March 05, 2010
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Mary Ann Lamb, Ph.D.
Vice President, Regulatory Affairs
Talecris Biotherapeutics, Inc.
8368 US 70 West
Clayton, North Carolina 27520
Re: Prolastin (Alpha1 Proteinase Inhibitor (Human))
BLA STN# 103174
Dear Dr. Lamb:
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) has reviewed a patient brochure, Prolastin Direct (ID # PR50-0409), for Prolastin (Alpha1 Proteinase Inhibitor (Human)) submitted by Talecris Biotherapeutics, Inc. (Talecris) under cover of Form FDA 2253.
This promotional material is false or misleading because it omits and minimizes the risks associated with Prolastin and overstates the efficacy of Prolastin. Therefore, this material misbrands Prolastin under sections 502(a) and 201(n) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. §352(a) and §321(n), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(i) and (e)(7)(viii).
According to the FDA-approved prescribing information (PI), Prolastin is indicated for chronic augmentation and maintenance therapy of individuals having congenital deficiency of alpha1-PI (alpha1-antitrypsin deficiency) with clinically demonstrable panacinar emphysema. Clinical and biochemical studies have demonstrated that with such therapy, it is possible to increase plasma levels of alpha1-PI, and that levels of functionally active alpha1-PI in the lung epithelial lining fluid are increased proportionately. As some individuals with alpha1-antitrypsin deficiency will not go on to develop panacinar emphysema, only those with evidence of such disease should be considered for chronic replacement therapy with Prolastin. Clinical data are not available as to the long-term effects derived from chronic replacement therapy of individuals with alpha1-antitrypsin deficiency with Prolastin. Only adult subjects have received Prolastin to date.
Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) should not receive Alpha1-Proteinase Inhibitor (Human), Prolastin, since these patients may experience severe reactions, including anaphylaxis, to IgA which may be present.
The Warnings section of the PI includes, but is not limited to, the following bolded risks associated with Prolastin:
Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C.
Adverse events reported with Prolastin include delayed fever, light-headedness, and dizziness. Mild transient leukocytosis and dilutional anemia several hours after infusion have also been noted.
Omission and Minimization of Risk Information
Promotional materials are misleading if they fail to reveal facts that are material in light of representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials, and if they fail to present information about risks associated with a drug with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug.
Specifically, the patient brochure presents multiple efficacy claims for Prolastin, such as “The Lung Preserver,” “helps protect your lungs” and “slow down any decline in your lung function” but fails to present the full contraindication for Prolastin. According to the Contraindications section of the PI, “Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) should not receive Alpha1-Proteinase Inhibitor (Human), Prolastin, since these patients may experience severe reactions, including anaphylaxis, to IgA which may be present.” Although the brochure states that individuals with selective IgA deficiencies should not receive Prolastin, it fails to include important information that these patients may experience severe reactions, including anaphylaxis.
Furthermore, the patient brochure has multiple pages of easy to read benefit information for Prolastin, presented with large lettering and white spacing. In contrast, the “Important Safety Information,” which includes the Contraindications, Warnings, and the most common adverse reactions associated with Prolastin, is difficult to read, presented in small font, with minimal white space, and presented in a blocked format on one-third of a page located on the second to last page of a 12-page brochure.
Misleading Efficacy Claims
Promotional materials are misleading if they represent or suggest that a product is more effective than has been demonstrated by substantial evidence or substantial clinical experience. For example, the brochure contains the following misleading statements [bolded for emphasis]:
- “They are the makers of PROLASTIN, which helps protect your lungs from damage by augmenting (increasing) your body’s level of alpha-1 antitrypsin (AAT).”
- “The goal of treatment is to slow “lung function decline,” or damage to your lungs. An effective drug therapy recommended for this is called “augmentation and maintenance” therapy.”
- “PROLASTIN is an augmentation therapy that helps protect the lungs from damage.”
- “It helps protect your lungs by raising AAT levels in both your blood and lungs above the level that is believed to be necessary to fight the progression of lung disease. It also helps slow down any decline in your lung function.”
- “When you receive augmentation therapy, your body gets a “boost” of AAT and its protective benefits. However if you smoke you are destroying that “boost” of protection.”
- “The Lung Preserver”
The above cited claims, “slow lung function decline,” “protect the lungs,” “slow down any decline in your lung function,” “protective benefits,” and “Lung Preserver,” are misleading because they imply a greater benefit for Prolastin-treated patients than is suggested by the PI or by substantial evidence or substantial clinical experience. These claims are not consistent with the INDICATIONS AND USAGE section of the PI, which states “Prolastin is indicated for chronic augmentation and maintenance therapy of individuals having congenital deficiency of alpha1-PI (alpha1-antitrypsin deficiency) with clinically demonstrable panacinar emphysema” (underlined for emphasis). Additionally, the PI states “Clinical data are not available as to the long-term effects derived from chronic replacement therapy of individuals with alpha1-antitrypsin deficiency with Prolastin.” Furthermore, the Dosage and Administration section of the PI states “the hypothesis that maintaining a serum level of antigenic alpha1-PI will restore protease-antiprotease balance and prevent further lung damage has never been tested in an adequately-powered clinical trial.”
FDA is unaware of any adequate and well-controlled clinical trials demonstrating protective benefits or long-term effects derived from Prolastin. If you have data to support such claims, please submit them to the FDA.
Conclusion and Requested Actions
For the reasons discussed above, your promotional material misbrands Prolastin under sections 502(a) and 201(n) of the Act, 21 U.S.C. §352(a) and §321(n), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(i) and (e)(7)(viii).
We request that Talecris immediately cease the dissemination of this violative promotional material for Prolastin, as well as promotional materials with the same or similar claims and representations. Please submit a written response within ten (10) business days of the date of this letter, stating whether you intend to comply with this request, listing all violative promotional materials for Prolastin and explaining your plan for discontinuing use of such materials. Please direct your response to Ms. Ele Ibarra-Pratt, RN, MPH, Branch Chief at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, Division of Case Management, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number. We remind you that only written communications are considered official responses.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Prolastin comply with each applicable requirement of the Act and FDA implementing regulations.
If you choose to revise your promotional materials, APLB is willing to assist you in assuring that your revised materials comply with applicable provisions of the Act by reviewing your revisions before you use them in promotion.
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research