18 May 2015
Division of Dockets Management (HFA–305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
Re: Docket No FDA-2007-N-0363: Electronic Distribution of Prescribing Information for Human Prescription Drugs, Including Biological Products, Proposed Rule
Dear Dockets Manager:
AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership consists of nearly 2,000 institutions and 8,000 individuals, including physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. AABB members are located in more than 80 countries.
We appreciate the opportunity to provide these comments on the proposed rule titled “Electronic Distribution of Prescribing Information for Human Prescription Drugs, Including Biological Products.” AABB accessed the expertise of the Circular of Information Task Force to review the recommendations contained in the proposed rule and in compiling this response that has been reviewed by the AABB Board. In a separate letter AABB’s Center for Cellular Therapies has submitted comments to this docket that are pertinent to HCT/Ps.
The Food and Drug Administration is “proposing to amend the labeling regulations to require electronic distribution of prescribing information for human prescription drugs. This is intended to facilitate the distribution of updated prescribing information as new information becomes available and as changes in prescribing information are made. FDA is taking this action so that the most current prescribing information for distributed prescription drugs will be available and readily accessible to health care professionals at the time of clinical decision-making and dispensing.” In doing this FDA aims to improve patient safety by ensuring newly added boxed warnings to alert prescribers about a new serious risk are not delayed by the standard packaging and inventory storage processes of the pharmaceutical industry which can result in outdated package inserts accompanying the use of in-date products before complete turnover has been realized. We applaud the agency’s interest in these efforts.
However, we respectfully submit that the process by which the Circular of Information for the Use of Human Blood and Blood Components (Circular) is created and made available to blood providers for submission to the FDA is unique, and modification per the proposals presents potential challenges neither faced by traditional pharmaceutical manufacturers nor contemplated by the FDA when drafting this rule. We believe consideration of these challenges, along with a balanced consideration of what benefit is reasonably achieved when applying the requirements of the proposed rule specifically to blood components vs. other types of drugs warrants exclusion of blood and blood components and the accompanying Circular from the final rule.
The Circular is significantly different from prescribing information for traditional drugs, and also for blood product derivatives. Much of the rationale in the
Section I. Background for cost savings and enhanced patient safety following posting to the
labels.fda.gov site does not apply to the Circular. The Circular is an extension of container labels for human blood and blood components, and differs from other prescription drug prescribing information because it is the product of a collaborative effort of members of the AABB Circular of Information (COI) Task Force, with joint representation by AABB, the American Red Cross, America’s Blood Centers – all not-for-profit organizations – and the Armed Services Blood Program. Rather than describe a single pharmaceutical, the Circular provides information on multiple blood components that are variably manipulated and modified from human blood donation. The information contained within it is compiled from current literature and practice guidelines, rather than proprietary research and development. Its intended use is as a resource for the physician contemplating prescribing a blood or blood component transfusion. It is not a comprehensive guide to transfusion practice, nor is it intended to convey specific administration instructions. Hospital policies, including transfusion guidelines, and standard operating procedures appropriately guide these activities. In addition, the Circular also serves as a reference point for the clinician engaged in consultative conversation with the hospital blood bank or blood establishment physician regarding specific patient needs. Hospital blood bank physicians and blood provider physicians serve consultative roles regarding availability and appropriate use of blood products within a particular institution. Transfusion procedures are performed per hospital standard operating procedures, not administration instructions provided in the COI.
Authorship of the Circular occurs through the voluntary work of AABB Task Force members, while the AABB provides Task Force support staff and liaises with the FDA to gain recognition of the Circular as an acceptable extension of the container label via FDA
guidance publication. Operational components currently provided by AABB include layout, typesetting and printing of the Circular. The cost of these activities is funded by the purchase of printed copies via the AABB Marketplace by blood establishments to be used as their package inserts. This facilitates the use of a common Circular by the majority of blood collectors, including hospital blood banks that collect only autologous donors. This process also greatly reduces the burden of review on FDA as the guidance (referenced above) provides implementation instructions for a common Circular (Annual Report) rather than a Prior Approval Supplement (PAS) that is otherwise needed.
Much of the rationale provided in
Section I. B. Who receives paper prescribing information and who uses it? (Reprinted here) does not apply to the Circular.
