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Biotechnology Industry Organization

1225 Eye Street NW, Suite 400

Washington, D.C. 20006

Dockets Management Branch (HFA-305)

Food and Drug Administration

# 5630 Fishers Lane, Rm. 1061

Rockville, Maryland 20852

Re: Docket No. 00N-1484, Federal Register: March 14, 2003 (Volume 68,
Number 50, Pages 12406-12497)

Dear Sir/Madam:

The following comments are provided by the Biotechnology Industry
Organization (BIO). BIO represents more than 1,000 biotechnology
companies, academic institutions, state biotechnology centers, and
related organizations in all 50 U.S. states and 33 other nations. BIO
members are involved in the research and development of health-care,
agricultural, industrial, and environmental biotechnology products. BIO
appreciates the opportunity to comment on the Food and Drug
Administration's (FDA's) Proposed Rule for *Safety Reporting
Requirements for Human Drug and Biological Products*.

**General Comments**

BIO agrees with FDA's goal of reducing or eliminating duplicative or
redundant safety-reporting requirements in New Drug Application (NDA)
and Biologics License Application (BLA) annual reports and with the
agency's intent to reduce disparities between requirements in the United
States and those in other developed nations of the world, in accord with
the goals of the International Conference on Harmonization (ICH). In
that regard, we applaud efforts to ensure consistency between FDA
requirements and definitions and those of other federal agencies such as
the National Institutes of Health (NIH), as well as those included in
the ICH E2C Guideline and Addendum (we particularly note FDA's
endorsement of the data lock point and International Birth Date (IBD) in
ICH E2C) and to adopt MedDRA terminology related to medical terms in
clinical safety. We also support requiring only a minimum data set for
all non-serious suspected adverse drug reactions and eliminating the
requirement for expediting reporting of cases from Class Action
lawsuits.

While BIO shares FDA's purpose of ensuring the highest quality of safety
reporting, in the interest of maintaining and improving public health,
we believe the net effect of the agency's proposals will increase the
cost and complexity of safety reporting for regulated industry without a
commensurate benefit to the public health. In key areas, FDA's proposals
appear inconsistent with the agency's forward-thinking approaches rooted
in science-based risk analysis and management and, rather than
streamlining safety reporting to ensure its usefulness, will complicate
and slow the process. We further are concerned that in several areas
FDA's proposals will result in the U.S. having requirements and
definitions that differ in fundamental ways from those of ICH and the
Council for International Organizations of Medical Sciences (CIOMS),
thus thwarting the objective of international harmonization.

The proposed rule requests comments on whether the agency should
implement the recommendations contained in the Addendum to ICH E2C. We
strongly endorse the adoption of the E2C Addendum, in its entirety, as
well as full adoption of the ICH E2C Guideline. Full adoption of the ICH
E2C Guideline is essential for true global harmonization. However, we
believe that global harmonization will not be achieved if the final rule
requires extensive new additions and appendices to the Periodic Safety
Update Reports (PSUR), as well as preparation of additional periodic
reports at slightly different time intervals and with different format
and content than required in other regulatory jurisdictions. We believe
these requirements will lead to apparent data discrepancies and
variances in interpretation of the data. Indeed, this would likely lead
to certain inconsistencies in the information provided to different
regulators, and resources required for the preparation of these reports
would not be available for other pharmacovigilance activities.

BIO enthusiastically endorses FDA's approach of working with
stakeholders to ensure that its safety reporting requirements
appropriately harmonize with those of international regulatory bodies
and, importantly, are in the best interest of consumers. We look forward
to a continuing dialogue with the agency to achieve this goal.

BIO is particularly concerned about the agency's assumptions and
conclusions regarding the financial impact of these proposals on the
regulated industry. The agency assumes, for example, that industry will
realize substantial savings (nearly \$40 million annually beginning in
year 4; shown in Table 12) from implementing the requirements of the
proposal. We question both the source of these numbers and the
assumptions on which the bottom line is based, including the assumption
of substantial savings from efficiencies in database management. We
estimate, to the contrary, that industry will need to establish and
maintain entirely separate databases to continue to comply with existing
global requirements and to comply with the new FDA requirements. We also
believe the estimated cost of additional and/or specialized personnel is
both seriously under-estimated and based on a flawed assumption that
personnel costs, including costs of medical professionals, can be
measured accurately by calculating a per-hour compensation (as shown in
Table 16). Therefore, BIO recommends that the agency, working with
industry, re-estimate these costs and, based on an improved and more
accurate estimate, re-propose the rule.

**Specific Comments**

**II. B. 2. Quality of** **Postmarketing Safety Reports**

BIO agrees that surveillance depends on the quality of adverse event
reports. We believe FDA can ensure quality by requiring that the
physician responsible for the content of adverse event reports be a
graduate of an accredited medical training program. BIO suggests that
the agency remove the additional requirement for licensure because it is
logistically more complex and adds little to the requirement for
certified medical training.

**III. A. 1. Suspected Adverse Drug Reaction**

BIO agrees that international consistency is appropriate and desirable,
but is concerned that neither the acronym SADR nor the definition
proposed is consistent with ICH E2A guidance. For example, there is
ambiguity as to whether the abbreviation SADR is to be taken to mean
"serious," as opposed to "suspected," adverse drug reaction. We believe
the discordance between the proposed definition and the ICH definition
may create confusion that would complicate maintenance of exemplary
compliance. However, BIO recognizes the merits of FDA's proposal to make
explicit the uncertainty inherent in causality assessment for individual
case reports. We recommend that the FDA work with ICH to resolve this
discrepancy.

The ICH E2A guidance defines "adverse drug reaction" as "all noxious and
unintended responses to a medicinal product related to any dose." The
phrase "response to medicinal products" means that a causal relationship
between a medicinal product and an adverse event is at least a
reasonable possibility, i.e., "the relationship cannot be ruled out."

Further, the EU Clinical Trial Directive Final Guidance on Adverse
Events (AEs) \[section 6.2.2 Assessment of Causality, April 2003\]
states "causality shall be determined according to the definition of an
adverse reaction as given in Article 2 of the Directive 2001/20/EC . . .
All adverse events judged by either the investigator or the sponsor as
having a reasonable suspected causal relationship to an investigational
medicinal product qualify as adverse reactions." In the spirit of global
harmonization, we recommend that FDA note that the international
definitions stress "reasonable" and "suspected" in their definition of
causal relationship. While perhaps technically consistent with ICH E2A,
we believe FDA's proposed approach does not incorporate all of the
concepts in that document or in the EU Clinical Trials Directive. In
particular, for example, the approach proposed by FDA does not include
the clearly delineated concept of "reasonable causal relationship,"
which prompts an assessment of actual evidence or arguments to support
causality.

