAWP including on the current standard of care in the product’s therapy area. The 2003 Communication could also put more emphasis on highlighting the benefit of ensuring consistency between the advice provided during protocol assistance and the discussion on significant benefit in the context of marketing authorisation application. Ideally, where companies seek protocol assistance, the conclusions on standard of care and level of evidence

2 EC Communication (2008/C 242/08 JO 23.9.2008)

3 According to article 5(12)(b) when the COMP verifies “if it is established before the market authorisation is granted

that the criteria laid down in Article 3 are no longer met in respect of the medicinal product concerned”

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to be provided at MA time should be consistent throughout the process, from orphan designation by the COMP to the marketing authorisation by the CHMP.

Re-evaluation of designation criteria at time of MA and COMP confirmation of designation

According to article 5(12)(b), a designated orphan medicine shall be removed from the Community Register of Orphan Medicinal Products “if it is established before the market authorisation is granted that the criteria laid down in Article 3 are no longer met in respect of the medicinal product concerned”. Therefore the COMP assesses a second time if the assumptions being the basis of the designation are confirmed and allow the market exclusivity. This second assessment supposes that any changes in the treatment landscape or any new approved products may vary the initial decision on significant benefit. Late approval of a new product may not allow substantiation of evidence and the sponsor may not be in a position to justify the significant benefit against that new product. In addition, the sponsor may not be aware of parallel submissions. The timing of the COMP opinion post CHMP opinion puts the applicant in a challenging position in the event a negative COMP assessment of significant benefit and a positive CHMP opinion. Industry would therefore welcome an early COMP confirmation of significant benefit, before the CHMP opinion, thereby providing more visibility on sponsors’ options in case of conflicting outcomes between COMP and CHMP.

Communication of significant benefit In line with the EMA and EUnetHTA collaboration to improve the transparency of the scientific assessment through the EU Assessment Reports (EPAR), and after deleting commercially confidential information, there is the need for more comprehensive public information on the assessment and decision-making of significant benefit performed by the COMP, particularly at time of marketing authorisation. Industry would therefore welcome clarification on the importance to provide clear, robust and well-structured information on the scientific basis for assessment of significant benefit, which can be of use to any other stakeholders with responsibilities on medicinal products after marketing authorisation.

Documents

COMMISSION NOTICE ON THE APPLICATION OF ARTICLES 3, 5 … · The BioIndustry Association (BIA) welcomes the opportunity to submit these comments and observations on the European Commission