In May 2016, Israel's Ministry of Health ("MoH") published substantial revisions to the guidelines appearing in Procedure No. 127, which regulates policy and procedure for the registration and use of biosimilar pharmaceuticals in Israel. These revisions ease requirements for registration and use of biosimilars in Israel. While the full effect of these revisions on the Israeli biopharmaceutical market are yet to be seen, it stands to reason that the innovative biopharmaceutical market in Israel may be adversely affected thereby.

These revisions, in particular: (1) refine comparative test requirements (with reference biopharmaceuticals), (2) outline interchangeability policy, (3) expand the list of reference countries on which to base a biosimilar application, (4) introduce labeling requirements, and (5) allow importation of a biosimilar in some cases, where the biosimilar is not registered in Israel.

Procedure 127[1], in which the MoH first provided detailed guidelines on policy and procedure for the registration and use of biosimilar pharmaceuticals[2] in Israel, was issued in April 2014 ("former guidelines")[3] and reported by us in our June 2014 newsletter. In May 2016, several substantial revisions ("revised guidelines") were made. This report is a review of the revised guidelines.

More lenient conditions for registration of biosimilars in Israel

In the former guidelines, the biosimilar pharmaceutical had to be previously registered either with the EMA or the FDA, in order to be registered in Israel. According to the revised guidelines, registrations in Canada, Australia, New Zealand, Japan or the Swiss Agency for Therapeutic Products ("Swissmedic") may also constitute a basis for registration in Israel.

As a general rule, according to both the former and the revised guidelines, registration of a biosimilar will not be permitted if the reference biopharmaceutical is not registered in Israel. Under the former guidelines, in special cases of a nationally justified clinical need, registration of a biosimilar may have been considered even if the reference biopharmaceutical was not registered in Israel; provided, however, that the biosimilar pharmaceutical had been approved by the FDA or EMA. According to the revised guidelines, the basis for such registration has been expanded to include Swissmedic[4] as well.

Revised (and more lenient) interchangeability policy for ongoing treatment with biosimilars

The former guidelines did not allow for automatic interchangeability of a reference biopharmaceutical with a biosimilar pharmaceutical by the medical authority. While no such automatic interchange is provided for by the revised guidelines, should a clinical need arise, a physician, upon consultation with the medical institution, is permitted to substitute a reference biopharmaceutical for the same indications, unless otherwise stipulated in the registration conditions thereof.

A biosimilar a priori may be defined as a substitute for the reference pharmaceutical. The revised guidelines also establish an advisory committee that may recommend interchangeability in certain cases; and may also convene on an ad hoc basis following registration, upon request of the biosimilar registrant. Interchangeability, when approved, must be indicated in the registration conditions, as well as in the physician leaflets and consumer leaflets.  

Extending indications and extrapolations for bioimilars

In the former guidelines, permitted indications for a biosimilar were only those previously approved (for said biosimilar) by the EMA and/or FDA[5]. This limitation is omitted from the revised guidelines. The MoH may approve any indication for which a biosimilar was clinically tested and approved in Israel for the reference biopharmaceutical.

The revised guidelines permit extrapolation to indications for which the biosimilar was not clinically tested, provided the reference pharmaceutical is registered for such indications and on the basis of the totality of available information, including quality, safety and efficacy data, with emphasis on the mechanism of action[6].

Allowing importation of biosimilars under Regulation 29

Under Regulation 29 of the Pharmacists' Regulations (Preparations) -1986, the importation of medicinal preparations into Israel is allowed, upon approval of the Director General of the MoH, even if the medicinal preparation is not registered in Israel under certain terms and conditions (e.g., for "off label" or compassionate use). For the first time, the revised guidelines allow implementation of the Regulation 29 procedure to biosimilars registered in the EMA, FDA or Swissmedic. In special cases, where a clinical need arises, biosimilars registered in Canada, Australia, New Zealand or Japan may also be imported under Regulation 29, upon approval of the MoH Director General.

Mandatory labeling of a biosimilar

The issue of labeling a biosimilar was also addressed in the former guidelines, according to which, inter alia, a biosimilar had to be labeled in a clear and prominent manner, so as to be distinguished from other biological pharmaceuticals[7]. The revised guidelines also obligates registrants to indicate a biosimilar as such in physician leaflets, in consumer leaflets and/or any related publication  addressing medical professionals or the public.

Pharmacovigilance - inclusion of additional requirements

Both the former and the revised guidelines recognize that given the lack of experience in the use of biosimilars, pharmacovigilance is of essential importance. Therefore, a risk management plan or risk evaluation and mitigation strategies need to be submitted as part of the application for registration of a biosimilar. The registrants are expected to proactively report adverse effects[8].

Additional requirements were included in the revised guidelines, such as the requirement to file an updated PSUR/PBRER (periodical safety update report/periodic benefit-risk evaluation report) and additional safety data.

Conclusion

The implications of the revised guidelines on the registration and use of biosimilars and/or reference biopharmaceuticals are yet to be seen. Generally, the revised guidelines reflect the MoH policy and intent to expand the use of biosimilar pharmaceuticals in Israel; among others, by easing registration and importation requirements and expanding the list of reference countries on which the MoH bases its decisions. Time will tell to what extent this policy will influence the biopharmaceuticals market in Israel.