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April 29, 2003

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

**RE: Docket No. 02N-0528: Risk Management Concept Papers.**

**Commentary submitted by Millennium Pharmaceuticals, Inc.**

Dear Sir or Madam,

Thank you for the opportunity to comment on the Risk Management Concept
Papers. We regard the safety of the patient as paramount, and we welcome
a thoughtful dialogue on how industry, regulatory authorities,
pharmacists and physicians can work together to ensure that safe,
breakthrough medicines get to the patients who need them.

![](media/image2.png){width="7.5in" height="3.7625in"}Millennium
Pharmaceuticals, Inc. is a biopharmaceutical company headquartered in
Cambridge, Massachusetts, with additional facilities in South San
Francisco, California and Cambridge and London, UK. By applying its
knowledge of the human genome, its leading understanding of disease
mechanisms, and its industrialized technology platform, Millennium is
developing breakthrough personalized medicine products.

Per FDA request, our comments which follow are organized by paper and
line number.

**[PREMARKETING RISK ASSESSMENT]{.underline}**

**Lines 61, 79-81: What is the appropriate size of the premarketing
safety database? FDA would be interested in input on what general
guidance could be provided on appropriate sizes of databases for
products intended only for acute use and/or for serious and
life-threatening conditions.**

The appropriate size of the premarketing safety database is dependent on
the nature of the adverse events one must determine (common, uncommon,
rare). The nature of the adverse events one must assess in premarketing
studies is dependent on the indication, the population to be treated,
and the expected benefit of the treatment. After determining the nature
of the adverse events which must be assessed, one can apply Hanley's
"Rule of Three" (*Hanley, J.A., Lippman-Hand, A. [JAMA]{.underline}
1983;259:1743-1745)* to determine the appropriate size of the
premarketing safety database.

For serious and life-threatening conditions in which the benefit of the
drug or treatment under study is most critical to assess, one would
generally only need to assess [common]{.underline} adverse events in
premarketing studies. Applying the Rule of Three, in order to ensure
that one captures at least one occurrence of adverse events happening at
a frequency of 1:100 or greater at a 95% confidence level, the
appropriate size of the premarketing safety database would be at least
300. Depending on the mortality and morbidity of the condition being
treated, however, it is possible that even smaller safety databases may
suffice in the premarketing phase. Again, applying the Rule of Three, if
one wishes to capture at least one occurrence of adverse events
affecting 5% or more of the population, then a safety database of 60
patients may be sufficient. Finally, the prevalence of the condition
being treated may also be a factor in determining the appropriate study
size; for many orphan conditions, it may be unrealistic to enroll
several hundred patients in a reasonable time period.

For products intended for acute use, again, much depends on the
indication and population to be treated when determining an acceptable
level of risk, and this should be assessed on a case-by-case basis.
Known toxicities in the drug class or the novelty of the agent may also
play a role in determining the appropriate size of the premarketing
safety database. In general, the nature of the adverse events one would
want to determine in these indications would not differ much from the
nature of adverse events one would determine for drugs intended for
long-term treatment of non-life-threatening conditions. That is, one
would aim to fully profile the range of [uncommon]{.underline} adverse
events. Thus, the current ICH E1A guideline of 1,500 patients (which,
applying the Rule of Three, should detect at least one occurrence of
adverse events occurring at a rate of 1:500 at a 95% confidence level)
may be sufficient. We note that the ICH guideline represents the
mid-range for the safety database size necessary for determining
uncommon adverse events (1:100 -- 1:1,000) when applying the Rule of
Three.

Finally, we believe that rare adverse events are best explored in the
post-marketing phase of development. For many companies, it would be
impractical in most indications to enroll 30,000 patients in
premarketing studies to detect just one possible occurrence of a
1:10,000 event.

**[Lines 92-94]{.underline} \...the 1500 patients should have been
exposed to doses equal to or exceeding the lowest proposed dose, with a
*substantial representation (emph. added)* of patients exposed at or
above the highest proposed doses.**

"Substantial representation" is not currently defined in the concept
paper. We are concerned about exposing significant numbers of patients
to doses above the highest proposed dose. Data from Phase I dose-ranging
studies need to be taken into consideration. Doses [above]{.underline}
the highest proposed dose should be evaluated only if the therapeutic
range is narrow due to dose-limiting toxicity (e.g. toxicity seen at 2X
the highest dose). This would be a more logical approach to gain
information on the potential for more rare adverse events.

**[Lines 128-129,136]{.underline} \...other reasons why a larger
database *(than the ICH recommendation of 1,500)* could be appropriate
include: 3. There is potential for rapid exposure to a large
population.**

How is the potential for rapid exposure defined/measured? The rapidity
of a drug's uptake once on the market is impacted by a variety of often
unpredictable factors, including the marketing skills of the sponsor
and/or formulary acceptance, which are difficult to assess early in
product development. If there is the potential for rapid exposure to a
larger population, then more intense monitoring immediately
"post-approval" may be necessary.