“The prescribing information that is the subject of this proposed rule is the paper version that is on or within the package from which the drug is to be dispensed (e.g., physically attached to the bottle containing the drug, inside the carton or box containing the drug, with the bulk pharmacy package). Usually, it is printed on thin paper in small size font, and is folded multiple times so that it can be contained within the drug carton or can be otherwise attached to drug packaging. Drug products, with the paper prescribing information on or within their packaging, are distributed to pharmacies for dispensing. This paper prescribing information is intended for use by all health care professionals. However, health care professionals have come to rely on electronic or other paper versions (e.g., compendia such as the Physicians’ Desk Reference (PDR)) compiled by third parties instead of this paper version. Prescribing physicians and many health care professionals (e.g., nurses) typically do not receive this paper version because they do not dispense drugs. Pharmacists do receive it along with the drug product from the manufacturer or distributer, but it is often difficult to read due to the small font size, thin paper, and multiple folds, and we have heard anecdotally that it is often discarded. In addition, pharmacies usually have some form of compendia purchased from a third party, and many hospitals and chain pharmacies rely on electronic compendia. Patients ordinarily do not receive the paper prescribing information because the pharmacist dispenses the drug to a patient in a different container than the packaging from the manufacturer, but they do receive other information intended for patients from the pharmacy.”
While traditional pharmaceutical paper package inserts optimally designed to contain large amounts of information occupying the smallest amount of space possible within the confines of the packaging (thin paper, small fonts, crowded text, multiply-folded)are described, the Circular is just the opposite. It is a
small booklet (3 ½” x 8 ½”) proportioned to easily fit in the lab coat pocket of the physician, nurse or laboratory professional. It is designed for easy readability in terms of table of contents, font size, white space and organization; the current version is 72 pages. An
educational version, available on the AABB website in pdf form is a 47 page document – a volume not amenable to the on-demand printing typically available to clinicians and others in the work environment. Pharmacists are not the recipient of the Circular; it is made available, by the blood collector, to the transfusion service and clinical staff responsible for ordering and infusing blood components.
Currently, the paper version of the Circular contains several blank pages for the easy addition of stickers to include interim language addressing new processes, products or tests until an updated version of the Circular is recognized by FDA via Good Guidance Practice and printed, as described above. Interim language is also crafted by the AABB COI Task Force, reviewed and recognized by the FDA, posted on the AABB website and publicized in AABB, ABC, ARC, and ASBP newsletters. Blood providers can then immediately print stickers and apply them to their existing stock of printed Circulars, and distribute them immediately. Because the Circular is not individually packaged with each component like traditional pharmaceuticals and therefore stockpiled in inventory with potentially outdated inserts, the delay in distributing the updated version in place of the older one is minimal.
The FDA projects net cost savings after initial investment in set-up costs for electronic prescribing information. This is based on the assumption that the individual manufacturer bears the cost of all steps in the process of printing, folding and packaging printed package inserts along with each individual pharmaceutical unit, including the purchase and maintenance of equipment. Because the Center for Biologics Evaluation and Research has not developed standards for electronic submission of labeling for blood components it is not clear what resources will be needed to produce an electronic version that would comply with FDA requirements in the future. It is not possible to say there will be a cost savings, indeed there could be a cost increase initially and each time the Circular must be updated. Responses to individual CFR Subjects below indicate our concerns that the benefits of the common Circular may disappear, for blood establishments and the FDA. The content of the Circular can be generated by the AABB COI Task Force but it appears that manufacturers must submit their own label, in a format as yet undetermined by CBER, under their own name in order for a healthcare provider to find the specific label on
labels.fda.gov. Each time an interim update to the Circular is needed it appears that each establishment must update its own copy of the common Circular and resubmit to
XIII. List of Subjects – 21 CFR
201.100 Prescription drugs for human use.
(8) The statement: ‘‘To obtain the current prescribing information, go to
labels.fda.gov or call (insert the toll-free telephone number) for a faxed, emailed, or mailed copy.’’ This statement must be no smaller than 6-point type.
Provided, however, that in the case of a container too small or otherwise unable to accommodate a label with sufficient space to bear the statement, the statement shall be affixed to the immediate container label by other means, such as a peel-back label.
Additionally, if the container is packaged within an outer container from which it is removed for dispensing or use, the statement shall also be included on the outer container or package.
