U.S. FDA Considerations:
Discussion by National Regulatory Authorities with World Health
Organization (WHO) On Possible International Non-proprietary Name
(INN) Policies for Biosimilars
September 1, 2006
Support of INN's Orginal Purpose
The United States Food and Drug Administration (U.S. FDA) continues
to support the original purposes, premises, and uses of the INN and
believes the system has provided many positive elements to the world’s
public health, especially in facilitating the exchange of scientific
data and reports on various products with the same active ingredient(s).
The USA recognizes the INN system as a cataloging system whereby
many products worldwide may share the same internationally recognized
nonproprietary name based on drug substance. In this manner, the INN
system provides a clear mechanism to health care professionals
worldwide for identifying medicines and communicating unambiguously
about them based on pharmacological class.
The U.S. FDA’s concerns in today’s discussion are (a) that the INN
not be used in ways that could jeopardize the health of patients, and
(b) that we not unnecessarily institute changes that could jeopardize
the public health benefits of the present INN system.
Specifically, INNs should not be used to imply pharmacologic
interchangeability of products with the same active ingredient(s) when
no credible scientific data exist that demonstrate such. Likewise,
INNs should not be used to differentiate products with the same active
ingredient(s) when credible scientific data demonstrate that no
pharmacologically relevant differences exist.
Pharmacologic Interchangeability
“Interchangeability” is a term used for purposes of this discussion
to designate the situation where scientific data convincingly
demonstrates that two products with very similar molecular
compositions or active ingredient(s) can be safely substituted for one
another and have the same biologic response and not create adverse
health outcomes, e.g., generation of a pathologic immune response.
With small molecular products, there is a long history to support
the use of various scientific approaches to establishing
“bioequivalence” between products with the same active ingredient(s)
produced by different manufacturers. We know now that these
“bioequivalent” products can indeed be expected to behave in a
pharmacologically interchangeable manner when used in patient care.
With protein products, as of today, the FDA has not determined how
interchangeability can be established for complex proteins.
Different large protein products, with similar molecular
composition may behave differently in people and substitution of one
for another may result in serious health outcomes, e.g., generation of
a pathologic immune response
When scientific data establishing pharmacologic interchangeability
do not exist, especially with more complicated protein molecules with
potential critical immunologic safety issues, it is important that
patients and physicians be aware that protein products with similar
molecular composition may indeed not be interchangeable.
U.S. FDA believes that the only way to establish pharmacologic
interchangeability is through scientific data, and nomenclature should
not be used as a way to imply such when there are not credible
supporting data.
Situation in the United States of America
Product Dispensing
To date, the USA does not use non-proprietary names as a vehicle
for communicating pharmacologic interchangeability. There are examples
in both small molecule products and more complex proteins of products
having the same non-proprietary name and there not being scientific
data establishing the interchangeability of the products. For example,
multiple innovator products containing interferon β-1a, insulin, or
somatropin share the same non-proprietary name and there are not
scientific data that support the pharmacologic interchangeability of
these products.
In the USA there are recognized mechanisms in place other than
non-proprietary names for assigning pharmacologic interchangeability:
e.g., equivalence ratings in the Orange Book; specific labeling
regarding pharmacologic interchangeability.
In addition, in the USA, there are drug dispensing systematic
“checks” to help assure appropriate dispensing of products based on
whether or not there are scientific data establishing
interchangeability. However, this might not be true in other
countries.
Because of the many alternative mechanisms in the U.S. for
preventing inappropriate substitution, at this time the U.S. FDA does
not consider the proposed change to the INN policy for naming
biosimilars to be necessary to prevent inappropriate substitution in
the United States. Appropriate prescribing and dispensing practices in
the U.S. encompass more than just conveyance of a drug name from
prescriber to pharmacist. Regulations concerning drug substitution by
pharmacists vary from state to state in the United States. However,
there is always a mechanism by which the prescriber can authorize that
the brand or innovator product be dispensed. As an additional
safeguard, many states utilize a state drug formulary that includes
listings of drugs with the “same” active ingredient(s) considered to
be pharmacologically interchangeable. Even if two biosimilars would
have the same nonproprietary name, they would only be included on a
list of interchangeable products, if there were scientific data to
justify such. Thus, a common INN in itself does not imply or warrant
inclusion on a state’s list of interchangeable drugs. The FDA
recognizes that the authorized prescribing information represents the
most important means of communicating information about an authorized
product to prescribers and pharmacists. The authorized prescribing
information should distinguish a product from others considered to be
biosimilar if indeed there is not data to substantiate pharmacologic
interchangeability. In addition, the role of continuing professional
education about interchangeability risks with biosimilars should be
further emphasized.
The issue of interchangeability is not an issue of nomenclature but
a scientific question that needs to be decided on its own merit. The
question of nomenclature is more relevant to concerns about
pharmacovigilance and the prevention of inappropriate substitution.
