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October 13, 2003

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 2052

**RE:** **Docket 00N-1484, 14 March 2003 "Safety Reporting Requirements
for Human Drug and Biological Products; Proposed Rule"**

To: FDA Dockets Manager

The American Association of Blood Banks (AABB) is the professional
society representing approximately 8,000 individuals and 1,800
institutions, including blood centers and hospital blood banks and
transfusion services involved in all aspects of blood collection and
transfusion medicine. AABB members are responsible for virtually all of
the blood collected and approximately 70 percent of the blood transfused
in the United States. For over fifty years, the AABB's highest priority
has been to maintain and enhance the safety and availability of the
nation's blood supply.

The AABB appreciates the opportunity to provide comments to this
proposed rule on reporting of suspected adverse reactions (SARs) and
serious SARs[^1]. The AABB supports efforts to harmonize adverse event
reporting systems where there is a benefit to patient and donor safety.
However, the AABB does not believe that the safety of blood and blood
products will be positively impacted by the use of the reporting
mechanisms described in the proposed rule. In fact, the schemes proposed
are so complicated and burdensome that it is likely focus will shift
away from blood collection and transfusion medicine issues that have a
greater impact on donor and patient safety.

The AABB supports FDA in adopting a risk-based approach to adverse event
reporting in which emphasis is placed on events that have the greatest
risk to patient and donor safety. Meaningful analysis of reported data,
whether it is mandatory or voluntary, should lead to changes within the
health care system to prevent or minimize recurrence. The AABB has a
long-standing commitment to ensuring quality in blood bank and
transfusion service operations. The concept of preventing, identifying,
investigating and correcting issues related to adverse events has long
been embedded in the AABB's *Standards for Blood Banks and Transfusion
Services*. However, AABB does not support this proposed rule and has the
following specific comments:

# Scope of Reports

FDA proposes to revise δ606.170 to require not only reporting of
fatalities, as is the current practice, but also to require reporting of
any complaints of suspected adverse reactions related to blood
collection or transfusion. FDA states that "This proposed safety
reporting requirement would not impose significant new burdens on blood
establishments." FDA postulates that all reports of serious SARs
required to be submitted under the proposed rule are already being
maintained by the transfusion service or blood collecting facility. This
simply is not true. Many of the events listed as reportable in the
examples in III.D.12, such as induced cardiac arrhythmias and induced
congestive heart failure, are external to the control of the transfusion
service and may not even be known to them. Blood establishments cannot
be accountable for such events, and do not maintain such records.

In δ600.80 the proposed rule changes the definition of adverse events
that should be reported to include all those where there is "a
reasonable possibility" that a causal relationship exists with the
collection or transfusion. Furthermore, the proposed rule is explicit
that "a reasonable possibility" means that the "relationship cannot be
ruled out." For the purpose of reporting "serious SARs" related to blood
collection and transfusion, FDA provides examples of what the agency
believes the term includes. **The terms "immediate medical
intervention," "followup medical attention" and "significant medical
intervention" require clarification.**

The agency estimates that this proposed rule will generate only 7,000
reports per year. Again, this simply is not a realistic estimate. When
one combines "a relationship cannot be ruled out" with "requires medical
attention," it is easy to see that a literal interpretation would
require hundreds of thousands of reports of non-fatal events. **The AABB
requests that "reasonable possibility" and "relationship cannot be ruled
out" be removed from the Final Rule and replaced with the current and
reasonable standard of "confirmed."** This will ensure the capture of
serious adverse events in which the transfusion is clearly considered to
be a contributing factor, but will not require reporting events in which
a transfusion is coincidental to the event.

As noted above, these changes to the definition of events that must be
investigated and documented also apply when a fatality is related to
transfusion. The implication of this is staggering. In the preamble to
the rule, the agency lists congestive heart failure, cardiac
arrhythmias, seizures, respiratory insufficiency, bacterial infection,
and other conditions as examples. Blood transfusion is a therapy for the
sickest patients in a hospital. Many transfused patients have cardiac
problems or are in respiratory distress. The differential diagnosis of
such problems often includes complications of blood transfusion. A
requirement to report every death of a transfused patient whenever the
relationship between the transfusion and the death cannot be ruled out
will cause an explosion in the number of reports submitted. **The AABB
again requests that "reasonable possibility" and "relationship cannot be
ruled out" be removed from the Final Rule definition as it relates to
fatality reporting, and replaced with the current and reasonable
standard of "confirmed."**