In a number of sections of the proposed rule, the agency defines
"reasonable possibility" as synonymous with "the relationship cannot be
ruled out." Thus, a causal relationship becomes the default assessment,
not only for spontaneous adverse experience reports, but also for
clinical trials and other organized data collections. We believe that,
should this emphasis remain in the final published rule, sponsors and
investigators participating in premarketing and postmarketing clinical
trials necessarily, interpreting \"the relationship cannot be ruled
out\" strictly, will report virtually every event, as nothing can ever
be completely ruled out. BIO believes this curtailing of clinical
judgment in assessment of causality would result in a substantial
increase in the volume of expedited reports (if the relationship to
study medication "cannot be ruled out" in clinical trial cases, we
calculate that the number of Investigational New Drug Application (IND)
safety reports will increase by 10- to 12-fold) and could also have an
adverse impact on the integrity of studies, given the need to break the
blind on an increased number of serious, unexpected, potentially related
events. In studies of serious chronic diseases such as cancer and AIDS,
it is not at all uncommon for most patients to have at least one serious
adverse event. The impact of breaking the blind for all study therapy
would reduce expected aggregate time-on-treatment in clinical trials and
have a negative impact on the efficiency of clinical trials (a larger
sample size would be needed to produce the required statistical power),
without a corresponding reduction of risk to study subjects. Indeed, it
would be difficult to estimate an appropriate sample size at the outset
of a Phase III clinical trial, when the "losses" due to breaking the
randomization code would be unknown.

Since the power of many trials depends less on total sample size than it
does on the expected number of outcome events, there will be a
significant risk of reducing power below nominal levels (particularly in
trials with failure-time endpoints). More importantly, knowledge of
treatment (including the post-treatment observation period) introduces
potential bias that could undermine interpretation of the
efficacy/effectiveness analysis (the potential for bias alone can
undermine a trial let alone confirmation of bias).

 

This risk (bias and power-reduction) may be difficult to measure during
the trial, let alone anticipate in the design stage. If the proposal is
implemented, we believe it will place a significant burden on both the
agency and companies to negotiate and manage exemptions to expedited
reporting and necessitate the creation of an FDA structure and process
around these negotiations to ensure consistency across products.

FDA invited comment on alternative ways to handle serious suspected
adverse drug reactions that occur during clinical studies to minimize
"over-reporting." While there may be certain clinical situations in
which it would be appropriate for FDA and companies to consider
alternative reporting methods for specific suspected adverse drug
reactions (e.g., progression of a disease under clinical trials in
HIV/AIDS, oncology, or specific cardiovascular endpoints for specific
protocols for which there is an independent safety data monitoring
board), we remain concerned that such "alternative reporting" would not
have the intended effect of reducing over-reporting and could exacerbate
the previously mentioned problems with the definition "cannot be ruled
out."

Absent other mechanisms for dealing with over-reporting, companies
routinely will seek alternatives to unblinding and expedited reporting.
BIO believes that negotiation of alternatives that are comprehensive
enough to protect study integrity will be difficult and
resource-intensive because the spirit of the proposed reporting is
antithetical to sufficiently restrictive alternatives. We believe the
FDA does not have the resources needed to deal with this eventuality.

However, if the agency, notwithstanding these concerns, decides to move
forward with the use of alternative ways to handle serious suspected
adverse drug reactions from clinical studies to "minimize
over-reporting," we recommend that any such approaches only be
considered in late stage development (Phase III and IV studies).

BIO also is concerned about the potential effect of this proposal on
signal identification and ultimately on drug labeling. Certainly the
rule change will result in many more adverse events being considered
"drug-related." We believe that, without the investigator being advised
to use reason and best medical judgment in determining causality, many
events will be listed as "drug-related" even though the likelihood of a
true causal relationship is minimal. We therefore are concerned that
should many of these events \-- where the causal relationship is
unproven or, at best, tenuous \-- find their way into the product
labeling, this could result in a significant and detrimental effect on
the utility of the labeling information and potentially of the product
itself. The consequence of expediting numerous reports would be to
obscure potential signals. Institutional Review Boards (IRBs), already
facing difficulties, would be faced with an order of magnitude increase
in the number of expedited reports they receive. Since only "active"
treatment cases would be unblinded and expedited, these would be
virtually uninterpretable but may raise concerns and introduce delay
without improving risk assessment.

We strongly recommend the FDA reconsider this proposed change and not
define "reasonable possibility" as meaning "the relationship cannot be
ruled out." We believe the ICH definition of "reasonable causal
relationship," i.e., "...there are facts (evidence) or arguments to
suggest a causal relationship" is more appropriate. The essence of the
ICH definition has been implemented successfully in the European
Directive on Good Clinical Practices (GCP) in Clinical Trials
(2001/20/EC) and specifically in the final wording of the "detailed
guidance on the collection, verification and presentation of adverse
reaction reports arising from clinical trials on medicinal products for
human use" (Annex 1, page 12) which states "The expression reasonable
causal relationship means to convey in general that there is evidence or
argument to suggest a causal relationship." We suggest that this is a
more appropriate choice than the definition "the relationship cannot be
ruled out."

The implications of "the relationship to product cannot be ruled out"
for IND safety can be summarized as threefold:

-   *increased number of IND Safety Reports*: as noted above, BIO
    believes there will be a significant increase in expedited reports
    because of the proposed change in the definition of causality. Since
    it is rarely feasible to "rule out" the possibility that an exposure
    contributed to a specific event, the overwhelming majority of events
    will be classified as related. Companies following CIOMS III/V will
    base expectedness on Developmental Core Safety Information (DCSI),
    as it is reflected in the Reference Document for the trial.
    Accordingly, they will classify reports as unexpected until the
    threshold for adding the event to the DCSI is crossed and continue
    to expedite those events that are serious and possibly related. As
    such, the majority of serious suspected adverse drug events in IND
    studies will be unexpected and possibly related, even in large phase
    III studies.

-   *excessive unblinding in IND studies*: as noted, the majority of
    events in IND studies will be subject to expediting under the new
    rule. In addition, the rule retains the existing requirement to
    unblind serious unexpected SADRs prior to expediting. In
    combination, the requirement to unblind and the "cannot rule out"
    clause will cause excessive unblinding in many programs. This is
    particularly true for studies of longer duration, indications
    associated with significant morbidity and studies of less common
    outcomes. It will increase sample size requirements and the risk of
    under-powering studies, as well as threaten conclusions by raising
    the specter of co-intervention and ascertainment bias.

