The Japan Pharmaceutical Manufactures Association agrees with the
PK/ADME approach of bridgeability in toxicity between new and existing
routes/formulations of approved drug products in "Guidance for
Nonclinical Safety Evaluation of Reformulated Drug Products and Products
Intended for Administration by an Alternate Route". We have following
comments on the draft guidance. We would appreciate it if you would take
them into account. The underlined words and clauses are indicated for
our proposed modification.

1\. Paragraph of Page 4, Line 135

\<Original\>

For all reformulations and all routes, depending on the route of
administration, acute and repeat dose local toxicity studies with
histological evaluation should be conducted either in one species (e.g.,
skin for dermal formulations or patches; lung for inhaled formulations;
gastrointestinal for oral formulations; injection site for intravenous,
subcutaneous, intraperitoneal, or intramuscular formulations; extended
release injected or implanted formulations; intracavernosal or
intraurethral; intrabladder) or in two species (e.g., ocular;
intrathecal or epidural).

\< Proposal\>

For all reformulations and all routes, depending on the route of
administration, acute and repeat dose local toxicity studies with
histological evaluation should be conducted either in one species (e.g.,
skin for dermal formulations or patches; lung for inhaled formulations;
gastrointestinal for oral formulations; [eye for topical ocular
instillation;]{.underline} injection site for intravenous, subcutaneous,
intraperitoneal, or intramuscular formulations; extended release
injected or implanted formulations; intracavernosal or intraurethral;
intrabladder) or in two species (e.g., [intraocular;]{.underline}
intrathecal or epidural).

\<Reason\>

As ocular administration routes, there are topical ocular instillation
and ocular injection (such as intravitreous injection, sub-conjunctival
injection and sub-tenon injection etc.). For topical instillation as a
new route of administration, one species may be enough since the results
of toxicity studies in two species by the original route and the
clinical experience in human are usually available. For ocular
injection, we agree that toxicity studies in two species are usually
needed. Hence we would suggest that the "ocular" route should be divided
into "topical ocular instillation" and "intraocular".

2\. Paragraph of Page 4, Line 165

\<Original\>

If the new formulation contains an active ingredient that has not been
used by the dermal route, the repeat dose local toxicity study mentioned
earlier should be conducted in a nonrodent species. This study should be
of at least the same duration as clinical use (up to 9 months) and
include both local and systemic evaluation.

\< Proposal\>

If the new formulation contains an active ingredient that has not been
used by the dermal route, the repeat dose local toxicity study mentioned
earlier should be conducted in a nonrodent species. This study should be
of at least the same duration as clinical use (up to 9 months) and
include both local and systemic evaluation [if there is cause for
concern]{.underline}.

\<Reason\>

The study of the same duration as clinical use might be unnecessary
unless other toxicity is observed in a relatively short-term (e.g. 13
weeks) repeated dermal toxicity studies. Such long-term (up to 9 months)
studies should be conducted when there is cause for concern.

3\. Paragraph of Page 5, Line 170.

\<Original\>

The skin dose from topically applied drug products can be orders of
magnitude larger than the skin dose after systemic administration.
Therefore, a dermal carcinogenicity study might be recommended for drugs
with a chronic indication even if systemic carcinogenicity studies are
available.

\<Proposal\>The skin dose from topically applied drug products can be
orders of magnitude larger than the skin dose after systemic
administration. Therefore, a dermal carcinogenicity study might be
[considered]{.underline} for drugs with a chronic indication even if
systemic carcinogenicity studies are available.

\<Reason\>

We agree that dermal carcinogenicity studies are recommended for some
dermal pharmaceuticals if there is concern about their dermal
carcinogenic potential. Several factors to trigger dermal
carcinogenicity studies which should be considered may include: (1)
previous demonstration of carcinogenic potential in the product class
that is considered relevant to humans; (2) structure-activity
relationship suggesting carcinogenic risk; (3) evidence of preneoplastic
lesions in repeated dose toxicity studies; and (4) long-term skin
retention of parent compound or metabolite(s) resulting in local skin
reactions. Necessity to conduct dermal carcinogenicity studies should be
low if no dermal carcinogenicity potential is estimated by adequate
evaluation considering these factors.

4\. Paragraph of Page 5, Line 175.

\<Original\>

The photococarcinogenic potential should be evaluated if the new
formulation is used chronically on sun-exposed skin. Evaluation of
photococarcinogenicity generally is not recommended for patch products.
(See the guidance for industry *Photosafety Testing*.)

\<Proposal\>

The photococarcinogenic potential should be evaluated if the new
formulation is used chronically on sun-exposed skin. [Sponsors also
could choose to strengthen warning statements without conducting the
photococarcinogenicity study.]{.underline} Evaluation of
photococarcinogenicity generally is not recommended for patch products.
(See the guidance for industry *Photosafety Testing*.)

\<Reason\>

According to the guidance for industry *Photosafety Testing*, an option
not to conduct the photocarcinogenicity study has been added.

5\. Throughout the document

The guidance requires conducting several types of local toxicity studies
including acute and repeated dose local toxicity, delayed
hypersensitivity, dermal carcinogenicity, blood compatibility, etc.
However, there is no specific FDA guidance for such types of local
toxicity studies. Therefore, please indicate appropriate technical
documents such as OECD test guidelines. In addition, please give us
clear definition of \"chronic\" by saying the approximate duration.

Thank you very much for your attention.