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Comments to FDA on Proposed Safety Reporting Requirements – 10/13/03

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 d606.170 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 d600.80 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

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.


Roger Y. Dodd, PhD

  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.