A peel-back label is not appropriate to incorporate into blood component labeling. The only components that are individually packaged are frozen plasma components. Other components are stacked in standing rows or placed in stacks while in storage or during shipping. In addition, it is not clear that blood establishments can make the investment required to print one portion of the 4 quadrant ISBT label in peel-back format.
See also RECOMMENDATION to
SECTION – 201.100 Prescription drugs for human use.
(4) Labeling containing prescribing information must be submitted to FDA in an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files). Upon initial approval of a new drug or biological product, labeling containing prescribing information must be submitted and posted before introducing the drug into interstate commerce. For drugs already approved under section 505 of the Federal Food, Drug, and Cosmetic Act or biological products licensed under section 351 of the Public Health Service Act, applicants must submit labeling containing prescribing information within 2 business days of a change to the prescribing information. For unapproved drugs, the person responsible for the content of labeling must submit labeling containing prescribing information within 2 business days of a change to the prescribing information. Other manufacturers, such as repackers or relabelers, must submit labeling containing prescribing information within 2 business days of the posting or new posting of an applicant’s labeling. The entity responsible for submitting the labeling for the drug must verify that the correct version of the prescribing information appears on FDA’s labeling repository Web site
labels.fda.gov. The entity responsible for submitting the labeling must contact FDA’s Structured Product Labeling Coordinator by calling 1–888–463–6332 or emailing
spl@ fda.hhs.gov within 4 business days of its submission if the labeling is not posted on FDA’s labeling repository Web site or within 2 business days of its posting if the labeling that is posted is incorrect. Products with missing, inaccurate, false, misleading, or outdated labeling on the FDA’s labeling repository Web site are misbranded.
RECOMMENDATION – CBER should clarify the process for the blood Circular, beyond what is described in the proposed rule, if it does not exempt the blood Circular from the proposed changes.
RATIONALE – The requirements of 201.100(c)(4) listed above infer that blood establishments will have to submit their Circular to the administrators of the website within two days of FDA recognizing the Circular as acceptable. There must be a mechanism for a blood establishment to differentiate its copy of the Circular from another establishment’s copy since each establishment is responsible for updating its own label, and a mistake posted by the establishment, or FDA and not detected by the establishment, results in a misbranded product.
SECTION – 201.100 Prescription drugs for human use.
(g) If FDA has granted an exemption of the drug from the requirements for the electronic distribution of labeling, the applicant, manufacturer, or person responsible for the content of labeling of unapproved drugs, distributes the content of labeling in paper form.
(1) On FDA’s initiative, or in response to a written request from an applicant, manufacturer, or person responsible for the content of labeling of unapproved drugs, the appropriate Center Director may exempt a human prescription drug from the requirements for electronic distribution of labeling set forth in this section. The exemption request must document why compliance with the electronic distribution of labeling requirements could adversely affect the safety, effectiveness, purity, or potency of the drug; is not technologically feasible; or is otherwise inappropriate; and must explain why the concerns underlying the request could not reasonably be addressed by other measures. If an exemption is granted, the applicant, manufacturer, or person responsible for the content of labeling of unapproved drugs must distribute the content of labeling in paper form.
RECOMMENDATION – Blood and blood components intended for transfusion (and the Circular of Information for the Use of Human Blood and Blood Components) should not be subject to the electronic distribution of prescribing information requirements in this proposed rule once the electronic submission standards accommodate these products.
RATIONALE – The FDA provided notice in the proposed rule that standards do not currently exist whereby labeling can be electronically submitted to the agency.
Section I. Background, C. Discussion of Special Considerations of Types of Human Prescription Drug Labeling, 2. Prescribing Information (Circular of Information) for Blood and Blood Components Intended for Transfusion, the following information is provided. “…labeling and registration and listing information for blood and blood components are currently not electronically submitted to the Agency. FDA is in the process of developing standards for the electronic submission of labeling for these products, and these standards will eventually accommodate blood and blood components. The Agency will consider progress in developing such standards when setting a compliance date for blood and blood components and/or on our own initiative granting an exemption for blood and blood components for a period of time until electronic submission of the labeling for blood and blood components is supported. Thus, the final regulation may include staggered compliance dates, with a later compliance date for blood and blood components and an earlier compliance date for all other drug products. We also invite public comment on whether blood and blood components intended for transfusion should be subject to the electronic distribution of prescribing information requirements in this proposed rule once the electronic submission standards accommodate these products.”