> FDA acknowledges the risk of over-reporting in section III.A.1.
> However, BIO is concerned that the list of diseases and events that
> will lead to over-reporting is much longer than the FDA anticipates.
> The extent and impact of unblinding will be difficult to predict in
> the design stage. Companies will go out of their way to ensure that
> they minimize the chance of running uninformative studies. This
> frequently will lead to iterative negotiations with the FDA, tax
> agency resources, and result in long lists of proposed reporting
> exclusions. We believe that in the end, it will create significantly
> more work, to gain little incremental information that may get lost in
> the attendant information overload.

-   *IRB/investigator information overload resulting from
    over-reporting*: Investigators and IRBs have stressed the difficulty
    they have interpreting the significance of Individual Case Safety
    Reports (ICSR). There is no reason to believe that the
    signal-to-noise ratio will improve with increased IND safety
    reporting. As such, the proposal will increase the volume of
    potentially confusing reports that are distributed to investigators
    and IRBs. Absent a better framework for investigator/IRB
    interpretation of IND Safety Reports, it will exacerbate
    investigator/IRB information overload and divert site resources from
    the task of reliably reporting high-quality safety information to
    sponsors.

> BIO recommends elimination of this proposal. However, if the proposal
> is implemented, alternatives to extensive expediting and unblinding
> will be required in blinded studies. There is no single alternative
> that mitigates BIO's concern about the risk to study integrity that
> this proposal represents. Some possibilities that might be considered,
> with analysis of their potential viability, include:
>
> [Expediting blinded safety reports]{.underline} -- We do not believe
> this is a good alternative, as it results in confusion and delays
> decision-making about potential safety issues. Moreover, it is not
> consistent with ICH.

[]{.mark}

> [Expediting a subset of cases that undergo unblinded
> evaluation]{.underline}: this would involve a two-pronged approach.
> First, restrict expedited reporting/unblinding to unexpected cases for
> which there is a reasonable possibility of a relationship to the study
> drug (based on the current definition of reasonable possibility; i.e.,
> that there are facts, evidence, or arguments to suggest a causal
> relationship). Second, use a small internal or external safety
> committee to monitor adverse events, by treatment arm (without
> knowledge of the actual treatment assignment). The exact makeup and
> function of the committee would require delineation; however, a small
> group of professionals who are not in a position to influence the
> outcome of the trial potentially could monitor evolving treatment arm
> imbalances and use a priori guidelines to inform the agency and
> investigators of noteworthy safety findings. The approach would permit
> ongoing safety analysis, without interfering with efficient trial
> management or the validity of study conclusions. While too cumbersome
> to use in all blinded studies, such an approach, when feasible, could
> be relatively efficient and protect study validity. For the sponsor,
> the approach could reduce the burden of over-reporting and eliminate
> power and bias issues. For FDA, it could reduce resources needed for
> data management and analysis and increase the likelihood of obtaining
> timely synthesis of potential safety issues. For the investigator, it
> could reduce information overload. In addition, it could provide an
> opportunity to increase the uniformity of ongoing safety evaluation in
> clinical trials.
>
> [Increase the scope of reporting to FDA and leave the scope of
> reporting to investigators unchanged]{.underline}: this alternative
> also could limit expedited reporting/unblinding to unexpected cases
> for which there is a reasonable possibility of a relationship to the
> study drug (based on the current definition of reasonable possibility;
> i.e., that there are facts, evidence, or arguments to suggest a causal
> relationship). In addition, it could allow for blinded expedited
> reporting of a broader range of cases to the agency only.
>
> We believe this approach could reduce investigator information
> overload, as well as ensure that the agency receives a more complete
> picture of the developing safety profile, albeit blinded, in a timely
> manner.

**III.A.2. A Life-Threatening SADR**

BIO agrees with the FDA proposal concerning life-threatening suspected
adverse drug events, as it applies to pre-approval safety. However, we
note that it will be difficult to obtain the investigator's view
consistently, when (s)he does not feel the event is life- threatening.
We believe sponsors should not be required to report the investigator's
reasons for classifying an event as non-life-threatening, when the
sponsor deems the event to be life-threatening.

**III. A. 4. Contractor**

BIO believes that, given the array of possible safety reporting
arrangements between "contractors" and "applicants," the rule should not
mandate that the applicant is always responsible for safety reporting.
However, recognizing the importance of this responsibility, the final
rule might suggest that applicants and contractors are responsible for
an agreement that specifies responsibilities for safety reporting. In
this regard, we note that draft ICH E2D guidance language may be useful:
"When companies co-develop, co-market, or co-promote products, it is
considered very important that explicit contractual agreements specify
the processes for exchange of safety information, including timelines
and regulatory reporting responsibilities."

There are certain situations where the applicant (e.g., NDA or license
holder) is a small company and the contractor is the large company. In
such a situation, the applicant and contractor often have detailed
written agreements whereby the contractor is responsible for safety
reporting. Indeed, many such agreements are already in place. BIO
suggests (1) that the rule take account of the large variability in
contractual arrangements, under some of which it would not be workable
for the applicant to be required to be the reporter and (2) that any
regulatory changes apply only prospectively, since various business
partners already have a wide range of safety reporting agreements in
place.

**III. A. 6. Active Query**

Under the proposal, FDA would amend its postmarketing safety reporting
regulations and define the term "active query" to mean direct verbal
contact ... with the initial reporter of a suspected adverse drug
reaction or medication error by a health care professional representing
the manufacturer (applicant). The proposal would mandate such active
query in a number of situations, based on FDA's belief that that in many
cases, use of active query during initial contact with these reporters
would provide manufacturers and applicants with adequate safety
information and could eliminate or decrease follow-up time expended.

However, in the postmarket setting, health care professionals are not
required to call the manufacturer to report an adverse event. It is
purely a voluntary system. In most instances, when a health care
provider contacts a manufacturer/applicant, (s)he is calling to gather
information. Most seem unaware of the need to provide any information
regarding an event/suspected event to the manufacturer, much less the
FDA. For this reason, health care professionals rarely have
comprehensive patient information available at the time they contact the
manufacturer. Health care professionals also have concerns about
liability and patient privacy, questioning, for example, whether they
should provide information to a third party without the patient's
express consent. For this and other reasons, we believe active query
will be difficult. Mandatory active query will be particularly
challenging with foreign-U.S. situations, as data privacy laws may act
to inhibit such activities and their transborder exchange.

Further, BIO believes direct query could pose an enormous burden on the
health care professional. Health care professionals are busy with
patient management during daytime hours and prefer not to be contacted
at those times when their primary concern is patient care. Many health
care professionals request communication from the applicant/manufacturer
via fax or by mail rather than by phone. Written communication allows
health care professionals or their staffs the freedom to collect the
required information and respond to manufacturer's queries as time
allows. BIO believes that to pursue direct verbal contact repeatedly to
obtain additional information could strain any working relationship
between the health care professionals and/or their staffs and the
applicant/manufacturer. Ultimately, the health care professional could
refuse any communication with the manufacturer/applicant, which would
decrease the amount of reporting overall.

