| Public Health Service Food and Drug Administration |
| Center for Biologics Evaluation and Research 1401 Rockville Pike Rockville, MD 20852-1448 |
Department of Health and Human Services
August 3, 2010
CBER-10-07
VIA FACSIMILE AND UPS
Robert L. Parkinson, Jr.
Chairman of the Board, Chief Executive Officer and President
Baxter International Inc.
One Baxter Way
Deerfield, IL 60015-4625
RE: Aralast NP [AlphaI-Proteinase Inhibitor (Human)]
BLA STN 125039
WARNING LETTER
Dear Mr. Parkinson:
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has reviewed the Aralast NP Physician Brochure (HYL 4084A/HYL4084B) for the promotion of Aralast NP [Alpha1-Proteinase Inhibitor (Human)] submitted by Baxter Healthcare Corporation (Baxter) under cover of Form FDA 2253.
The brochure misbrands Aralast NP in violation of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 352(a) & (n); 321 (n)) and FDA implementing regulations, Cf 21 CFR 202.1(e)(6)(i), and (x), because it makes misleading efficacy claims for Aralast NP.
Moreover, we are very concerned by your continued violative promotion of your products. Baxter was cited for similar violations (overstatement of efficacy and unsubstantiated claims of superiority) in an April 14, 2009, Warning Letter and a July 7, 2008, Untitled Letter from OCBQ.
Background
According to the INDICATIONS AND USAGE section of the approved product labeling (PI):
Clinical data demonstrating the long-term effect of chronic augmentation or replacement therapy of individuals with ARALAST NP or ARALAST are not available.
The effect of augmentation therapy with ARALAST NP on pulmonary exacerbation and on the progression of emphysema in alpha1-antitrypsin deficiency has not been demonstrated in randomized, controlled clinical trials.
The CLINICAL PHARMACOLOGY section of the PI also states, in relevant part:
The intended theoretical goal [of Alpha1-Proteinase Inhibitor (α1-PI) augmentation therapy] is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors. Whether augmentation therapy with ARALAST NP actually protects the lower respiratory tract from progressive emphysematous changes has not been evaluated. Although the maintenance of blood serum of α1-PI (antigenically measured) 11 above µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection, this has not been proven.
The clinical benefit of the increased blood levels of Alpha1-Proteinase Inhibitor at the recommended dose has not been established.
Misleading Efficacy Claims
Promotional materials are misleading if they represent or suggest that a drug product is "more effective ... than has been demonstrated by substantial evidence or substantial clinical experience." Cf 21 CFR 202.1(e)(6)(i). The physician brochure (under "ARALAST NP THERAPY BENEFIT" heading) contains the following misleading statements of efficacy:
"ARALAST NP exceeds ATSIERS standards/or [alpha1-proteinase inhibitor] A1-PI serum concentrations by 31%"
"Studies show that blood levels of AAT in patients receiving ARALAST NP therapy are elevated above the protective threshold recommended by the ATSIERS standards. The protective threshold is the level of AAT below which there is an increased risk/or developing emphysema. "
"ARALAST Exceeds ATSIERS-recommended Serum Concentrations/or A1-PI" (title of graph)
These claims are misleading because they overstate the efficacy of Aralast NP. Specifically, they misleadingly imply that there is an alpha1- antitrypsin level that has been demonstrated to have a protective effect even though the clinical benefit of the increased blood levels of A1-PI at the recommended dose of augmentation therapy has not been established. Furthermore, the statements that emphasize a hypothetical threshold misleadingly imply that there is substantial evidence or substantial clinical experience that this threshold is clinically meaningful when such is not the case.
Conclusion and Requested Action
For the reasons discussed above, the brochure misbrands Aralast NP in violation of the Act (21 U.S.C. 352(a) & (n); 321(n)) and FDA's implementing regulations. Cf. 21 CFR 202.1(e)(6)(i) and (x).
We request that Baxter immediately cease the dissemination of violative promotional materials for Aralast NP such as the brochure described above. Please submit a written response to this letter within ten (10) business days of receipt of this letter, stating whether you intend to comply with this request, listing all promotional materials in use for Aralast NP that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials.
Additionally, since we have cited you for similar violations in the recent past, we request a response in writing indicating what policies and procedures your firm intends to adopt to ensure your prescription drug promotional activities comply with the Act and its implementing regulations, and an explanation of why/how you expect these policies and procedures to succeed. Please direct your response to me at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, HFM-600, 1401 Rockville Pike, Rockville, Maryland 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number and to CBER-10-07. We remind you that only written communications are considered official responses. If you choose to revise your promotional materials, we are willing to assist you with your revised materials by commenting on your revisions before you use them in promotion.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Aralast NP comply with each applicable requirement of the Act and FDA implementing regulations.
Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.
Sincerely,
/s/
Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
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