However the FDA believes that these issues transcend a naming
convention. It would be the U.S. FDA’s preference that INNs continue
to be granted based only on molecular characteristics and
pharmacological class of the active ingredient(s). Regarding similar
protein products, this view is predicated on the situation in the
U.S., where there are alternative mechanisms in place for preventing
potentially dangerous substitutions and ensuring that potentially
unsafe drug dispensing decisions are not made because of a
misperception that the same INN implies pharmacologic
interchangeability. These mechanisms might not exist in other
countries. In the event that granting the same INN name to similar
drugs that are nonetheless pharmacologically distinct may lead to
inappropriate substitutions, then it may be determined at a later date
that changes to the INN policy are needed to ensure safe prescribing
and dispensing of drug products including similar protein products
throughout the world. Concerns about inappropriate substitutions that
can create safety issues may be beyond the scope of the INN program to
address through nomenclature alone, and may be better addressed by
specific steps taken by individual regulatory authorities to ensure
appropriate prescribing."
Pharmacovigilance:
In the USA, the non-proprietary name may serve as a useful tool in
pharmacovigilance as it may be one means of product identification,
but it should not be relied upon as the sole means of product
identification. Pharmacovigilance is the dual responsibility of the
manufacturer and the U.S. FDA. In order to practice the most robust
pharmacovigilance, all involved should employ all the various tools
available for product identification, including lot numbers, NDC codes
or other such national coding systems, etc.
As such, the USA does not see any reason to change present INN
practices for pharmacovigilance purposes when there are other
identification systems in place to allow product identification beyond
the level of the non-proprietary name.
U.S. FDA Concerns Regarding INNs and Complex
Proteins
If the outcome of assigning the same INN to two products with
highly similar ingredient(s) created the implication that the two
products were pharmacologically interchangeable AND there were NO
scientific data to support that finding, then the U.S. FDA would have
serious concerns about such an outcome, especially with more
complicated proteins. As of today, FDA has not determined how
interchangeability can be established for complex proteins.
If the outcome of assigning different names or names with unique
identifiers to two products with highly similar active ingredient(s)
created the implication that two products were not interchangeable
when indeed there were scientific data establishing such, the U.S. FDA
would have serious concerns.
It is beyond the role of the INN Expert Committee to make product
interchangeability determinations. This would place an unrealistic
burden of responsibility with accompanying liability on the INN Expert
Committee. The INN should not be used as a determinant of
interchangeability. It would be bad public health policy to allow,
just because they share the same INN, the substitution of products
with a shared INN in patient care when there are no scientific data to
demonstrate pharmacologic interchangeability.
Likewise, it would be bad public health policy to disallow, solely
because they have different INNs, the substitution of products with
different INNs which indeed have scientific data that demonstrate
pharmacologic interchangeability.
Each national regulatory authority should oversee the evaluation of
interchangeability based on bioequivalence and/or other validated
scientific data and not link such decisions to INNs.
Conclusions
This discussion among national regulatory authorities and the WHO
should be a first discussion on this issue to fact find and to
determine how changes to the INN system would impact both positively
and adversely, the regulatory systems and public health of WHO member
states.
- The FDA is concerned that some countries may be using the INN as
an indicator of interchangeability. Although this is not the case in
the U.S., the U.S. FDA considers this apparent inappropriate use of
the INN to be a public health concern.
- The U.S. FDA encourages the WHO to further investigate the
worldwide prevalence of using the INN as a determinant of
interchangeability (note: the BCG study sponsored by Amgen
investigated 6 EU countries and use of the INN in prescribing was
encouraged in most of these 6 countries, but not required).
- The U.S. FDA suggests that the WHO/INN Expert Committee clarify
and re-iterate the intent of the INN with participating countries.
It would be the U.S. FDA’s preference that INNs continue to be
granted based only on molecular characteristics and pharmacological
class of the active ingredient(s). Regarding similar protein products,
this view is predicated on the situation in the U.S., where there are
alternative mechanisms in place for preventing potentially dangerous
substitutions and ensuring that potentially unsafe drug dispensing
decisions are not made because of a misperception that the same INN
implies pharmacologic interchangeability. These mechanisms might not
exist in other countries. In the event that granting the same INN name
to similar drugs that are nonetheless pharmacologically distinct may
lead to inappropriate substitutions, then it may be determined at a
later date that changes to the INN policy are needed to ensure safe
prescribing and dispensing of drug products including similar protein
products throughout the world. Concerns about inappropriate
substitutions that can create safety issues may be beyond the scope of
the INN program to address through nomenclature alone, and may be
better addressed by specific steps taken by individual regulatory
authorities to ensure appropriate prescribing."
At this time, the U.S. FDA acknowledges that biosimilars have not
been demonstrated to be interchangeable through any scientific
process. The world community may ultimately decide that INN policy for
this class of products should be treated differently than that for
small molecule drugs. A different naming scheme for these products
might involve utilizing a different level of granularity, which may be
more detailed or less detailed depending upon the utility in the INN
system. Considering the inherent difficulties in additional INN
product distinctions (e.g. retroactive and lifecycle changes in
naming, additional INN responsibility and liability), if the world
community decides to proceed with a change in the policies regarding
the assigning of INNs, it should be preceded by (a) appropriate
exploration of alternatives (e.g. improvements in education and/or
labeling), (b) assuring the such changes fall within the scope,
competence, and expertise of the INN program, and (c) the performance
and independent validation of a formal risk assessment and/or
documentation of events with appropriate statistical treatment.
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Date created: September 5, 2006 |