The Israel Biosimilars Regulatory Scheme Becomes More Lenient

In December 2023, Israel’s Ministry of Health (“MoH”) published substantial revisions to the guidelines regulating policy and procedure for the registration and use of biosimilar pharmaceuticals in Israel (Procedure No. 127).

The new guidelines ease requirements for registration and use of biosimilars in Israel.

While the full effect of these revisions on the Israeli biopharmaceutical market is yet to be determined, it stands to reason that the MoH’s continued push for regulatory leniency, coupled with the MoH’s continued election not to provide regulatory exclusivity to biopharmaceuticals, might have an adverse effect on the innovative biopharmaceutical market in Israel.

Procedure 127^[1], in which the MoH provides detailed guidelines on policy and procedure for the registration and use of biosimilar pharmaceuticals^[2] in Israel, was issued in April 2014 and, prior to December 2023, was amended several times, with the last amendment thereof coming in October 2021 (the “Former Guidelines”).

We previously reported on the issuance of Procedure 127 in 2014 and on their amendment in 2016.

In December 2023, the latest version of the procedure – version number four – was released (the “Revised Guidelines”).

New name, new purpose

Unlike the Former Guidelines, whose name included both registration and use of biosimilars in Israel, the name of the Revised Guidelines includes only registration.

This change is also reflected in the “Purpose” section of the Revised Guidelines, which no longer includes the language included in the Former Guidelines regarding the terms of using biosimilars in Israel or the switching policy in respect thereof.

Also missing from the Revised Guidelines is the statement included in the Former Guidelines about biosimilars not considered to be generics – it remains to be seen whether that had been removed because it was viewed as superfluous or whether it reflects a change in the way biosimilars are viewed by the MoH.

Additional leniency on the conditions for registration of biosimilars in Israel

In the Former Guidelines, the biosimilar pharmaceutical for which registration is sought had to be previously registered in at least one of several territories mentioned therein (the U.S., any EU state, the UK, Canada, Australia, New Zealand, Japan, Iceland, Norway, or Switzerland), with it also being possible to file an application in Israel based on a positive opinion alone, if it was from either the EU’s EMA or the U.S.’s FDA.

This has now changed, with it being possible to file an application in Israel based on a positive opinion (or a letter of approval) from any of the regulators of the countries mentioned above.

Moreover, while the Former Guidelines allowed for the registration of an otherwise ineligible biosimilar in Israel in “exceptional cases of a clinical need justified from a national viewpoint”, the latest version of the guidelines omits the words “justified from a national viewpoint”, hinting that a clinical need alone could be sufficient for the registration of such otherwise ineligible biosimilar. The Revised Guidelines maintain that the issue of registering an otherwise ineligible biosimilar will be decided by a forum comprising several senior functionaries in the MoH.

This trend of leniency is also discernible from the Revised Guidelines introducing a new section, according to which the MoH’s chief of staff may authorize deviating from the Revised Guidelines if they are convinced that such deviation is “justified”. This new authority is complemented by a change in the “responsibility” section in the Revised Guidelines, which no longer requires the Pharmaceutics Division to conduct itself in accordance with the Revised Guidelines, thereby allowing it to deviate therefrom.

Changes to the Reporting Duties

The Revised Guidelines introduce a new reporting requirement, according to which the data provided to the MoH for the purposes of the registration is to be the same information filed with the foreign regulator in respect of that biosimilar, and it is further provided that “the entire data is to be transferred as it was provided to the authorized regulator abroad”.

Another change was made regarding the duty to report any differences between the reference medicinal product and the biosimilar. Under the Revised Guidelines, a note regarding those differences would need to be made only in the dossier, whereas the Former Guidelines if notices were to be given to both the MoH’s Institute for Safety and Standards as well as the MoH registration department.

Also removed from the Revised Guidelines is the specific schedule for safety reports; under the Former Guidelines, owners of registrations for biosimilars had to file safety reports (pharmacovigilance) every six months for the first two years of marketing and an annual report for the following three years. After these five years, the registrations’ owners would be subjected to the general MoH guidelines on reporting. Under the Revised Guidelines, owners of registrations for biosimilars are to be subjected to the general MoH guidelines already from day one, eliminating the specific reporting schedule.

Switching policy to be determined during the examination of the application

The Revised Guidelines include a dedicated chapter on the issue of switching the biosimilar with either the reference medicinal product or with other biosimilars thereof, as well as a definition of switching as “the possibility of switching between the reference medicinal product and a biosimilar and vice versa, or between different biosimilars of the same reference medicinal product”.

The Former Guidelines included a chapter (chapter B) – now removed – which provided guidance on the issue of switchability policy, instructing that the issue be decided separately, after the registration, by a dedicated committee.

According to the Revised Guidelines, the switchability of a biosimilar for which registration is sought will be determined during the examination of the registration application – rather than following its completion – and would be noted in the registration certificate thereof, with switchability being allowed for all indications for which the biosimilar in question was registered. To that end, applicants would be required to provide the MoH with all available information from abroad regarding the switchability of the biosimilar under consideration.

Complementing this change is the addition of two sections in the “labeling” chapter of the Revised Guidelines, which provide that if at the time the biosimilar was registered, switchability was not yet authorized, it should be noted in the leaflet, and that if there is a specific reference in the immunogenicity chapter of that biosimilar’s leaflet authorized in the reference country, it should be made in the Israeli leaflet as well.

In this regard, the Revised Guidelines add a duty for health organizations, according to which they are to act to distribute information sheets regarding biosimilars, the switching policy, and the necessary follow-up, with those sheets to be prepared by the MoH.

Conclusion

Given the very recent entry into effect of the Revised Guidelines, their implications on the registration of biosimilars and, vicariously, on reference medicinal products are yet to be seen. The Revised Guidelines reflect the MoH’s continued policy of expanding the use of biosimilar pharmaceuticals in Israel; time will tell how the new policy will influence the market for biopharmaceuticals in Israel.

[1] Under the name: “Policy regarding Registration Conditions of Bio-Similar Pharmaceuticals“.

[2] The revised guidelines define a biosimilar pharmaceutical as a biological pharmaceutical that is similar to a registered innovative biopharmaceutical in aspects of quality, biological activity, safety, and efficacy.