Health Canada has released the final version of its guidance
document Guidance for Sponsors: Information and Submission
Requirements for Subsequent Entry Biologics (SEBs) (Final
Guidance), which is an update of the draft guidance released by
Health Canada on January 30, 2008 and March 27, 2009 and applies to
all pending and future drug submissions for SEBs in Canada.
Biologics are drug products derived from biological sources and
include gene therapies, vaccines, antibodies and other therapeutic
products derived through biotechnology. An SEB is defined by Health
Canada as "a biologic drug that enters the market subsequent
to a version previously authorized in Canada, and with demonstrated
similarity to a reference biologic drug." SEB manufacturers
may make reference to the information contained in an
innovator's biologic drug submission – that is, the
reference biologic drug submission – in order to reduce
the amount of clinical data required to obtain marketing approval
for its product.
In their new drug submission, manufacturers are required to
clearly identify the product that an SEB is subsequent to. As in
the draft guidance, the Final Guidance indicates that the reference
biologic drug should be marketed in Canada. However, a manufacturer
may be permitted to use a non-Canadian reference biologic drug for
comparative studies if the manufacturer can show that the foreign
product is a suitable proxy for the version that is approved in
Canada. The Canadian and non-Canadian versions of the reference
biologic drug must be marketed by the same innovator company in the
same dosage form, and the non-Canadian reference product must be
from a jurisdiction with an established relationship with Health
Canada. Data are required to demonstrate the safety of a
non-Canadian reference biologic drug that is to be used in clinical
studies in Canada.
SEB manufacturers may apply for one or more of the indications
for use granted to the reference biologic drug. In some cases,
additional indications may be granted to the SEB in the absence of
clinical data if extrapolation to other uses is justified and
persuasive. In designing clinical trials, manufacturers should note
that equivalence trials are generally preferred, but
non-inferiority trials may be permissible in certain cases. If
trials reveal superior efficacy to a reference biologic drug
product, or an increase in adverse reactions, the product would not
be considered an SEB. Demonstration of non-inferiority between an
SEB and its reference biologic drug product would not necessarily
permit extrapolation of approval of the SEB for all indications,
especially if the indications include different dosages from those
tested in the trial.
Unlike generic drug products, SEB manufacturers will not be able
to use the entire product monograph of the reference product as its
own. Product monographs must explicitly state that the drug is an
SEB. No claims are to be made in the monograph that the SEB and the
reference product are bioequivalent or are clinically equivalent.
Sponsors are required to develop a risk management plan prior to
The Final Guidance document has been published concurrently with
amendments to the Health Canada Guidance for the Data Protection
provisions of the Food and Drug Regulations and
PM(NOC) Regulations. The Data Protection guidance has been
amended to expressly capture new drug submissions for SEBs that are
based on a comparison to a Canadian or non-Canadian reference
product, if the Canadian reference product is on the list of
innovative drug products. Excluded are new drug submissions that
include independent clinical trials and are not based on such a
comparison. An SEB will not be regarded as an innovative drug
(i.e., SEBs will not be eligible for data protection). The guidance
on the PM(NOC) Regulations has been amended to expressly
capture new drug submissions and supplemental new drug submissions
for SEBs that demonstrate similarity to a Canadian or non-Canadian
reference product. Such submissions are stated as being subject to
the PM(NOC) Regulations. If the Office of Patented
Medicines and Liaison is uncertain whether the new drug submission
is for a biologic or an SEB, it is directed to consult the relevant
bureau within Health Canada.
For further information as well as the amended guidance
documents on Data Protection and the PM(NOC) Regulations,
access the Final Guidance
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