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Approval Memorandum - Voluven, December 20, 2007

APPROVAL MEMORANDUM

DATE: December 20, 2007
 
FROM: Elena Karnaukhova, Ph.D.; HFM-343; LBVB, DH, OBRR, CBER; (301) 402-4635, FAX (301) 402-2780
SUBJECT: Overview memo for original NDA 70012/0.0, including DMF2 IND#-------, and the related twenty two Amendments, for 6% hydroxylethyl starch (HES) 130/0.4 in 0.9% sodium chloride infusion (Voluven®), submitted by Carolina Research Group on behalf of Fresenius Kabi Deutschland GmbH
THROUGH: Abdu Alayash, Ph.D., Chief; HFM-343, LBVB, DH, OBRR, CBER; (301) 827-3813, FAX (301) 435-4034 Jonathan Goldsmith, M.D.,Deputy Director CBER/OBRR
TO: File NDA BN70012/0.0
CC: Franklin Stephenson, Pauline Cottrell, Mahmood Farshid, Basil Golding, Larry Landow, Paul Buehler, Yiping Jia, Iftekhar Mahmood, Tie-Hua Ng, Nancy Chamberlin, Chiang Syin.

ACTION RECOMMENDED: Based on multidisciplinary review of NDA BN070012 and the individual conclusions of all members of the review committee, 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride infusion (Voluven®) can be approved with post marketing commitments.

SUMMARY

Submission date: 2-28-2007
CBER receipt date: 3-1-2007 (L#412822)
Sponsor: Fresenius Kabi Deutschland GmbH (FK)
US Agent: Carolina Research Group, Inc. (CRG)
Type of submission: Original NDA
Product licensed name: 6% HES 130/0.4 in 0.9% sodium chloride infusion
Proposed Proprietary Name: Voluven®
Proposed Indication: treatment and prophylaxis of hypovolemia
Route of Administration: Intravenous use
Dosage Form: Solution for intravenous infusion
Proposed Marketing Status: Prescription Product

Manufacturing facilities

Voluven® is manufactured by:
Fresenius Kabi Norge AS,
Svinesundveien 80,
NO-1753 Halden
Norway

HES for Voluven® is manufactured by:
Fresenius Kabi Austria GmbH,
Estermannstraße 17
A-4020 Linz
Austria

Sponsor:
Fresenius Kabi Deutschland GmbH
Else-Kröner-Straße 1
61352 Bad Homburg v.d.H.
Germany

This memo is an overview of the review process of a new drug application (including the original NDA BN070012, original Master Files DMF2 IND#-------, and the related twenty two Amendments) for 6% HES 130/0.4 in 0.9% sodium chloride infusion (Voluven®).

Review responsibilities for this NDA were as follows:

Pre-Clinical Toxicology: Paul Buehler, Ph.D.
Pre-Clinical Pharmacology: Iftekhar Mahmood, Ph.D.
Clinical Pharmacology and Clinical Data: Laurence Landow, M.D.
Statistical Analysis of Clinical Data: Tie-Hua Ng, Ph.D.
Proprietary Name and Labeling: Nancy Chamberlin, Pharm.D.
Chemistry, Manufacturing, and Controls (CMC): Yiping Jia, Ph.D., and Elena Karnaukhova, Ph.D. (chair)
Establishment Inspection: Ms. Janie Russell.
Regulatory Project Manager: Mr. Franklin Stephenson

Background

HES 130/0.4 is a white to yellowish white, odorless and tasteless, amorphous powder, soluble in water in every concentration, soluble in DMSO, and practically insoluble in most organic solvents.

Voluven® is a clear 6% hydroxyethyl starch (HES 130/0.4) solution in isotonic sodium chloride solution for intravenous infusion for the "Therapy and prophylaxis of hypovolaemia". The product is supplied in freeflex® bags made from co-extruded polyolefines of --------------------- and ship-shape ports. The nominal fill volume is 500 mL with filling limits of ------- mL.