# Utility of Information

Furthermore, the AABB does not agree that mandatory reporting of these
events to FDA will "enhance donor safety \[nor contribute to an increase
in assurance of\] the safety, purity and potency of blood and blood
components for administration to patients." The agency lists several
examples of information that were voluntarily reported and postulates
that had such reporting been mandatory, the issues could have been
addressed earlier. The AABB is concerned that the exact opposite would
be true, and that significant reports would not be identified, but would
simply get lost among all of the other required reports. FDA already has
a system in place for mandatory reporting of biological product
deviations. To date, FDA has not returned any useful analysis of this
information to the blood community that resulted in enhanced donor
safety or an increase in safety to the transfusion recipient. It appears
that this proposed rule will result in a huge database that will be
counted and categorized but will have little impact on care provided to
donors and patients. AABB is concerned about how this information will
be analyzed and how it will be used to benefit donor and patient safety.

[Reporting Format]{.underline}

The proposed rule will mandate safety reporting via the use of Form
3500A and the appropriate "preferred term" in the latest version of the
Medical Dictionary for Regulatory Activities (MedDRA). MedDRA was
developed by the International Conference on Harmonisation (ICH) to
facilitate global communication of safety information for human drug and
biological products. MedDRA is a hierarchical system composed of various
levels of terminology with each preferred term representing a unique
medical concept accepted internationally. The Proposed Rule states that
there is a limited range of terminology available within MedDRA for
blood facility use. The applicability of the MedDRA system to the realm
of blood collection and usage must be ensured before applying this
system to the field of transfusion medicine.

FDA Form 3500A is ill suited for reporting donor reactions or unexpected
transfusion reactions. The form is currently being used to report
adverse events or product problems related to suspect medications or
medical devices. Data intended to enhance donor and patient safety
cannot be submitted utilizing Form 3500A.

**The AABB proposes that FDA exclude blood collection facilities and
transfusion services from the requirement to use MedDRA terminology. The
Department of Health and Human Services (HHS) has signed an agreement
with the College of American Pathologists (CAP) to standardize the
medical vocabulary system and make it available for free. This appears
to be a more relevant, practical and cost-effective method to
standardize terminology used by hospitals and blood centers in reports
to HHS/FDA.**

# Financial Impact

The expense to blood facilities will be enormous if the Rule goes into
effect as proposed. The agency's estimates of the costs of compliance
are unrealistically low. The assumption that a facility is already
preparing all of these reports for internal use is invalid. Even if the
wording of the reporting requirements is restricted to those reactions
that are "confirmed" to be transfusion-induced, the costs will still be
far greater than estimated. Many more hours go into any report for
external regulatory purposes than are needed for internal quality
assurance. Even the Proposed Rule estimates that 16 more hours will be
spent preparing and submitting each of these reports. Further, all
suspected but non-serious SARs will also have to be studied, recorded
for internal use, and the records made available to FDA investigators
during their inspections. This Proposed Rule would require thousands of
additional working hours for an already overburdened blood banking and
transfusion service workforce.

FDA estimated the cost of this proposed rule to industry and believes
that the cost to a blood facility for planning and coordination will
range from \$450 − \$2,260 for very small and very large firms,
respectively. FDA further states that FDA thinks blood facilities will
have no costs associated with the development and validation of
information technology systems to accommodate MedDRA. Yet, the MedDRA
MSSO Web site discusses the importance of validation of the quarterly
updates and version upgrades. Validation is clearly necessary, and must
be incorporated into any time and expense estimates. The agency
suggested that eight hours is sufficient time for a small blood center
to accomplish appropriate SOP revisions, while large blood centers will
need 50 hours. Training costs are estimated to be as low as \$1,300 --
\$4,300; however, the MedDRA MSSO Web site lists many training classes
for firms beginning use of MedDRA. The classes are not inexpensive. The
AABB questions the accuracy of FDA's cost estimates. Small blood centers
use the same cGMP processes as large blood centers, and to suggest there
is a difference in the amount of SOP revisions required by each
demonstrates a lack of understanding on the part of FDA, in regard to
blood facility operations. However, simply changing the SOP may be only
a minor portion of the time needed, and it is correct that
implementation of SOP changes, including staff training, does require
more time at a larger facility.