When consumers contact manufacturers/applicants, they generally provide
as much information as they have available during the initial contact.
They can, however, be distraught regarding their diagnosis, treatment,
and/or the event, and refuse to give any substantial information
concerning the event. They can be reluctant to provide information
regarding their health care providers. They do not want the
manufacturer/applicant to "bother" their physicians. Or perhaps they
have not contacted their physicians for whatever problems they are
reporting. If the consumer works, (s)he is not available during the
workday hours.

While BIO agrees that information received via direct verbal contact is
valuable, we believe written follow-up, especially medical records, can
be more accurate. We recommend active query be focused on cases where
specific information from the health care professional is required to
clarify important elements in case characterization. If active query is
used excessively, we believe it could discourage voluntary reporting.
Years of experience in data collection in the postmarket setting suggest
that there is no single "best" means of communication with consumers and
health care professionals.

BIO suggests, in the spirit of an efficient application of resources,
that the focus of any active query (that is, a particular line of
questioning designed to capture clinically relevant information
associated with the drug product), as a possible tool among many to gain
full information, be concentrated on follow-up of selected adverse
events (expected and unexpected) for those products for which a sponsor
and the agency, as well as other regulatory authorities, have formulated
Risk Management Programs as the approach to manage safety-related risks
for a product through its life cycle, from first in human studies to
product senescence. Applicants/manufacturers strive to provide full data
sets on such serious and non-serious suspected adverse drug reactions
and thereby improve the quality of the ICSR for all stakeholders. This
also facilitates analysis of such reports when reviewed in an aggregate
setting. It would be desirable that the final rule specify that the
intention is to apply the term "full data set" to the existing 3500A
form and not to the data elements specified in the ICH E2B(M) Guideline.
Certain other clinical events on older products (i.e., those more than 5
years old), such as "Death, Cause Unknown" reports or sudden death in a
young patient, or reporting of an unlisted Drug Interaction, and certain
serious unexpected events, may also meet criteria for active query
follow-up.

The concept of active query already exists, both in the context of
clinical trials and spontaneous cases. However, if active query beyond
the follow-up that currently exists is contemplated in the final rule,
BIO believes there may be an undesired impact on the human and financial
resources that must be applied to these activities.

We disagree that a sponsor may have difficulty in making an initial
determination of "serious" or "non-serious" criteria regardless of
outcome. Much of the decision making regarding "serious" and
"non-serious" decisions was dealt with in the final regulations on
important medical events. In the rare instance (less than 1% of cases)
that an initial determination of "serious" or "non-serious" cannot be
made, we suggest that the default in such a setting would be to process
the report as "serious." The sponsor then would employ a variety of
mechanisms, which could include active query, to obtain the needed
information.

BIO also believes that submission of an autopsy report, hospital
discharge summary, or death certificate for reports of death and
hospitalization should not be required in the final rule. This may
infringe on or breach mandates of the Health Insurance Portability and
Accountability Act (HIPAA) and raise other confidentiality issues
regarding both U.S. and foreign data. Further, clarification as to the
ability to meet this requirement within electronic reporting capability
is requested. As we strive for quality data, we believe it should be up
to the applicant to have appropriate processes in place to obtain source
documentation and to analyze it, as necessary, to complete a case. In
most cases, applicants include the relevant information in the 3500A
form. BIO believes separate, systematic submission of such documentation
to the agency is not necessary and would create an enormous burden for
FDA. In cases where the information has been supplied to the applicant,
it could be provided to FDA to fulfill a specific need upon request.

We also note that the definition of health care professional differs
from that used in the EU. This means that it would be impossible to have
the same listings of health care professional cases in the various ICH
regions, if this requirement remains as currently proposed.

**III. A. 7. Spontaneous Reports**

BIO appreciates the agency's clarification that spontaneous reports do
not include cases identified from information solicited by the applicant
or contractor, such as individual case reports of findings derived from
a study, company-sponsored patient support program, patient registries,
etc. However, we are concerned about the definition that a spontaneous
report always must be assumed to indicate a reasonable possibility of
causality. In the context of medical information queries and other
contact with health professionals, particularly in the case of chronic
drug treatments for life-threatening illnesses (e.g., enzyme replacement
therapy), it is not uncommon for sponsors to identify an "adverse event
case report," although the reporting health professional unequivocally
states that in his/her professional opinion there is no reasonable
possibility that the drug product caused the event. In such cases, it
would seem that FDA's proposal would result in reporting that runs
contrary to the considered medical judgment of the health professional.

**III. A. 8. Medication Error**

BIO is very concerned with FDA's proposed way to handle medication
errors. We suggest that a differentiation be made between clinical
trials, in which setting this provision is unnecessary, and spontaneous
sources. We believe that non-prescription products should be considered
separately because medications that have been approved for over the
counter use generally have a broader therapeutic index and higher safety
margin than most prescription medications. Further, many reported cases
of medication errors either result in no adverse event(s) or in
events(s) that are non-serious and self-limiting. (Although product
defects that cause adverse events should be appropriately reported.) We
also suggest that before imposing requirements for reporting medication
errors, FDA reach an international consensus on how to address this
issue on a global basis; ICH is best equipped to spearhead this effort.

According to the Institute for Safe Medication Practices, there are four
potential causes of medication error: (1) failed communication
(handwriting or oral communication, drugs with similar names or
packaging, missing or misplaced zeros and decimal points, confusion
between metric and apothecary systems of measure, use of non-standard
abbreviations, or ambiguous or incomplete orders); (2) poor distribution
practices; (3) complex or poorly designed technology; and (4) access to
drugs by non-pharmacy personnel. As many of these causes reach far
beyond control of the pharmaceutical industry, there must be greater
emphasis on individuals and settings directly associated with dispensing
medications. In addition, when patients are responsible for
self-administration, i.e. prescription or non-prescription products
taken in an outpatient setting, we believe that efforts to engage
pharmacies, healthcare professionals, and patients would be a more
direct means to prevent or reduce medication errors.

The agency proposes to define medication error as "any preventable event
that may cause or lead to inappropriate medication use or patient harm
while the medication is in the control of the health care professional,
patient, or consumer. Such events may be related to professional
practice, health care products, procedures, and systems including:
prescribing, order communication, product labeling, packaging, and
nomenclature, compounding, dispensing, distribution, administration,
education, monitoring, and use."

