Changes To EU Orphan Similarity Concept Could Change Innovation Threshold For 10-Year Exclusivity

The European Commission has proposed changes to the existing criteria used for determining whether a new medicinal product is similar to an already authorized orphan drug and, therefore, whether it can be accepted for evaluation and granted 10-year market exclusivity.

The European Commission has proposed changes to the concept of "similar medicinal products" within the context of the EU orphan drugs legislation, which could have implications for awarding 10-year market exclusivity to new products in the future.

When the 10-year marketing exclusivity period for an authorized orphan drug is in place, the European Medicines Agency and the EU member states are not allowed to accept or grant another marketing authorization for a "similar medicinal product" for the same therapeutic indication, unless the sponsor can prove that its product is subject to certain derogations, such as the new drug is more effective, safer or otherwise clinically superior to the one already authorized.

The legislation specifies that all drug sponsors must assess whether there are similar orphan drugs already designated or authorized for a condition related to their proposed therapeutic indication, and submit a similarity report where needed. To assist with the similarity assessment, the legislation (Article 3 of Regulation (EC) No 847/2000) defines "similar medicinal product" and also offers numerous examples of what kind of products should be regarded as similar.

The commission has proposed changes to this definition, taking note of the technical progress made due to major developments in the field of biological medicines, including advanced therapy medicinal products. It will accept stakeholder feedback on its proposal until Nov. 4, 2016.

As the commission's proposal includes changing the definition of "similar active substance", it could redefine the "innovation threshold" that is required for awarding 10-year exclusivity to new orphan products, Helen Roberts and Vincenzo Salvatore of Italian law firm Bonelli Erede told the Pink Sheet.

However, it is not immediately clear whether the commission's proposal would make it more difficult or easier for orphan drug-makers to bring their products to the market, and secure 10-year exclusivity.

As awarding 10-year exclusivity for orphan drugs is a key incentive, an initiative to modernize this aspect should generally be acknowledged "as a step forward", said the two lawyers, who are part of the firm's healthcare and life sciences focus team.

They warned that "a broader definition of ‘similarity’ must not turn into a disincentive." (Also see "All Orphans Must Get 10-Year Exclusivity, Says Top EU Court " - Pink Sheet, 18 Mar, 2016.)

As the commission would want the EU pharmaceutical market to remain attractive for investors and research, the lawyers believe that the revised definition of "similar active substance" would still allow "proven innovation to be rewarded". Also, the proposed changes, it is hoped, will not lengthen the development time for new orphan medicines or the approval time for new indications.

Roberts and Salvatore pointed out that a revised definition will, however, affect the plans and potential funding of drug companies with products that apparently meet the current criteria of "similar active substance". Hence, they believe that the commission's final proposal must include a timetable for implementing the new definition as "companies affected will request delays in the introduction of the revised definition."

Just how the commission intends to change Article 3 of Regulation (EC) No 847/2000 is not clear, though the lawyers noted that "this process may take over 18 months."

Current Challenges

The current definition of "similar active substance" dates back to 2000 and its interpretation has been fraught with some challenges, the two lawyers pointed out.

For example, there have been instances where sponsors developing competing medicinal products in the same or similar fields have faced uncertainty as to which substance would benefit from the 10-year exclusivity because of the scope of the current definitions. While the EMA and the commission have frequently received questions on these definitions, "when they answered or published their decisions, they were often challenged," said Roberts and Salvatore.

"The decade of litigation relating to Orphacol illustrates the challenges (even for the European courts) in interpreting and providing definitive guidance for researchers and for companies seeking to market orphan medicines," the two lawyers noted. (Also see "Orphacol ruling a blow for European Commission, but brings some legal clarity" - Pink Sheet, 4 Jul, 2013.) (Also see "Orphacol ruling bolsters EU orphan exclusivity rules" - Pink Sheet, 22 Jun, 2015.)

Complex Issues At Stake

The commission's proposal includes, among other things, a new definition for the term "principal molecular structural features" in relation to similar active substances. (Also see "EMA Works On Definition To Support Similarity Assessments For Orphan Drugs" - Pink Sheet, 8 Mar, 2016.)

A clear definition of "principal molecular structural features" will likely be considered positive, but it may be difficult to apply to complex substances with more than one "structural element" and various characteristics, the lawyers noted.

For example, the commission has proposed that "sameness" be tested for chemical products by a "comparison of their structures". For biological products, the test would be "relevance to the functionality of that substance". Though the term "functionality" is not defined, the commission does state that "substances… using similar methods of modification or conjugation technology" would be considered similar. None of these terms are defined by reference to existing international or scientific guidance, the lawyers noted.

"What will raise questions is the proposal that for genetically modified cells, there would be similarity if biological and functional characteristics of two active substances determine it. Such an analysis will be complex for gene therapy, cell-based products and monoclonal antibody technology," Roberts and Salvatore said.

The lawyers believe that the commission might delegate authority to a group of experts to publish occasional guidance on what constitutes or does not constitute "similarity".

They believe that it would be useful for future guidance to acknowledge more clearly the role of the EMA and its expert committees in assessing similarity. "The EMA's own transparency on the decisions it publishes will provide further illustration of how in practice future definitions are applied," the lawyers added.

As such, Roberts and Salvatore believe that the commission's initiative is timely and "pragmatically proposes to address 'similarity' in chemical, biological and radiopharmaceutical medicinal products." The proposed changes will help reflect recent scientific developments "though they will raise complex pharmaceutical and legal interpretation questions," they added.

In parallel to reviewing the concept of similarity, the commission is working to update its 2003 Communication on Regulation (EC) No 141/2000 on orphan medicinal products, which outlines the criteria and procedures for orphan drug designation, as well as the EU marketing authorization and market exclusivity. (Also see "Action on 'weaknesses and challenges' in EU orphan drug system could lead to tougher designation requirements" - Pink Sheet, 21 Apr, 2015.)

The initiatives form part of the commission's ongoing efforts to improve the implementation of the EU orphan drugs framework that has been in place for over 15 years. (Also see "EU Orphan Law A 'Remarkable Success' But Approval Speed and Patient Access Still Poor" - Pink Sheet, 16 Mar, 2016.)

From the editors of Scrip Regulatory Affairs.