December 16, 2011
VIA FACSIMILE AND USPS
Lora Peknik-Graham, Pharm.D.
Product Manager, Global Regulatory Affairs
275 N. Field Drive
Dept 0389, Building H2
Lake Forest, IL 60045
Re: NDA#: BN070012
Voluven (6% Hydroxyethyl Starch 130/0.4 in 0.9% sodium chloride injection)
Dear Dr. Peknik-Graham:
The Advertising and Promotional Labeling Branch (APLB) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) reviewed your sales aid (P10-2699/R1) submitted February 10, 2011 under cover of Form FDA 2253 for your product Voluven® (6% Hydroxyethyl Starch 130/0.4 in 0.9% sodium chloride injection).
Your promotional material is false and misleading because it makes unsubstantiated efficacy and comparative claims, and minimizes risk information. Therefore, your material misbrands Voluven 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), (e)(6)(ii), and (e)(5)(iii).
According to the FDA-approved prescribing information (PI), Voluven is indicated for the treatment and prophylaxis of hypovolemia. It is not a substitute for red blood cells or coagulation factors in plasma.
The CLINICAL STUDIES section of the PI states that Voluven was studied in patients undergoing various types of surgery (orthopedic, urologic, cardiac) and trauma intensive care for situations in which hypovolemia is treated (pre-, intra-, and postoperative) or prevented (autologous blood donation, acute normovolemic hemodilution, hypervolemic hemodilution before cardiac surgery).
According to the Pharmacokinetics subsection of the PI, no significant plasma accumulation occurred after daily administration of 500 mL of a 10% solution containing hydroxyethyl starch 130/0.4 over a period of 10 days.
The Postmarketing Experience subsection of the PI states that, with the administration of hydroxyethyl starch (HES) solutions, disturbances of blood coagulation can occur depending on the dosage.
Unsubstantiated Efficacy Claims
Promotional materials are false or otherwise misleading if they contain a representation or suggestion, not approved or permitted for use in the labeling, that a drug is better, more effective, or useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.
The pictorial at the top of page 12 broadens the indication for Voluven by including cardiac pump priming and major abdominal surgery. The PI makes no mention of cardiac pump priming or major abdominal surgery as an approved indication for Voluven.
On page 18, the sales aid states that Voluven “can help avoid edema.” This statement is misleading because it has not been demonstrated by substantial evidence or substantial clinical experience that Voluven minimizes edema. If you have data to support such claims, please submit them to the FDA.
Unsubstantiated Comparative Claims
Promotional materials are misleading if they represent or suggest 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.
The sales aid contains claims that there is a lack of accumulation associated with Voluven as compared with hetastarch. For example, the sales aid states that 6% hetastarch is “not easily eliminated and can accumulate in plasma and tissues.” Then, the following claims are made about Voluven throughout the sales aid:
- “complete elimination without accumulation”
- “molecularly engineered to avoid accumulation”
- “less potential for accumulation”
- “helps facilitate metabolism and avoid accumulation”
- “sustained plasma volume expansion efficacy without accumulation”
- “no evidence of accumulation with Voluven”
- “can be dosed up to 10 days with no significant accumulation”
- “engineered for effective plasma volume expansion without accumulation”
- “distinct molecular properties result in rapid elimination to avoid accumulation”
Support for these claims is based on a small (n=12) study in healthy male volunteers that reported, "No significant plasma accumulation occurred after daily administration of 500 mL of 10% hydroxyethyl starch 130/0.4 over a period of 10 days." However, the volume a 70 kilogram patient could receive according to the DOSAGE AND ADMINISTRATION section of the PI is seven-fold higher, equivalent to 3500 mL per day of 6% hydroxyethyl starch 130/0.4. The sales aid is misleading because the above claims are not based on doses cited in the PI.
In addition, the graph on page 8 indicates that the mean transfusion of packed red blood cells (RBC) plus whole blood and salvaged blood was lower (p-value <0.03) in patients receiving Voluven (8.0 mL/kg) than hetastarch (13.8 mL/kg). The table is considered misleading because the analyses do not represent substantial evidence from comparative clinical trials or substantial clinical experience with both products.
Furthermore, the sales aid attributes the benefit of sustained plasma volume to the high C2:C6 ratio of Voluven. There is no substantial evidence or substantial clinical experience demonstrating that a C2:C6 ratio of 9:1 results in more sustained volume expansion compared with a hetastarch solution of a 5:1 ratio. If you have data to support such claims, please submit them to the FDA.
Minimization of Risk Information
Promotional materials are misleading if they fail to reveal facts material in the light of representations or material with respect to consequences that may result from the use of the drug as recommended or suggested in the advertisement.
The table on page 3 of the sales aid is misleading because it fails to mention disturbances of blood coagulation with the use of Voluven. The PI describes disturbances of blood coagulation with the administration of hydroxyethyl starch solutions, depending on the dosage.
Conclusion and Requested Actions
For the reasons discussed above, your promotional materials misbrand Voluven 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), (e)(6)(ii), and (e)(5)(iii).
We request that Hospira immediately cease the dissemination of this violative promotional material for Voluven, 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 Voluven, and explaining your plan for discontinuing use of such materials. Please direct your response to 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 NDA 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 Voluven 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
Center for Biologics Evaluation and Research