Elsewhere in this document we have explained the process currently used to produce the contents of the Circular and the process, or guidance document, used by the FDA to recognize the “common” Circular. The guidance document used to recognized the common Circular also provides implementation instructions for users of the common Circular (Annual Report to the FDA) that avoids unnecessary PAS submissions. A PAS is needed only when the manufacturer amends the Circular to reflect a unique local practice.
Currently, the paper version of the Circular contains several blank pages for the easy addition of stickers to include interim language addressing new processes, products or tests until an updated version of the Circular is printed. This language is also crafted by the AABB COI Task Force, reviewed and recognized by FDA, posted on the AABB website and publicized in AABB, ABC, ARC, and ASBP newsletters. Blood providers can then immediately print stickers and apply them to their existing stock of printed Circulars, and distribute them immediately. Because the Circular is not individually packaged with each component like traditional pharmaceuticals and therefore stockpiled in inventory with potentially outdated inserts, the delay in distributing the updated version in place of the older one is minimal.
Because CBER has not developed standards for electronic submission of labeling for blood components it is not clear what resources will be needed to produce an electronic version of a “common” Circular that would comply with FDA requirements in the future. For that reason we believe it is appropriate to exempt Blood and blood components intended for transfusion (and the Circular of Information for the Use of Human Blood and Blood Components) from the requirements of the proposed rule.
SECTION – 606.121 Container label.
(ii) ‘‘See circular of information for indications, contraindications, cautions, and methods of infusion. To obtain the current circular of information, go to
labels.fda.gov, or call (insert toll-free telephone number) for a faxed, emailed, or mailed copy.’’ This statement must be no smaller than 6-point type.
RECOMMENDATION – §606.121(c)(8)(ii) should not be updated to include “To obtain the current circular of information, go to
labels.fda.gov, or call (insert toll-free telephone number) for a faxed, emailed, or mailed copy.”
RATIONALE – In accordance with FDA and ISBT labeling guidelines, the current information placed in the upper left quadrant of the blood label is required by the Code of Federal Regulations, 21 CFR 606.121, and fills almost the entire quadrant (see figure below). It is not clear how the requirements of the proposed rule are supposed to conform with version 3.0 of the ISBT labeling standards. Information regarding the Circular is communicated in the minimum font size, and the proposed language would require several more lines. Reduction in font size of unit-specific attributes (such as volunteer donor) in this or other quadrants would not be an appropriate accommodation, and would in fact create a crowded label with very small type – the very thing the FDA is seeking to avoid with electronic package inserts. To ensure patient safety and appropriate use, labels must remain uncluttered, clearly legible and able to emphasize important unit-specific information. AS noted above, the current information on the label is required by the CFR and cannot be shortened or removed. The language required by the new proposal will not fit onto the label. ‘‘See circular of information for indications, contraindications, cautions, and methods of infusion.
To obtain the current circular of information, go to
labels.fda.gov, or call (1(800-XXX-XXXX) for a faxed, emailed, or mailed copy. This product may transmit infectious agents. Rx only.”
SECTION – 606.122 Circular of Information, Introductory text
Remove the words ‘‘must be available for distribution’’ and add in their place ‘‘must be distributed electronically.’’
RECOMMENDATION - The change to this section should be the addition of “may be distributed electronically.”
RATIONALE – Electronic distribution should be an available option for the Circular but the process described by the proposed rule does not seem to fit a document that is commonly derived and utilized by multiple establishments.
In summary, we thank the FDA for the opportunity to provide comments on this proposed rule. At this time, for the reasons outlined above, we respectfully submit that blood and blood components intended for transfusion and the Circular of Information for the Use of Human Blood and Blood Components be excluded from the requirements of the proposed rule. We do not believe that requiring an electronic submission of the Circular to
labels.fda.gov will significantly improve patient safety, advance patient care, or provide healthcare labor or cost savings. Clarifying 21 CFR 606.122 to ensure electronic distribution of the Circular is an available option will be helpful to the process currently in place for use of the common Circular.
We look forward to continuing to work with the FDA on patient and donor safety initiatives. Questions concerning these comments may be directed to
M. Allene Carr-Greer
Director, Regulatory Affairs