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October 13, 2003

Food and Drug Administration

Dockets Management Branch (HFA-305)

5630 Fishers Lane, Room 1061

Rockville, MD 20852

> **Re: Safety Reporting Requirements for Human Drugs and Biological
> Products; Proposed Rule**
>
> **Federal Register/Vol. 68, No. 50/Friday, March 14, 2003/Proposed
> Rules- Docket No. 00N-1484**

**WRITTEN COMMENTS ON THE PROPOSED RULE**

Dear Sir or Madam,

Reference is made to the aforementioned Federal Register notice of March
14, 2003 requesting comments on the Proposed Rule. On behalf of Fujisawa
Healthcare Inc, we wish to provide written comments and questions
regarding the Proposed Rule.

1\. As this Proposed Rule represents an effort by the FDA to harmonize
U.S. safety reporting with international regulations, a key area of
concern that we have as a global company, is whether the Proposed Rule
applies only to U.S. cases. In many instances, the impact on foreign
cases is not specified in the Proposed Rule, and this issue will need to
be clarified in the final rule. Specifically, with respect to medication
errors (III.D.5), information sufficient to consider product
administration changes (III.D.2), and supporting documentation
(III.D.7), do these categories apply to both domestic and foreign cases?
If those apply to both, will supporting documentation need to be
translated into English, and how will various foreign patient privacy
laws be met?

2\. According to the Proposed Rule, expedited reporting would be
applicable when a causal relationship to the drug cannot be ruled out
for a serious unexpected event from a clinical trial (III.A.1). This
means that events considered to be unlikely related to drug could meet
the criteria for expedited reporting. We are concerned about the
interpretation that "reasonable possibility" means that "the
relationship cannot be ruled out." Although this definition is
technically consistent with ICH E2A, it does not agree with the EU
Clinical Trials Directive on ADR reporting. Both of these documents are
based on the premise that "reasonable possibility" is meant to convey
that medical judgment and clinical evidence supports an association with
the drug. In making a causality determination, an investigator and the
Applicant would consider a temporal relationship, a positive dechallenge
or rechallenge, a known pharmacological effect, and other factors such
as concomitant medications, concurrent illness, or relevant medical
history. If Applicants were forced to use the FDA's proposed definition
for clinical trials, it would result in the reporting of almost every
serious unexpected adverse event, since a relationship can rarely be
completely ruled out.

> A consequence of such an interpretation would be a significant
> increase in the number of IND Safety Reports submitted to FDA,
> investigators and IRBs. This would also cause an inconsistency in the
> numbers of cases reported to other health authorities. This increase
> in reporting in the U.S. would also make it more difficult to detect a
> true safety signal and accurate risk assessment.

3\. Another area of concern is the category of "Always Expedited"
reports. We believe that the Proposed Rule indicates that "always
expedited" reports are to be submitted only for post-marketing reports.
It is also our understanding that this proposed category represents
adverse events, not an underlying disease. However, it seems
unreasonable and of little value to submit expedited reports for
expected SADRs, which are already described in product labeling. These
types of cases are currently reported to FDA in periodic submissions.
Also, it is not clear if this category will apply to both nonserious and
serious cases of the identified events. This point will need to be
clarified if this category of events is incorporated in a final rule.
Therefore, we suggest it may be useful to combine the concept of "always
expedited" with "always serious". CIOMS has suggested events that would
be considered as always serious, and we believe this is a better
approach to take in a final rule. Also, the FDA is proposing to require
use of the latest version of MedDRA in safety reporting (III.F.2). Under
this grouping, what level of MedDRA hierarchy should be used to judge if
an SADR falls into this category? If high level term (HLT) is to be
used, should all preferred terms (PTs) linking to the HLT be the subject
of an Always Expedited report? If this category of events is part of a
final rule, then we suggest that FDA provide the list in MedDRA terms to
allow applicants to more easily identify these specific events.

