The effects of the EU orphan legislation are substantial: over 1,950 orphan designations have been issued by the European Commission since the year 2000, of which 142 have resulted in
However, with more and more drugs getting approved while maintaining the designated orphan status, developers of drugs within the same orphan drug condition see themselves faced with a higher raised bar. Questions like “what are the options for a product to enter the market in case of an already approved drug for the same therapeutic indication” are frequently asked? The situation is complex as two different set of criteria of the orphan drug regulation apply, each with its own conditions and consequences:
- Market exclusivity of the competitor
- Maintaining the orphan drug designation status by showing significant benefit.
The criteria and options for entering the market in case of another orphan drug approved for the same therapeutic indication with market exclusivity period are summarized in the scheme below:
MA: Marketing Authorisation; ODD: Orphan Drug Designation
*Similar being defined as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism (EC 847/2000 Art 3.3(c), amended by EC 2018/781).
**Clinical superiority being defined as a medicinal product is shown to provide a significant therapeutic or diagnostic advantage over and above that provided by an
***Significant benefit means a clinically relevant advantage or a major contribution to patient care (EC 847/2000, Art 3.2)
1. SIMILAR PRODUCTS: MARKET EXCLUSIVITY
The first criterium in getting your product registered relates to the presence of a 10-year market exclusivity for another designated orphan drug being granted a marketing authorisation. I.e. another similar medicinal product can in principle not be placed on the market in the EU for the same therapeutic indication (Art 8(1) EC 141/2000). In this concept, a similar medicinal product is defined as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism (for detailed explanation, refer to EC 847/2000 Art 3.3(c), C(2008)4077, and EC 2018/781). The market exclusivity period can be extended by two additional years when the results of studies in the paediatric population are presented in accordance with a Paediatric Investigation Plan. The market exclusivity incentive prevents other companies to easily place a generic product on the market, irrespective of the legal basis of the original application and of the patent situation.
authorisation for similar products
If the active substance is indeed similar, your product can only be placed on the market for the same therapeutic indication when
- consent of the original marketing
authorisationholder is obtained,
- the original marketing
authorisationholder is unable to supply sufficient quantities or
- the medicinal product is safer, more effective or otherwise clinically superior despite having a similar active substance (for a detailed explanation see: C(2008)4077).
In these cases, marketing
If the situation and clinical program of your similar product allow, the planned indication might be adjusted to target a patient group not protected by the market exclusivity. Alternative indications might already be explored during the development of your product in case of the expected competition of a similar product. The adapted indication can but might not necessarily have an orphan drug status.
authorisation for non-similar products
If your product contains a non-similar active substance while the intended indication is similar, marketing
2. MAINTAINING ODD AFTER MA FOR NON-SIMILAR PRODUCTS: SIGNIFICANT BENEFIT
In case ODD status is wished additional to the marketing
This concept of significant benefit can be based on improved efficacy, improved safety or a major contribution to patient care and there has to be a high probability for patients to actually experience this benefit when using your product. At the time of marketing
The concept and requirements for the significant benefit are further explained in Recommendations from the Committee for Orphan Medicinal Products (EMA/COMP/15893/2009), Guideline on the format and content of applications for designation as orphan medicinal products (ENTR/6283/00) and Commission notice 2016/C 424/03.
3. WHAT STEPS CAN YOU TAKE?
The approval of a competitor orphan drug product with rights of market exclusivity in the target indication of your product will raise the bar, but options still remain to register and market your product. If not similar in active substance, market
- Continuously follow-up on programs of competitor products, similar or non-similar, in the orphan drug condition not to be surprised by granting of approval of another orphan drug in your target indication.
- Even though competitor products have not been granted marketing
authorisation, evaluate similarity and significant benefit criteria explained in this blog and the pros and cons for each option.
- Anticipate if you need to prepare for alternative routes in your development program.
- In case extra investments in the clinical program are needed to maintain the ODD status at the time of marketing
authorisation, assess whether the investments balance the expected profits on the market.
4. RECOMMENDED READING
- Regulation (EC) No 141/2000 on Orphan Medicinal Products.
- COMMISSION REGULATION (EC) No 847/2000 of 27 April 2000 laying down the provisions for
implementationof the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’.
- Guideline on aspects of the application of Article 8(1) and (3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus
authorisedorphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity. C(2008)4077 (2008/C 242/08).
- Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation. EMA/COMP/15893/2009.
- 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. ENTR/6283/00 rev 4. 2014.
- Commission notice on the application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on orphan medicinal products. 2016/C 424/03 (replacing communication 2003/C 178/02).
- EMA Annual report on the use of the special contribution for orphan medicinal products 2017, 31 January 2018 EMA/19529/2018.
- COMMISSION REGULATION (EU) 2018/781 of 29 May 2018 amending Regulation (EC) No 847/2000 as regards the definition of the concept ‘similar medicinal product’.
Blog by: Patricia Baede, Liesbeth Hof