The proposal also has additional separable definitions for medication
errors. An actual medication error is one that involves a patient,
whether or not the product was administered. A potential medication
error is actually a product complaint, referring to the product name,
labeling, or similarities in product packaging that could result in a
medication error in the future, but does not involve a patient.

BIO recommends the agency develop one definition for the term
"medication error." As the definition is written now, it could be
interpreted as meaning that the agency is requiring industry to monitor
prescribing practices of physicians, dispensing practices of
pharmacists, and use/compliance of the patient taking the product.

FDA proposes to require that each domestic report of an actual
medication error be submitted as an expedited report, whether a
suspected adverse drug reaction has occurred or not; the minimum data
set would be required to be reported as an expedited report.

Most medication errors are related to the practice and dispensing of
medication. If a medication error is made by a health care provider, the
provider should be responsible for reporting it. The agency should be
informed of medication errors, but the justification to expedite these
reports is unclear. BIO recommends changes in the proposal to require
that expedited reports be submitted if the medication error was reported
because of a misunderstanding of the product name or labeling or package
instructions and to require that medication error reports received by
the sponsor that currently are not subject to expedited reporting
requirements (serious and unlabeled reactions) be reported and discussed
in the aggregate in the next periodic report.

In general, BIO believes that a significant portion of the proposal on
medication errors is unnecessary in that much of it duplicates and
carries over from the agency's proposed *Bar Code Label Requirements for
Human Drug Products and Blood*. Much of the current proposal would deal
with post-manufacturer concerns (e.g., mis-communication by a health
care professional, etc.) that will be addressed with the implementation
of the Bar Code rule. We suggest a considerable portion of this proposal
be eliminated, thus focusing it strictly on those matters that will not
be dealt with under the Bar Code rule.

**III. A. 10. Data Lock Point and International Birth Date**

We agree with the proposal to use data lock point and International
Birth Date to define reporting period of postmarketing periodic safety
reports. This is consistent with ICH E2C. However, we seek clarification
as to why the reporting period as defined per IBD would preclude a
company from changing the periodicity of a report prior to what would be
dictated by the U.S. approval. We recommend the revised wording state
that the IBD should be utilized for determination of the periodicity
globally. We believe alternative reporting should be considered only in
rare instances. BIO suggests the final rule allow for discussion and
agreement with FDA on a case-by-case basis.

**III.B.2.a. Minimum data set**

FDA proposes to amend § 312.32(c) to state that sponsors must not submit
an IND safety report for a suspected adverse drug event if the report
does not contain a minimum data set (i.e., identifiable patient,
identifiable reporter, suspect drug or biological product, and suspected
adverse drug event). BIO requests clarification regarding the meaning of
"identifiable." In at least one public discussion of the proposed rule,
the agency's representative appeared to suggest that the potential for
contacting an individual is central to the notion of identifiableness.
However, this is inconsistent with the lower threshold for
"identifiable" used by many companies, as well as guidance provided by
some regulators. The latter interpretation holds that an individual is
identifiable if the available information pertains to a specific
individual and does not depend on the potential to establish contact
with that individual; e.g., a patient is identifiable if age or gender
is available. Clearly, age and gender alone do not permit establishing
contact.

**III.B.2.b. Serious and unexpected SADRs**

BIO sees value in requiring that sponsors expedite serious and
unexpected suspected adverse drug events, if either the investigator or
the sponsor determines there is reasonable possibility that an event is
attributable to an investigational drug or biologic.

BIO agrees with FDA's proposal to require that companies maintain
records delineating due diligence in investigating outcome and
expectedness. However, requiring inclusion of this information in IND
safety reports will not clarify the safety profile and will tax
resources that would be applied to doing so. While the minimum dataset
proposal is consistent with the ICH E2A guidance (60 FR 11284 at 11286),
the need to report due diligence efforts, on an expedited basis, is not.

**III. C.** **Postmarketing Safety Reporting**

Clarification is needed regarding what constitutes a human subject
significant risk deriving from animal and in vitro studies. These
non-human studies often are done at different dosing regimes, in
specialized models, and, especially in biological products, with other
antibodies than those under development (e.g., murine antibodies perhaps
with slightly different biological activity). We also believe it is
important to clarify when the clock starts with animal and in vitro
studies.

**III. C. 3. Reporting Requirements**

BIO believes that for Traditional Periodic Safety Reports (TPSRs) and
Interim Periodic Safety Reports (IPSRs), reporting cycles of 7.5 and
12.5 years should not be required, as 5 and 10 years post-approval
should provide an adequate safety profile. If this recommendation is
retained, consideration should be given, in line with ICH E2C, to
require reports at these time periods only if there has been a new
indication/dosage form approved, there is use in new population, or
there has been a prescription status change, such that the safety
profile of the drug is expected to be significantly different.

We also seek a rationale for the use of January 1, 1998, as a
demarcation point for preparation of TPSRs vs. PSURs. It would be
extremely difficult, if not impossible, reliably to identify cases that
should be included in subgroups (e.g., suspected adverse drug reactions
from Class Action lawsuits, medication errors, etc.), as proposed in
TPSR and PSUR/IPSR format. Difficulty in identifying cases for subgroups
retrospectively is primarily a practical matter, owing to the challenges
of retrospective application of coding conventions and necessary changes
in system capabilities.

**III. C. 5. Determination of Outcome, Minimum Data Set, and Full Data
Set**

The proposal would amend current rules to require immediate
determination of the outcome of a suspected drug reaction (whether
serious or not). BIO suggests that the language be changed from
\"determine the outcome" to \"determine the serious nature of the
suspected drug reaction."   We believe it is confusing to use "outcome"
interchangeably with \"seriousness.\"

 

FDA is proposing that, where the needed information is not immediately
available, the sponsor use active query. As noted above, BIO believes
that active query should be reserved for specific situations in which no
other information collecting method is likely to yield adequate results
and should be at the discretion of the sponsor. For example, a report of
poison ivy should not require a telephone call to the physician even if
the \"seriousness\" was not specified in the initial report.

The agency proposes that manufacturers and applicants immediately obtain
data regarding medication errors that do not result in an adverse
reaction and for potential medication errors. Potential medication
errors are already covered under product complaint regulations. We
recommend they not be included in the safety sections.  

It would be more appropriate to update the product complaint regulations
to require expedited reporting of certain medication errors which do not
lead to product recalls. (Currently, reports under product complaint
rules are only expedited when there is a product recall.) BIO believes
that forcing this issue to be handled via the adverse drug reaction
reporting system introduces redundancies as well as inconsistencies with
ICH practices. Rule changes along these lines are even less justifiable
with potential medication errors.