**[Lines 138, 141-157]{.underline} Characteristics of an ideal safety
database: Long-term controlled studies**

Long-term safety of a drug is best assessed through post-marketing
surveillance. Long-term controlled safety studies in the premarketing
phase are unrealistic due to difficulties in recruitment, time, and
costs. Case-matched independent databases should be considered to
evaluate safety in the post-approval phase.

**[Lines 138, 159-168]{.underline} Characteristics of an ideal safety
database: Diverse safety database**

Broadening the inclusion/exclusion criteria of registration studies has
the potential of reducing the ability to measure primary efficacy
endpoints. The trend of the future will be towards "more focused"
therapies targeted to specific patient populations. Broadening, rather
than focusing, patient populations is contrary to this approach.

An alternative would be to conduct a "Phase IIIB" study which would
allow a few select study centers to broaden patient recruitment to
include, e.g. elderly patients, or patients with liver impairment, etc.,
with the objective of generating some preliminary safety data on these
populations pre-marketing.

**[Lines 138, 170-181]{.underline} Characteristics of an ideal safety
database: Use of dose ranges in Phase III**

Dose ranges and selections are typically chosen before a drug reaches
Phase III. The recommendation to continue evaluating doses in Phase III
will significantly increase the size of these trials. In addition, Phase
III studies are not typically powered for safety. We recommend instead
that the focus should be placed on conducting well-designed dose-ranging
studies in Phase II, incorporating pharmacogenetic information and
analyses whenever practical and relevant.

**[RISK ASSESSMENT OF OBSERVATIONAL DATA]{.underline}**

**[Lines 374-380]{.underline} Reporting safety signals to the FDA**

First, it is critical to define a safety signal. The World Health
Organization defines a safety signal as "reported information on the
possible causal relationship between an adverse event and a drug, the
relationship being unknown or incompletely documented previously." Note
too that the detection of a signal also depends on the nature of the
adverse event. If the event is rare, then one well-characterized case
could qualify as a signal. For common and uncommon events, an
observation of a clinical pattern based on a case series would typically
form the basis of signal identification.

Given the above definition, we do not agreed that certain facts which
might constitute safety signals should be automatically reported to the
FDA at the first instance they are identified. Rather, the reporting of
safety signals and development of pharmacovigilance plans should follow
the philosophy of CIOMS III (*Guidelines for Preparing Core
Clinical-Safety Information on Drugs, Including New Proposals for
Investigators Brochures, 2^nd^ ed.* 1999.) Safety signals must be
prudently explored, documented and characterized to determine the causal
relationship. If it is then determined that the product's Core Safety
Information should be changed to incorporate information about this
signal -- that is, an Adverse Drug Reaction has been established and/or
there is "practically useful" information which should be conveyed to
practitioners and patients -- that is when the FDA should be informed
and, if necessary, a pharmacovigilance plan developed.

**[Line 462]{.underline} How can the quality of spontaneously reported
case reports be improved? and [Lines 79-104]{.underline} Characteristics
of a good case report**

A good case report depends on the quality of the narrative -- both its
form and content. CIOMS V (*Current Challenges in Pharmacovigilance:
Pragmatic Approaches*, 2001) contains a recommendation for the format of
the case report narrative. The recommended format consists of 8
elements, or sections. This format enables one to define metrics to
measure the quality of each element or section.

We agree with the agency that direct contact and follow-up with
reporters is essential to good pharmacovigilance practice. Reporters are
already qualitatively different from other practitioners in their
willingness and availability to cooperate. We disagree with the
contention by some that spontaneous case reports do not represent
quality data for post-marketing surveillance, and we conduct
comprehensive follow-up with reporters to ensure we have collected all
relevant data. We would caution against a bias towards relying primarily
on the use of claims and similar types of databases to detect safety
signals, although these databases are certainly another useful tool to
exploit when appropriate.

[Closing Comments]{.underline}

We believe that a discussion of and emphasis on already-existing
fundamentals in product safety and risk management is missing from the
current dialogue. In determining appropriate safety and efficacy study
designs and product surveillance activities -- whether pre- or
post-approval - one must decide first the nature of the adverse events
which one wishes to describe, mitigate or prevent. This can only be
determined on a case-by-case basis, and depends on the indication, the
population to be treated, the drug class, preclinical safety signals,
the novelty of the drug, etc., although we agree that the treatment of
serious and life-threatening conditions differs qualitatively from the
treatment of other conditions, and a higher degree of risk may be
acceptable.

We also believe that the recommendations included in the reports of the
CIOMS Working Groups on drug safety have not been fully applied and that
meaningful improvements in drug safety would be possible if these basic
fundamentals were more universally incorporated into practice. We would
strongly encourage FDA to incorporate these provisions into these
guidances.

Regards,

Robert G. Pietrusko, Pharm. D.

Vice President, Worldwide Regulatory Affairs & Pharmacovigilance

**Direct Tel 617 374 7631**

**Facsimile 617 444 2399**

**Email Robert.Pietrusko@mpi.com**

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