4\. Regarding medication errors, we certainly recognize the importance
of monitoring medication errors in an attempt to understand and prevent
them (III.D.5). However, requiring "potential" medication errors to be
captured and reported as expedited reports is excessive. This proposed
requirement would be extremely demanding. Potential medication errors
should be covered under the medication error program rather than safety
reporting requirements. There are many practical questions regarding
potential medication errors. As the FDA acknowledges, potential
medication errors do not involve a patient. Therefore, it contradicts
the minimum data set requirements described under Section III.A..5.
Minimum Data Set and Full Data Set for an Individual Case Safety Report.
Because potential medical errors are theoretical or hypothetical, it
would be difficult to assess the possibility or impact. Under the
existing medication error program, potential medication errors could be
examined, or further information obtained through pharmacy surveys and
then final assessment could be made. If however, this proposal is
incorporated into a final rule, it would be reasonable to allow an
Applicant to collect only minimal data on actual medication errors and
allow the Agency's current system for medication errors to obtain
additional details as needed and to track potential medication errors.

5\. The proposed category of "Information sufficient to consider product
administration changes" is also troublesome (III.D.2). Further
clarification is needed regarding this proposed requirement. The kind of
*in vitro* studies that would fall into this category need to be
specified. Also, the proposed requirement to submit expedited IND safety
reports when the information is sufficient to consider changes in either
product administration or in the overall conduct of a clinical
investigation is extremely vague. Furthermore, many of these
considerations already take place as part of routine development
programs and safety surveillance activities, and are monitored
accordingly by the Applicant.

6\. The proposed requirement for active query by a healthcare
professional may be too restrictive (III.C.5). Does this mean that the
person making contact with the initial reporter must be a licensed
healthcare professional, such as a physician, pharmacist or nurse, or
can the person be a qualified employee that has received internal
training in this area? Does a person with a science background qualify?
What effect would this proposal have on foreign safety collection sites?

7\. The definition of contractor is too broad and should be limited to
the extent possible (III.D.9). As currently written, anyone with a
business or licensing arrangement with a company would be considered a
contractor. The proposed definition of contractor also would include
licensing partners. Many companies are involved in many different types
of arrangements (in-licensing, out-licensing, co-promotion,
co-marketing, co-development). Some are more complex than others, and
some involve international companies, while others involve only domestic
companies. Due to the wide range of possible safety reporting
arrangements between Applicants and contractors, the Proposed Rule
should only require that Applicants and contractors have an agreement
that specifies responsibilities for safety reporting. The FDA should
also provide a clear definition of contractor and specify which types of
companies and institutions are considered as contractors.

8\. The Proposed Rule requires that each event be coded with the
appropriate preferred term (PT) in the latest version of MedDRA
(III.F.2). As the FDA knows, it is extremely difficult for companies to
constantly upgrade to the latest version of MedDRA. In fact, it may even
be very difficult for the FDA to consistently implement the use of the
latest version of MedDRA internally. Each upgrade requires reviewing the
content of the new version, recoding terms, validating coding, and
updating local documents to reflect the upgrade. This process is very
labor intensive and can be more time consuming for larger companies with
many drug products. Applicants will require a reasonable time period for
implementing MedDRA version upgrades and will require extensive guidance
from FDA on how to handle updating legacy cases, clinical trial
databases, package inserts and company core safety information to
reflect the use of MedDRA.

9\. Regarding the company core data sheet (CCDS), the Proposed Rule
requires that a copy of the CCDS be provided with the periodic safety
update report (PSUR) (III.E.2.k.i). According to section III.A.9, the
purpose for the CCDS is to provide the company core safety information
(CCSI) for the PSUR. Therefore, it is reasonable to require Applicants
to provide only the CCSI for a PSUR and not the CCDS. Also of major
concern is the requirement for additional appendices for a PSUR. This
proposed requirement would lead the FDA regulations away from
international harmonization, because it is not consistent with ICH. It
does not promote standardization of worldwide regulations, and it adds
confusion and extra work for U.S. Applicants. Furthermore, the proposed
additional requirements for reports such as transitional periodic safety
reports (TSUR) and interim periodic safety reports (IPSR) with very
complex timeframes for reporting will only add to the workload and
complicate the reporting process. We suggest that the FDA take into
consideration ICH E2C addendum when revising this section.