By proposing that manufacturers and applicants continue to use active
query to attempt to determine the outcome of a suspected drug reaction,
the agency is introducing a third classification of \"seriousness;\"
i.e., \"outcome unknown.\" We believe this will introduce
inconsistencies with other regulatory agencies and will require
substantial changes to all systems and business processes. It will make
harmonization essentially impossible. It is not apparent that this
classification has inherent value in assessment of patient safety.

FDA's focus on active query, in a large number of situations, neglects
to acknowledge that active query is not the only way to contact the
health professional and obtain important information. Written inquiries
may sometimes be more successful or appropriate (for example, if
hospital discharge summaries can be obtained). Again, BIO recommends
that active query not be a default but rather a tool that is used
selectively at the discretion of the sponsor, not as a regulatory
mandate.

 

Finally, FDA proposes that accounting of a manufacturer or sponsor's due
diligence in obtaining data be included in the report of the suspected
drug reaction. BIO believes that use of the 3500A to document due
diligence distorts the usefulness of this document. It is already
sometimes difficult to provide a medically coherent narrative while
separating the information into initial and follow-up sections. If, in
addition, a log of attempts to reach the health care provider by
telephone must be included, the character of these reports is changed.
We recommend due diligence efforts be documented in company files and
not in the 3500A. If included in the 3500A, the due diligence records
are then also open to disclosure under the Freedom of Information Act,
which could lead to deleterious consequences for both the sponsor and
the health care provider.

**III. D. 4. Always Expedited Reports**

FDA proposes to require manufacturers and applicants to submit to FDA
ICSR for suspected adverse drug reactions received or otherwise
obtained, whether foreign or domestic, that are the subject of an Always
Expedited Report.

We believe that Always Expedited Reports should have clearly defined
medical conditions (described using included MedDRA terms) that are
subjected to the rulemaking process. FDA proposes to change the
definition of "medically significant" event from "jeopardy and
intervention," to "jeopardy and/or intervention." For example, the
agency raises the issue of whether placement of an intravenous line --
which is consistent with intervention for the underlying condition --
would alone meet the proposed "Important Medical Event" (IME) criteria.
Moreover, in addition to the proposed list of Always Expedited Reports,
FDA proposes also to include "\[a\]ny other medically significant SADR
FDA determines to be the subject of an Always Expedited

Report."

BIO recommends that the final rule retain "jeopardy and intervention"
for the IME criteria and any addition to the list be subject to
notice-and-comment rulemaking. We also suggest that the MedDRA terms
that should be used to define each of the medical conditions listed be
clarified. Because of the complexity of MedDRA, an international
consensus process (such as CIOMS or ICH, in conjunction with the
Maintenance and Support Services Organization, MSSO) should develop and
maintain the MedDRA groupings that describe these conditions. Use of
included MedDRA term groupings will be especially important for those
medical conditions that are often reported in vague terms or are
otherwise poorly described by reporters in spontaneous reports. We
recommend these groupings of included MedDRA terms be reviewed by FDA
(preferably in cooperation with an international consensus body) with
each new release of MedDRA and updated, as appropriate, to maintain the
intended relevance. Timing of the required maintenance activities will
be very important to keep "current" with international agreements
regarding the implementation of each version of MedDRA. Finally, we
believe that the list of conditions that trigger Always Expedited
Reports should be negotiated on a product-by-product basis as part of an
overall approach to risk management.

The agency has identified a list of adverse events it considers
medically significant owing to the possibility they could jeopardize the
patient or subject and/or require medical or surgical intervention to
treat the patient or subject. These events would be submitted to the
agency on an expedited basis whether expected, unexpected, serious, or
non-serious. At this time, the agency receives all of these reports, but
not in an expedited manner.

These events include congenital anomalies, acute respiratory failure,
ventricular fibrillation, torsades de pointe, malignant hypertension,
seizure, agranulocytosis, aplastic anemia, toxic epidermal necrolysis,
liver necrosis, acute liver failure, anaphylaxis, acute renal failure,
sclerosing syndromes, pulmonary hypertension, and pulmonary fibrosis.

Further, confirmed or suspected transmission of an infectious agent by a
marketed drug or biologic would be reported to the agency on an
expedited basis as this type of event would be considered a public
health problem. The agency retains the right to add additional events to
this list if it determines an event to be medically significant.

BIO strongly recommends that the FDA reconsider its proposed rule change
and delete this section. We believe that the value of company analyses
and/or medical interpretation of events is not appropriately weighted in
this proposal. The proposed rule does not take into consideration the
indication for use or the information contained in the product
Investigator's Brochure or Package Insert. This will increase the number
of expedited reports sent from the manufacturer to the agency for any
given drug or biologic and will place an undue burden on both the agency
and industry as potentially every suspected adverse drug reaction could
be expedited.

**III. D. 6.** **Follow-up Reports**

The proposal would amend FDA's postmarketing safety reporting
regulations to define the term "full data set," require manufacturers
and applicants to submit a 30 day follow-up report to FDA for any
expedited report that does not contain a full data set, and require
submission of unexpected suspected adverse drug reactions with unknown
outcomes in an expedited manner.

30-Day Follow-up \-- Under the proposal, a complete data set would be
required for postmarketing events that meet the following criteria:
serious and unexpected events, "always expedited" events, and medication
errors. If the complete data set is not available with the initial
submission, a 30-day follow-up would be required even if new information
has not been obtained and efforts to acquire the missing data are
required.

45-Day Follow-up \-- The proposal would require that manufacturers and
applicants reporting an unexpected suspected adverse drug reaction with
unknown outcome include in the expedited safety report the reasons for
their inability to classify an suspected adverse drug reaction as either
serious or non-serious (i.e., unknown outcome). For this purpose,
manufacturers and applicants should include in the expedited report a
chronological history of their efforts to determine the outcome of the
suspected adverse drug reaction.

In the postmarket setting there are inherent difficulties in data
collection and often tenuous willingness of "reporters" to provide
information to sponsors. Included among data collection challenges from
the non-professional public are expressed "privacy" issues,
unwillingness to involve their physician \-- often coupled with lack of
sufficiently detailed medical information \-- and non-response to either
phone or written requests for information. Additional challenges from
medically trained professionals include non-response, lack of interest
in providing information, lack of time (either themselves or office
staff), and concern that the report might potentially have unintended
legal consequences. Given the above constraints, regardless of the
number and type of attempts made, additional detail may never be
obtained. We believe the added burden to sponsors of providing the
proposed 30- and 45-day follow-ups will yield useful follow-up in only a
very small number of cases. Efforts to improve the quality of data might
better be spent in education of health care professionals and the
general public about the value of adverse event reporting and their
responsibility to report. Although regulatory agencies have more
immediate control of sponsor/manufacturer activity, the ultimate gain
may be significantly less than if change were initiated earlier in the
process (i.e. public education). Both FDA and sponsor resources might be
put to better use by focusing attention on this earlier point of
contact. We recommend FDA focus on the adequacy of sponsor Standard
Operating Procedures (SOPS) and Guidelines during audits rather than
request real-time proof of due diligence.