MedDRA must be licensed for a fee. FDA estimates recurring costs for
drug and biologics firms to be \$5,000 − \$40,000, yet "judged" that
blood facilities would incur modest annual fees due to a "limited" range
of terminology available for their use and "assumes" that blood
facilities would negotiate a lower cost or contract with a research
organization to obtain the necessary codes. However, the MedDRA MSSO Web
site (MedDRA FAQs) is clear on the subject of licensure. "**Q:** The CRO
we use has MedDRA. Why should my company also have to subscribe,
considering how expensive MedDRA is? **A:** It is the intent of both the
ICH, the creators of MedDRA, and the IFPMA, the holders of the property
rights to MedDRA, that all pharmaceutical companies have a current
MedDRA license in order to code, analyze, report, or hold MedDRA coded
data. CROs who code, report, or hold MedDRA coded data also must have a
current license to MedDRA. Otherwise, the sharing of data violates the
MedDRA licensing agreement created by the IFPMA regarding the
distribution of MedDRA to another party." **Please clarify why FDA
"judges" and "assumes" that blood facilities will not incur significant
costs associated with the use of MedDRA that must be licensed for a fee,
even while acknowledging that it has "limited" range of terminology
available for use by blood facilities.**

MedDRA quarterly updates and periodic new versions are estimated to cost
drug and biologics firms in the range of \$5,700 − \$43,000, yet no
costs were assigned to blood facilities. From the MedDRA MSSO Web site:
"The updated versions of MedDRA are both the strength of the terminology
and one of its greatest challenges," and recommendations are given that
new releases should become the reporting version on the first Monday of
the second month after it is released. The stated change over date and
time are used to allow all users enough time to prepare and validate
their systems. (For example, if a blood facility submits a report using
the new version terminology prior to FDA updating its system, then the
blood facility's report may be rejected). It appears that updates will
be released no less often than twice per year. **Please clarify why FDA
believes there are no costs for blood facilities associated with updates
and new versions.**

The AABB requests that FDA consider alternate proposals for blood banks
and transfusion services:

## Alternative System of Reporting

> Given the frequency of significant issues cited on FDA inspection and
> the acknowledgment of the incredibly large number of significant
> errors throughout the medical system, the AABB believes that an
> alternative system for dealing with error in our field must be
> implemented. The blood banking community has already made a
> significant initial investment in the development of such a program.
> The MERS ^TM^ system is user friendly, Web-based, and most
> importantly, permits the users to utilize not only its own
> institutional data, but also aggregate data from the entire reporting
> system.

## Reporting to Third Party

> The AABB supports reporting of adverse events to an independent third
> party, such as the system currently used by the airline industry. In
> the reporting of deviations/errors/adverse events, many behavioral and
> quality systems experts strongly counsel that punitive actions against
> the reporter are counterproductive, as they deprive the system of the
> information needed to solve problems. Because the FDA is the
> regulatory agency involved in blood establishment oversight, it is
> inappropriate for FDA to be the designated agency to receive reports
> of serious adverse events. The AABB believes that serious
> underreporting will occur if reports are submitted to the FDA.

In conclusion, the AABB is concerned about the safety of patients and
donors and supports efforts to harmonize systems where there is a
benefit to patient and donor safety. Simply noting adverse events and
reporting them will not improve our operations. We need to utilize our
quality management systems to detect and analyze adverse events in order
to improve our processes and then share these experiences nationally
through a system that can fruitfully and confidentially examine and
tally them. Further, a reasonable definition of serious adverse event
must be adopted in order to provide information that will be useful for
patient and donor safety improvements.

The requirements of this Proposed Rule will not result in meaningful
advances in the arena of donor and patient safety as it relates to the
collection and transfusion of blood products. In fact, it is more likely
that patient and donor care will be negatively impacted as facilities
struggle to find manpower and stretch financial resources to deal with
the massive paperwork required by this proposal. The American
Association of Blood Banks strongly supports initiatives that advance
the cause of donor and patient safety. However, the AABB cannot and does
not support this Proposed Rule. The AABB strongly urges FDA to consider
alternative systems for gathering meaningful data to assist the agency
in monitoring and assessing safety-related information concerning the
collection and transfusion of blood and blood components.

Sincerely,

Roger Y. Dodd, PhD

President

[^1]: AABB notes that FDA should consider a new acronym for adverse
    event reporting now that SARS has taken on a new meaning (Severe
    Acute Respiratory Syndrome) that is internationally recognized.