10\. A point requiring reconsideration and clarification is the
requirement for the submission of scientific literature (III.D.8).
Currently, the regulations require that expedited reports based on
information from the scientific literature be accompanied by a copy of
the published article. These regulations apply only to reports found in
scientific and medical journals either as case reports or as the result
of a formal clinical trial. The Proposed Rule would amend the current
regulations by removing the phrase "either as case reports or as the
result of a formal clinical trial" to require that all reports from the
scientific literature, including case reports and results of a formal
clinical trial, epidemiological study, in vitro study, or animal study
qualify for expedited reporting. This proposed change would dramatically
increase the workload and would result in an abundance of reporting of
useless information with little clinical meaning. The scientific
literature is full of articles that discuss possible side effects often
times without any clinical significance, causal relationship, or
identified patients. Also, the scientific literature contains massive
numbers of retrospective reviews of data that discuss adverse events in
patients, but don't necessarily provide individual patient identifiers
and patient-specific information. The FDA will need to provide detailed
guidance on how to handle these types of articles if this provision is
incorporated into a final rule.

11\. Also of concern is the proposed category of Unexpected SADRs with
Unknown Outcome (II.B.3.b). This category would result in many reports
being submitted as expedited reports unnecessarily. When an event is
reported with an unknown outcome, additional information often indicates
that the event is nonserious. In the case where the additional
information identifies the event as being one that is serious, then an
expedited report is warranted. We believe that the initial preliminary
reporting of an event with an unknown outcome will overburden the
Applicant and the FDA with unnecessary reports. We feel that the better
solution is to allow for additional information to be obtained in order
to make a determination of the exact classification of an event, and we
believe the current definition of serious already accommodates this
mechanism. We also support the use of medical judgment as an important
component of decision making regarding serious versus non-serious. By
allowing this proposed category into the regulations, the FDA will be
reducing the need for medical input in the review of adverse event
reports. Also, this new category with its new follow-up timeframe will
contribute to confusion in tracking follow-up reporting timelines.

12\. The Proposed Rule requires that a licensed physician at the company
be responsible for the content of post-marketing safety reports
submitted to the FDA (II.B.2). Further, the Proposed Rule indicates that
it is unacceptable to have clerical personnel with no healthcare
training prepare and submit reports. We believe it is reasonable to have
a physician responsible for the content of post-marketing safety
reports; however, we question the need for this person to have a U.S.
license. The FDA will need to clarify what is meant by "licensed"
physician. Does the physician have to have a U.S. license or can he/she
have a license from a foreign country? Is it sufficient to have a
medical doctorate degree without completing a U.S. residency? We are
also concerned about the proposed requirement to have the name of the
licensed physician responsible for the content and medical
interpretation of the data provided in each individual report. For most
large companies, especially global companies, this is logistically
difficult. It is not uncommon for different physicians to review the
initial and subsequent follow-up reports. The FDA will need to provide
guidance on how this is to be handled if this provision is incorporated
into a final rule. Also, we see no problem with trained clerical
personnel handling the paperwork, preparing the transmittal letter and
mailing to the FDA once appropriate review by a physician has occurred.

13\. Please clarify Section III.B.4 IND, Safety Reporting for Drugs
Marketed in the United States. In the second paragraph it states, \"A
sponsor of a clinical study under an IND for a drug marketed in the
United States\... The sponsor must also submit to FDA safety information
from these clinical studies as prescribed by the postmarketing safety
reporting requirements under 310.305, 314.80, and 600.80 of this
chapter.\" This statement directs the Applicant to the postmarketing
reporting safety requirements, but there is no specific mention of
foreign studies under postmarketing safety reporting requirements. We
request the FDA clarify the requirements under 310.305, 314.80, and
600.80.

14\. Our final comment is regarding Section III.J. Postmarketing
Approved New Drug Application (NDA) and Biologics License Application
(BLA) Annual Reports. The FDA's proposal to remove this requirement is
most welcome. This proposal will avoid duplication and make safety
reporting more efficient.

In conclusion, we are supportive of the FDA's efforts to harmonize the
U.S. safety reporting with international regulations, increase worldwide
consistency, and promote quality and a risk-based approach with greater
emphasis on serious events. We also fully support the position of PhRMA
with regards to this Proposed Rule and are in concurrence with PhRMA's
comments provided to the FDA regarding this Proposed Rule. We encourage
the FDA to consider our comments, as well as those from PhRMA and other
industry representatives and to provide additional clarification and
specific guidance when a final rule is issued.

Sincerely,

Denice L. Simon, R.Ph., J.D.

Director, Regulatory Affairs and Safety