October 24, 2011
VIA FACSIMILE AND UPS NEXT DAY AIR
Richard A. Scotland
Senior Vice President - Regulatory Affairs and Pharmacovigilance
GTC Biotherapeutics, Inc.
175 Crossing Boulevard
Framingham, MA 01702
Re: BLA STN# 125284
ATryn (Antithrombin [Recombinant])
Dear Mr. Scotland:
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 Visual Aid (ATR102) and Booth Panels (ATR104, ATR105, ATR107, and ATR108) for ATryn (Antithrombin [Recombinant]) submitted by GTC Biotherapeutics, Inc. (GTC) under cover of Form FDA 2253.
These promotional materials are false, misleading or lacking in fair balance because they make unsubstantiated superiority safety and efficacy claims, and minimize the risks associated with ATryn. Therefore, they misbrand ATryn under section 502(a) and 502(n) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. §352(a) and 352(n), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(5) and (e)(6)(ii).
According to the FDA-approved prescribing information (PI), ATryn is a recombinant antithrombin indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin (AT) deficient patients. It is not indicated for the treatment of thromboembolic events in hereditary antithrombin deficient patients.
As stated in the DESCRIPTION section of the PI,
Antithrombin (recombinant) (rAT), the active ingredient of ATryn, is produced by recombinant DNA technology using genetically engineered goats into which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, which directs the expression of the antithrombin into the milk.
The amino acid sequence of rAT is identical to that of human plasma-derived antithrombin (hpAT). rAT and hpAT both contain six cysteine residues forming three disulphide bridges and 3-4 N-linked carbohydrate moieties. The glycosylation profile of rAT is different from hpAT, which results in an increased heparin affinity. When assayed in the presence of excess of heparin, the potency of the recombinant product is not different from that of plasma derived product.
When compared to hpAT, the CLINICAL PHARMACOLOGY section of the PI states:
ATryn has a shorter half-life and more rapid clearance (approximately nine and seven times, respectively). Pharmacokinetics may be influenced by concomitant heparin administration, as well as surgical procedures, delivery, or bleeding.
Unsubstantiated Superiority Efficacy and Safety Claims
Promotional materials are misleading if they represent or suggest that a drug product is safer or more effective than another drug in some particular when it has not been demonstrated to be safer or more effective in such particular by substantial evidence or substantial clinical experience.
In terms of safety, the Visual Aid and Booth Panels ATR104 and ATR107 contain the following claim:
ATryn: An effective way to avoid the risks of plasma-derived products
This claim is misleading because it suggests that ATryn, a recombinant antithrombin, is safer than hpAT. This misleading impression is furthered emphasized by the following statements on the inside and back pages of the Visual Aid:
… recombinant AT avoids risk of plasma-derived products
No risk of transmission from any human blood-borne diseases.
The overall presentation implies that hpAT presents a greater risk than ATryn which has not been demonstrated by substantial evidence or substantial clinical experience. In terms of potential risks, you fail to disclose that ATryn has the potential safety issue of developing an immunological reaction to the recombinant protein itself, not just to any contaminating proteins. A post-marketing patient registry has been established to collect additional data on the immunogenic potential of ATryn.
In terms of efficacy, the Visual Aid and Booth Panels ATR105 and ATR108 present the following misleading graphs:
“Maintains more consistent target plasma AT activity in hereditary AT deficiency 24 hours after start of continuous infusion.” (Graph # 1 – This graph is in the middle of the left side panel of the Visual Aid and Booth Panel ATR105)
Graph #1 shows that, at 24 hours after start of therapy, 80% of ATryn treated patients have plasma AT activity between 80-120% of normal values, compared to only 23% of hpAT treated patients, who had AT activity within the 80-120% range at the peak level at the end of infusion (15 minutes after the 24 hour trough level).
“Lower concentration of heparin required for thrombin inhibition” (Graph #2 – This graph is on the lower portion of the left side panel of the Visual Aid and Booth Panel ATR105)
Graph #2 shows that ATryn requires less heparin for half-maximal thrombin inhibition than that required by hpAT, 0.045 nmol/L compared to 0.151 nmol/L, respectively. These data were referenced to “Data on file,” but were actually from a study published by Edmunds et al. in 1998.
“Restores 96.3% of functional AT levels in hereditary AT deficiency at completion of continuous infusion therapy” (Graph #3 – This graph is on the upper right side panel of the Visual Aid and on the upper half of Booth Panel ATR108)
Graph #3 shows that AT levels were above 80% of normal AT activity in 82.7% of samples taken during treatment and 96.3% of samples taken on the last day of treatment from ATryn treated patients compared to 63.9% and 42.1% of samples from hpAT, respectively.
By implying that ATryn provides more consistent target plasma AT activity, requires lower concentration of heparin for thrombin inhibition, and restores higher functional AT levels at completion of therapy than hpAT, these graphs misleadingly suggest that ATryn is more effective than hpAT, when such has not been demonstrated by substantial evidence or substantial clinical experience. Moreover, ATryn and hpAT have different dosing frequencies and regimens which confound comparisons of this nature.
According to the CLINICAL STUDIES section of the PI, ATryn was found to be non-inferior to hpAT in terms of the prevention of peri-operative or peri-partum thromboembolic events. Specifically, the efficacy of ATryn to prevent the occurrence of venous thromboembolic events was assessed in two prospective, single-arm, open-label studies by comparing the incidence of the occurrence of such events during treatment and up to 7 days after stopping AT treatment in 31 ATryn treated hereditary AT deficiency patients versus 35 hpAT treated hereditary AT deficiency patients. There was one confirmed diagnosis of an acute deep vein thrombosis in the ATryn treated group compared to none in the hpAT treated group.
Claims or comparisons that represent or suggest that a product is safer or more effective than another product are misleading if not supported by substantial evidence or substantial clinical experience. FDA is unaware of any adequate and well-controlled clinical trials comparing ATryn to hpAT or any data to support the claims that ATryn is safer or more effective than hpAT. If you have data to support such claims, please submit them to FDA.
Minimization of Risk Information
Promotional materials are misleading if they fail to present information about risks associated with a product with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the product.
The Visual Aid presents the following statement on the front page:
In the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin (AT)-deficient patients … ATryn: An effective way to avoid the risks of plasma-derived products.
Using this claim as the sole headline on the page, you fail to present a fair balance between risk information and efficacy information on that page spread.
Conclusion and Requested Actions
For the reasons discussed above, your promotional materials misbrand ATryn under section 502(a) of the Act, 21 U.S.C. §352(a), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(ii).
We request that GTC immediately cease the dissemination of these violative promotional materials for ATryn, 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 other violative promotional materials you have found for ATryn, and explaining your plan for discontinuing use of such materials. Please direct your response to Dr. Lisa Stockbridge, Ph.D., 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 ATryn 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
Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
 Edmunds T, Van Patten SM, Pollock J et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 1998 June 15;91(12):4561-71.