**III. D. 7. Supporting Documentation**

The proposed rule would require manufacturers/applicants to include a
chronological history of all attempts to secure a minimum data set and
determine seriousness and expectedness of suspected adverse drug
reactions in postmarketing expedited reports. In addition, the agency is
requesting copies of documents such as discharge summaries and autopsy
reports/death certificates. The agency is proposing this action to
clarify the importance of acquiring complete information for serious
suspected adverse drug reactions.

BIO believes the rationale to include information on the FDA form 3500A
that applicants/manufacturers maintain in their corporate drug or
biologic product safety files is unclear. Manufacturers/applicants have
maintained records of their attempts to secure additional information
for many years. Submitting copies of hospital discharge summaries and
autopsy reports/death certificates for serious, unexpected adverse drug
reactions creates patient record privacy issues both in the U.S. and
overseas. In addition, we believe such requirements will impose
additional burden and cost for purging these records to remove
patient-identifiable information. Relevant information from these
documents already is summarized and included in the appropriate boxes on
FDA form 3500A. These records should be on file, but not included as
part of the narrative summary. A field on the 3500A form indicating that
the manufacturer/applicant has received a copy of the discharge summary
or autopsy report/death certificate would be sufficient. BIO believes
the narrative section should be limited to pertinent clinical details
only. We recommend a written request be submitted to the
manufacturer/applicant from the agency if a copy of any of the
documentation retained in corporate files is required. Requiring
submission of these documents is inconsistent with the Paperwork
Reduction Act and ICH E2B.

Many manufacturers have worldwide reporting requirements, and it is
appropriate to have one report satisfy both domestic and international
requirements. No other regulatory authority worldwide has requested this
type of information for inclusion in any adverse event report or
aggregate safety report. BIO believes that preparing different reports
for different regulators is redundant, resource wasteful, and does not
advance public health.

**III. E. 1-4. Traditional Periodic Safety Reports, Periodic Safety
Update, Interim Safety Reports, Semiannual Submission of Individual Case
Safety Reports**

The FDA is proposing that industry submit TPSRs, PSURs or IPSRs
depending on when the drug was first approved. If the approval date were
prior to January 1, 1998, then a TPSR would be required. However, if the
approval date were after January 1, 1998, then the PSUR format would be
required. In addition, the proposed rule would require that a number of
U.S.-only appendices be submitted with the PSUR. The suggested time
frame for submission of these reports over the lifetime of the product
is also different from the schedule set out in the ICH guidance.

It would seem prudent to add the requirements for IPSRs to the PSUR and
submit all the information at one time. Moreover, the requirement that
U.S. ICSRs be submitted using the MedWatch form is retained. BIO
recommends the agency consider allowing industry to submit ICSRs using
either the MedWatch or the CIOMS form.

FDA also proposes to remove the current requirement for submission of
ICSRs in the TPSR. Instead, ICSRs would be included in a separate report
submitted on a semiannual basis (ICSRs - semiannual submission). BIO
recommends that the previous requirement remain in place -- that ICSRs
continue to be included in TPSRs and/or PSURs/IPSRs and that a new
semiannual report not be required. We believe semi-annual submission of
ICSRs would place undue burden on industry, since this would require a
similar amount of effort as preparation of TPSR, PSURs, and IPSRs and
would require retrieval of cases meeting TPSR/PSUR/IPSR criteria. The
associated review and processing activities would essentially be
equivalent to preparing a TPSR/PSUR/IPSR on a semiannual basis in
addition to the proposed reporting schedule.

We also seek clarification as to the methodology suggested for increased
frequency and the assessment of whether frequency of lack of efficacy
reports is greater than what would be predicated by the premarketing
clinical trials for the products, as an accurate denominator is not
available. Finally, BIO believes that the addition of an increased
frequency requirement is not in keeping with international
harmonization.

BIO believes that public health is best served by safety staff with
appropriate training and experience. We disagree with the proposal that
only a licensed physician can be responsible for the content and medical
interpretation of the data and information contained within the safety
periodic reports. BIO believes manufacturers should be responsible for
the medical content and allowed to determine appropriate health care
professional qualifications required for the preparation of such
reports.

In the spirit of embracing ICH E2C principles, we suggest updating
section III.E.2.d. in accordance with the recently published Addendum to
ICH E2C regarding Company Core Safety Information (CCSI). Overall, in an
effort to provide global harmonization, line listings requirements
should fully endorse ICH E2C; similarly the agency could provide more
flexibility regarding the content of the appendices such that relevant
information is contained in the body of the report as opposed to
appendices.

Further, again in a move toward international harmonization, we suggest
that the Core Data Sheet (CDS) requirement be aligned with that of the
ICH E2C and Addendum. The applicant would be responsible for ensuring
that all changes to the CCSI made during the reporting period are
described in Section 4 of the PSUR. For 6-month and 1-year reports, the
version of the CCSI in effect at the beginning of the period covered by
the report should be used as the reference. For 5-year reports, the
version of the CCSI in effect at the end of the period covered by the
report should be used as the reference.

We seek clarification regarding the implementation of the TPSRs (as well
as PSURs and IPSRs) as we believe that reporting of specific suspected
adverse drug reactions such as "always expedited reports," "actual or
potential medication errors," and "reports of class action lawsuits"
will be captured in most vendor-designed company safety systems as such
only after the effective date of the final rule. We therefore suggest
that the content of summary tabulations as specified in the proposed
rule be prospective.

BIO also suggests that the final rule include a recommended method for
the determination of increased frequency as well as a recommended method
for the assessment of changes in frequency of lack of efficacy, as an
accurate denominator is unavailable.

Additional new sections are proposed to include details on location of
safety records and contact information for the "licensed physician or
licensed physicians responsible for the content and medical
interpretation of the data and information contained within the TPSR"
(or PSUR). BIO suggests (1) this information not be required as
additional sections and (2) the report include the contact information
of a health care professional responsible for the content of the
document. We believe the manufacturer should be responsible for ensuring
that the assigned personnel are qualified and that TPSRs, PSURs, and
other safety-related records on a product be readily available to FDA
upon request.

