**Comments and Suggestions on the draft Guidance for Industry: Diabetes
Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and
Prevention**

*The following suggestions and comments are restricted to the main
clinical points related to type 2 diabetes mellitus, excluding insulin
therapy.*

A\) Major Comments

**1)** The FDA has confirmed that HbA1c is considered a well-validated
surrogate for the [short-term]{.underline} clinical consequences of
hyperglycemia [and long-term]{.underline} [microvascular
complications]{.underline} of diabetes. The guidance states that FDA
recognizes that diabetes is associated with increased risk of
[macrovascular complications]{.underline} and that reducing long term
cardiovascular complications in diabetes should be an important goal of
disease management.

**Lines 77-81**

The FDA wrote that "however, a premarketing recommendation to
demonstrate macrovascular risk reduction in the absence of a signal for
an adverse cardiovascular effect may delay availability of many
effective antidiabetic drugs for a progressive disease that often
requires multiple drug therapy". The FDA also proposed that "a
reasonable approach may be to conduct long-term cardiovascular studies
post approval in an established time frame".

**Lines 922-924**

The FDA wrote that "Therapies that have not demonstrated a deleterious
effect on cardiovascular outcome during extensive premarketing
evaluation may need further post approval assessment for their effects
on long-term macrovascular disease".

**COMMENTS**

**Please clarify if the post approval assessment mentioned would require
further clinical study or if other assessment methods would be
acceptable.**

**If a clinical study is required, please clarify if the main goal of
these post marketing studies would be safety, efficacy, or both. While
it is understood that development plans for individual compounds should
be discussed and agreed upon with FDA at appropriate formal meetings, it
would be helpful if this guidance could provide a general recommendation
for drugs under development as well as address under what conditions
previously approved drugs that have not yet met this recommendation will
be required to do so.**

**2) Lines 919-921**

The FDA wrote that "sponsors should conduct large outcome trials before
submission of marketing applications for drugs in development that show
non clinical or clinical evidence of increasing macrovascular risk".

**COMMENT**

**Please provide further guidance and definition of signals of
increasing macrovascular risk. Assuming the main objective of these
large, pre-approval outcome trials is safety, please provide guidance on
the study design -- for example, no increase of events compared to
active controls.**

**[B) Other comments]{.underline}**

**1) Lines 247-251**

When planning exploratory phase 2 studies, the FDA recommends that
sponsors include a 6- to 8-week run-in period before randomization to
allow for diabetes education and optimization of compliance with diet
and exercise.

**COMMENT**

**Given that exploratory phase 2 studies include placebo control group
that allows for correction of the analysis on the placebo effect,
reflecting the potential better adherence to diet and exercise in
trials, the proposed run-in period of 6- to 8- week period seems long.
It would be helpful if the guidance could further explain the rational
for the recommended 6- to 8-week run-in period.**

**2) Lines 399-402**

The FDA wrote that sponsors can conduct extensive dose titration and
dose exploration in phase 2 studies in subjects taking two or more
antidiabetic agents and to substitute one of the existing medications by
the investigational agent or matching placebo.

**COMMENT**

**Please clarify whether FDA intends for insulin to be included in these
antidiabetic agents. The proposed design is interesting, but the
availability of fixed-dose combination therapies, and the great number
of doses and combinations of oral anti-diabetics used to treat the
patients, could lead to some difficulties. Please comment on whether
phase 2 dose titration could also be performed as add-on therapy, on top
of subject's current therapies (with two or more agents) in populations
with HbA1c not at target.**

**3) Lines 662-402**

The FDA requires that in case of a fixed-dose combination of a new agent
and an established agent, each of the individual components makes a
contribution to the claimed effects.

**COMMENT**

**Please clarify the level of the contribution of each component and
statistical hypotheses of the full factorial design, if applicable.**

**4) Lines 878-880**

The FDA requires that for all new development programs, phase 3 studies
be sized to allow meaningful evaluation of the consistency of the
effects across subgroups based on sex, age, ethnic background, duration
and severity of the disease, concomitant medications.

**COMMENT**

**While it is understood that statistical analysis plans should be
discussed and agreed with the Agency for individual development
programs, it would be helpful if this guidance would provide general
recommendations, to the extent possible, on how the phase 3 studies
should be powered to demonstrate a statistically significant effect in
each of these subgroups.**

**Please comment on at what level should the "consistency" be analyzed:
at the level of each study, or at the level of a pooled analysis of the
phase 3 studies?**

**5) Lines 906-909**

The FDA requires that studies lasting longer than 1 year that employ an
appropriate active comparator are strongly encouraged and may be needed
if preclinical or phase 2 or phase 3 studies reveal a safety signal.

**COMMENT**

**Please clarify in the guidance whether FDA would consider that 1-year
or more extensions of the 6- to 12- month active-controlled studies
fulfill with their requirement.**

**6) Lines 995-997**

**COMMENT**

**Please provide further guidance and definitions of "clinically
meaningful differences" for superiority trials.**