On Dec. 7, 2015, Health Canada released a revised Guidance Document for sponsors of Subsequent Entry Biologics (SEB).1The proposed revisions introduce a number of changes regarding the eligibility, submission and evaluation, and marketing requirements for SEBs from the current Guidance Document, in force since 2010.
Interested parties have until Feb. 15, 2016 to submit comments to the Biologics and Genetic Therapy Directorate (BGTD) of Health Canada on the revised Guidance Document.2
Below is an overview of some of the possible consequences for pharmaceutical stakeholders involved in SEBs, followed by a detailed explanation of the proposed changes.
If adopted, increased eligibility for SEB designation may be possible because under the proposed revisions, SEB sponsors will be permitted to refer to clinical studies from more than one biologic drug, so long as each version is similar at the level of quality.3
The process for preparing and evaluating SEB regulatory submissions may also become easier. Under the proposed revisions, SEB submissions must be filed in common international formats, while SEB sponsors will be able to obtain early guidance from Health Canada for their regulatory submission.4
However, if adopted, SEB manufacturers will also be subject to new submission, evaluation, as well as pre- and post-marketing requirements that are more extensive and onerous than those that currently exist.
As examples, clinical data submitted must be customized for each SEB so as to detect differences in responses between the SEB and reference drug.5 SEB sponsors seeking to gain approval for additional indications based on extrapolation from clinical data of the reference drug must also now consider additional SEB specific factors.6
If adopted, SEBs will also be classified as "new drugs".7 Thus SEB sponsors will be subject to all the associated regulatory requirements as new drugs, including the obligation to evaluate and report on post-notice of compliance changes, and, where appropriate, submit periodic benefit risk evaluations reports.8
The specific proposed changes include the following:
New Policy:9 Three new principles are included in the proposed revisions.
First, it is now explicit that an SEB is eligible to apply for both the indications and conditions of use as authorized by the Canadian reference drug.
Second, an SEB designation does not amount to a declaration of bioequivalence, in addition to pharmaceutical and therapeutic non-equivalence.
Third, an SEB becomes a "new drug" upon receipt of its NOC, and subject to all associated regulatory requirements.
Criteria for Reference Drugs:10 Two new criteria are imposed on reference drugs.
First, SEB sponsors can now refer to more than one reference drug in a submission.
Second, when referring to a non-Canadian reference drug, new conditions will apply. These conditions include the non-Canadian reference drug must be the same medicinal ingredient, dosage form, and route of administration as the Canadian reference biological. The drug must also be from a jurisdiction that has an established relationship with Health Canada, is widely marketed and uses ICH guidelines, and has regulatory standards and principles that are similar to Canada.
SEB Drug Submission Format:11 All drug submissions should be filed in the Common Technical Document format established by the ICH. Specific requirements will also apply to the preparation of data for assessment of similarity.
Determining Similarity:12 Under the proposed revisions, determining similarity will no longer be based on the weight of analytical and biological testing. Instead, the analytical and biological data will be used to inform the scope of clinical and non-clinical data to be gathered and submitted, and should address the potential areas of residual uncertainty.
Requirements for Submitting and Referring to Clinical and Non-Clinical Information:
At least three new requirements are included for submission of clinical data, non clinical data, and extrapolation from clinical data of the reference drug.
In submitting clinical data for an SEB, the sponsor is now required to customize its clinical trials. In particular, sponsors must consider the sensitive population in clinical trial design, and use both clinically relevant and sensitive endpoints. Sponsors will also be required to justify to Health Canada its clinical trial strategy to evaluate immunogenicity using methods with sensitivity sufficient to detect (i) differences between reference drug and SEB, and (ii) potential impact on safety and efficacy.13
For non clinical data, where similarity is well established by analytical, biological, and in vitro testing, then a single arm non clinical studies in a relevant species can replace comparative non-clinical studies prior to the first human study.14
For SEBs seeking approval for additional indications based on "extrapolation" from comparative clinical data of the reference drug, additional and considerations now apply. Those considerations include (i) characteristics of study population and clinical trials, (ii) risk and impact of immunogenicity, and (iii) impact of concurrent therapies.15
Labelling Requirements:16 SEB sponsors are subject to new requirements to disclose additional information in their product monograph that includes the following:
- Data generated by the SEB sponsor
- Information on the basis for which each indication is authorized
- For all indications, safety information including warnings, precautions, adverse drug reactions or effects, and key post market safety information
Post- Marketing Requirements:17 As part of the designation of SEBs as "new drugs", SEBs will now be subject to all the associated "new drug regulatory requirements. This includes obligations to report post-notice of compliance changes affecting the safety, efficacy, and quality.
Consultation with BGTD:18 The BGTD is launching a three year pilot that would allow for regulatory review to occur alongside SEB development. As part of this pilot program SEB sponsors will be able to request a Scientific Advice Meeting from BGTD for advice on the preparation of their comparability package.
The current guidance document and other resources can be found on the Government of Canada website.
3 Draft Guidance, Reference Biologic Drug, s 2.1.3
4 Draft Guidance, Organization of data, s 2.3.1, and Consultation with BGTD, section 3
5 Draft Guidance, Clinical Studies, s 184.108.40.206, and Non Clinical Studies, s 220.127.116.11
6 Draft Guidance, Extrapolation, s 18.104.22.168
7 Draft Guidance, Policy Statements, s 1.3.7
8 Draft Guidance, Post Marketing Requirements, s 2.4
9 Draft Guidance, Policy Statements, ss 1.3.5; 1.3.5; 1.3.7
10 Draft Guidance, Reference Biologic Drug, s, 2.1.3, and Considerations for the use of a non-Canadian Reference Biologic Drug, s 22.214.171.124
11 Draft Guidance, Information requirements for new drug submissions, s 2.3, and Organization of data, s 2.3.1
13 Draft Guidance, Clinical Studies, s 126.96.36.199
14 Draft Guidance, Non Clinical Studies, s 188.8.131.52
15 Draft Guidance, Extrapolation, s 184.108.40.206
16 Draft Guidance, Labeling requirements- Product monograph, s 2.3.4
17 Draft Guidance, Post Marketing Requirements, s 2.4
18 Draft Guidance, Consultation with the Biologics and Genetic Therapies Directorate (BGTD), s 3