Periodic reporting for products approved for pediatric use should be
treated as those for a special population, according to the ICH E2C
Guideline. FDA proposes that applicants submit separate PSURs and IPSRs
regardless of application approval date. However, for products that
otherwise would be subject to periodic reporting, i.e., products
approved for use in adults, we believe that it is appropriate to provide
pediatric safety data and analyses in one report. Further, BIO believes
that the requirement to provide data for special populations, such as
pediatric age groups, should be applied prospectively because, as a
practical matter, it will be extremely difficult (if not impossible) to
identify the relevant patient subset (e.g., Class Action lawsuits,
medication errors, etc.) because of the challenges of applying coding
conventions retrospectively and making necessary changes to system
capabilities. We believe that, in general, reporting periods should not
be different simply because special populations are included.

**III. E. 5. Reporting Requirements**

Several sections of the proposed rule state that the submission of the
single core report (excluding appendices) to multiple regulatory
authorities would significantly reduce time spent preparing reports,
thereby permitting more time for evaluation of the medical significance
of any safety information reported. However, given the proposed
additional requirements for PSURs beyond what is specified in the ICH
guidelines as well as additional types of reports that the FDA proposes
to require, the spirit and focus of the ICH E2C \-- avoiding duplication
of effort and ensuring that data are submitted to authorities with
consistency (one standard, format/content), are minimized. We believe
cases meeting PSUR criteria (with line-listing, summary tabulations)
should be accepted throughout the three regions.

As currently drafted, BIO believes the proposed rule on PSURs does not
allow for true international harmonization (for example, non-serious
listed suspected adverse drug reactions are proposed to be included in
this rule; they are not specified in ICH E2C). Additionally, the
appendices are extensive and would contain a subset of the information
already included in the core document (or unattainable information, such
as information on U.S. microbial *in vitro* susceptibility data and the
relationship of any observed changes to clinical outcomes for the
reporting period). BIO recommends that the final rule not include a
requirement for these appendices. However, if such a requirement is
retained, we recommend that the time period allotted to prepare PSURs be
extended from 60 to at least 90 days.

We agree with the possibility of alternative reporting frequency.
However, we believe it is essential that this section of the rule also
state that the Marketing Authorization Holder be able to negotiate the
existing reporting cycle or frequency for the periodic safety reports,
should the IBD be different from the U.S. birth date.

Finally, the proposed rule indicates that the PSUR would allow
applicants to submit a single core document for products that have an
approved application (i.e., BLA, NDA, ANDA). We seek clarification on
how to handle products with multiple formulations or multiple active
ingredient combinations, some of which are only approved outside the
U.S.

**V. Analysis of Impacts**

BIO believes that FDA's impact analysis underestimates the resources
that are needed to implement the proposed rule. In particular, some of
the data upon which analyses related to pre-approval reporting are based
appear to be erroneous. Further, as we stated in our introductory
comments, many of the estimates -- including those that calculate
substantial "savings" to the industry -- appear to be based on flawed
assumptions or on data from unknown or unverifiable sources. We
recommend the agency work with the affected industry to achieve numbers
that more correctly reflect the true costs to industry, before it moves
to finalize the proposal. We most strongly urge that the agency
re-propose this rule, based on a re-calculation of costs and burdens, a
re-evaluation of the harmonization of many of these proposals with those
of other regulatory bodies, and a refined re-assessment of the true
cost-benefit of the proposed requirements.

**Effective Date**

FDA proposes an effective date of 1 year after publication of the final
rule for requirements related to coding suspected adverse drug reactions
in individual case safety reports using MedDRA but that the effective
date for all other components of the proposal become effective 180 days
after publication in the Federal Register.

We believe that if the final rule is not significantly modified from the
Proposed Rule, there will be an extensive impact on systems
(modification of the existing safety databases to meet the specific
requirements of the rule, requiring extensive and time-consuming
validation) and processes (which, if implemented, will require training
of employees, suppliers, investigators, etc.). Therefore, BIO strongly
urges, first, that FDA re-propose the rule, as discussed above, and,
second, that FDA set the effective date of the entire final rule at 18
months after publication in the [Federal Register]{.underline}. We
believe this amount of time is needed by industry to evaluate and
implement the required changes. Such a delay in implementation is
consistent with several recent examples of implementation of new federal
regulations including an 18-month delay in implementing changes in FDA
labeling requirements concerning aluminum in small volume parenterals
and pharmacy bulk packages, "to give industry sufficient time to comply"
with the regulations. (68 Fed. Reg. 32979; June 3, 2003)

We recommend the impact on systems be carefully evaluated to provide a
clearer picture of the global resource requirements and the timing
needed for full implementation of the final changes. In addition, full
evaluation of the needed personnel and their qualifications and training
requirements must be completed. Finally, BIO believes FDA's estimates of
reasonableness and burden are low and recommend that these numbers be
evaluated carefully to gain better insight into the implications of
implementing the proposed rule throughout the pharmaceutical industry.
BIO strongly urges the agency to re-evaluate components of the rule
after reviewing all comments and having an opportunity to consider fully
the total burden of new requirements, balanced against gains for the
public health, and to re-propose the rule based on this finer tuned
evaluation.

**Conclusion**

Throughout the proposed rule, the FDA emphasizes the need for
manufacturers/ applicants to exercise due diligence, to continue to seek
additional information from adverse event reporters, to document efforts
to obtain additional information, to send numerous follow-up reports,
and to send to the agency a myriad of documents formerly kept in
manufacturers' files and summarized on FDA form 3500A. However, BIO does
not believe that industry is likely to gather any more information or
better quality information unless the agency (1) educates physicians,
pharmacists, and other health care personnel as to the type and quality
of information the agency is seeking and why this information is
important and (2) makes adverse event reporting to manufacturers
mandatory.

In conclusion, BIO believes that although the new proposals would reduce
reporting obligation for certain non-serious events, this would not
balance other additional efforts that would be required. FDA states that
"Many of the postmarketing safety reports that FDA receives are complete
and of high quality. Others are incomplete, of mediocre or poor quality
or both, making it difficult to ascertain the significance of these
reports."

BIO urges the agency to focus on those manufacturers who consistently do
not use due diligence and who, upon FDA audit, have not demonstrated
that processes are in place to address FDA concerns. We believe that
those who adhere to recommendations will be penalized unduly under the
new proposals.

BIO appreciates the opportunity to comment on this proposed rule. We are
in full agreement with FDA on the need for quality safety reporting and
the desirability of international harmonization of such reporting.
These, we agree, are in the best interest of the industry, the agency,
and the public. However, we are concerned that in a number of areas,
this proposed rule over-reaches, frustrates the goal of international
harmonization, and -- most importantly -- will not result in better or
more useful safety information. As we stated earlier in our comments, we
welcome the opportunity to continue to work with the agency to achieve
the best quality and most useful system for safety reporting for the
products our industry develops and manufactures.

> Sincerely,
>
> Gillian R. Woollett, MA, DPhil
>
> Vice President Science and Regulatory Affairs