February 13, 2008
Our reference: NDA BN070012
Fresenius Kabi Deutschland GmbH
Attention: W. Gerald Cohn
c/o Carolina Research Group, Inc.
P.O. Box 32295
Raleigh, NC 27622
Dear Mr. Cohn:
Please find enclosed a corrected approval letter. Your approval date remains December 27, 2007. Correction has been made to your applicant name, your product proper name, and the pediatric study fulfillment requirements.
Please refer to your new drug application dated February 28, 2007 and received March 1, 2007, submitted under section 505(b)/pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride Injection (Voluven® 500 mL freeflex® flexible plastic intravenous solution container).
We acknowledge receipt of your submissions dated February 28; March 30; June 25 and 26; July 26; August 16 and 17; September 6 and 20; October 2, 4, 12, and 17; November 9, 14, 16, 27, and 30; and December 3, 10, and 18, 2007.
This new drug application provides for the use of 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride Injection (Voluven® 500 mL freeflex® flexible plastic intravenous solution container) for treatment and prophylaxis of hypovolemia.
We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling text.
The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert, text for the patient package insert). Marketing the product with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug.
Please submit an electronic version of the FPL according to the guidance for industry titled Providing Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15 of the copies on heavy-weight paper or similar material. For administrative purposes, designate this submission "FPL for approved NDA BN070012." Approval of this submission by FDA is not required before the labeling is used.
All applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We have reviewed your submission and agree that a deferral of your pediatric studies for 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride Injection for ages >2-12 years until 12 months after approval for the submission of the study protocol and until 36 months for the final study report is justified because adult studies and studies in age group 0-2 are completed and ready for approval.
We remind you of your postmarketing study commitments in your submission dated November 30, 2007. The commitments are listed below.
Postmarketing Studies subject to reporting requirements of 21 CFR 314.81
To perform a multiple-dose randomized controlled trial (RCT) to be conducted in subjects with severe sepsis including subjects with renal dysfunction and at risk for deterioration of renal dysfunction. Fresenius Kabi will submit the final Clinical Study Protocol of this Phase 3b study entitled "Crystalloids or colloids in patients with severe sepsis: effects on hemodynamics and tolerability of enteral nutrition" (Short title: CRYSTMAS, study code 06-HE06-01) within 3 months of the Approval Letter and will submit the final Clinical Study Report to FDA within 36 months of the Approval Letter.
Protocol Submission: by within 3 months of the date of this letter
Final Report Submission: by within 36 months of the date of this letter
Fresenius Kabi commits to perform a randomized controlled trial (RCT) to be conducted in children in the age group of 2 to 12 years. Fresenius Kabi will submit the final Clinical Study Protocol of this Phase 3 study entitled "Efficacy and safety of 6 % hydroxyethyl starch 130/0.4 (Voluven®) vs 5% HSA in volume substitution therapy during open-heart surgery in 2 to 12 years old pediatric patients" within 12 months of the Approval Letter and will submit the final Clinical Study Report to FDA within 36 months of the Approval Letter.
In addition, submit three copies of the introductory promotional materials that you propose to use for this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to this division/ the Division of Blood Applications and two copies of both the promotional materials and the package insert(s) directly to:
Food and Drug Administration
Center for Biologics Evaluation and Research
Advertising and Promotional Labeling Branch (HFM-602)
1401 Rockville Pike, Suite 200 North
Rockville, MD 20852-1448
We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81).
The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at www.fda.gov/medwatch/report/mmp.htm.
FDA has determined that referral of this application to the Blood Products Advisory Committee (BPAC) prior to approval (FDAAA [HR 3580-138 SEC. 918: REFERRAL TO ADVISORY COMMITTEE]) was not needed for the following reasons: Voluven®'s mechanism of action as a plasma volume expander indicated for the treatment and prophylaxis of hypovolemia is well studied and understood. The European-approved Voluven® product manufactured by Fresenius Kabi has demonstrated comparable safety and efficacy with similar products, such as hetastarch and pentastarch. Studies to evaluate the efficacy of Voluven® were adequate and the results did not raise any concerns related to safety. Review of information submitted in the NDA for Voluven® did not raise any controversial issues or pose unanswered scientific questions which would have benefited from advisory committee discussion and recommendations.
If you have any questions, please contact Franklin T. Stephenson, Regulatory Project Manager, at (301) 827-6165.
/Jonathan C. Goldsmith, M.D./
for Jay S Epstein, M.D.
Office of Blood Research and Review
Center for Biologics Evaluation and Research