Voluven® contains HES 130/0.4 in a colloidal solution which expands plasma volume when administered intravenously. The effect of the HES contained in Voluven® on intravascular volume expansion and hemodilution is a function of the mean molecular weight (130,000 daltons; range 110,000 - 150,000 daltons), the molar substitution by hydroxyethyl groups (0.42; range 0.38 - 0.45) on glucose units of the starch, the pattern of hydroxyethyl substitution (C2/C6 ratio) of approximately 9:1, and the concentration (6%), as well as the dose and infusion rate.

The starting material for HES 130/0.4 is a thin boiling waxy corn starch, a polymeric glucose derivative (amilopectine) that mainly consists of α-1,4-connected glucose units with several α-1,6-branches, also containing a small amount of amylase. Hydroxyls at the 2, 3 and 6 positions of glucose are subject to partial derivatization to hydroxyethyl groups (see Attachments 1 and 2).

Stability

The post-approval stability protocol and stability study will be performed according to -------------------------- ---------------------- primary packaging material (see Attachment 2). The monitoring parameters are Appearance: white to yellowish white powder; -------------------------- ----------------------- ---------------------------------- ------------------- Mw: 110,000 - 150,000 Dalton; M at --- --------------------------------------------------------- ----------------------------; --------------------; Molar substitution: 0.38 - 0.45; C2/C6 ratio: ------ ------- -------------------------------- ------------------- -------- ----------------------------------------------------------

Total -- batches of Voluven 6% drug product in the freeflex® container have been produced at Fresenius Kabi Norge AS (FK Norway). The ongoing stability studies will be continued up to a storage period of ----------------------. The results of all stability studies demonstrate that Voluven 6% is stable during the tested period, independent of whether the product was manufactured at the facilities in Norway or in Germany. Stability data will be reported annually (21 CFR 314.81).

Adventitious agents safety evaluations

None of the raw materials used in the manufacturing of Voluven® is of ruminant origin as defined in section 2 of the CPMP-Guideline (CPMP/BWP/1230/98. No ruminant-derived materials from BSE countries as defined by the US Department of Agriculture (9CFR 94.11) are used.

Labeling

The proposed labeling was subject to multiple significant changes by the members of the review committee and by the sponsor. All reviewers agreed on the final version of the labeling.

Post-marketing commitments

There are two post-marketing commitments agreed to for clinical studies related to efficacy and safety of Voluven® as follows:

  1. Completion of a multiple-dose, randomized, controlled trial (RCT) to be conducted in subjects with severe sepsis with or without renal dysfunction (see Attachment 6), and
  2. According to the recommendation of the Pediatric Review Committee, the sponsor will conduct a clinical study of the efficacy and safety of 6% HES 130/0.4 vs. 5% HSA in volume substitution therapy during open heart surgery in 2 to 12 year old pediatric patients (see Attachment 10).

     


During the review process, there were several information requests and several telecons regarding CMC and clinical issues. The firm's responses were provided in twenty two Amendments to the referenced submission. The responses were found to be generally acceptable for the fore-mentioned post-marketing commitments.

Recommendation for approval of NDA BN07012 with the post-marketing commitments reflects the individual recommendations of all members of the review committee as evident from the following authorized review memos:

Attachment 1: Manufacturing Process and Controls (Yiping Jia)

Attachment 2: Analytical Procedures (Elena Karnaukhova)

Attachment 3: Establishment (Janie Russell)

Attachment 4: Pre-Clinical Toxicology (Paul Buehler)

Attachment 5: Pre-Clinical Pharmacology (Iftekhar Mahmood)

Attachment 6: Clinical Pharmacology/Data (Laurence Landow)

Attachment 7: Statistical Analysis (Tie-Hua Ng)

Attachments 8&9: Proprietary Name and Labeling (Nancy Chamberlin)

RECOMMENDATIONS

Based on a multidisciplinary review of NDA BN070012 and the individual conclusions of all members of the review committee, 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride infusion (Voluven®) can be approved with two post marketing commitments.

 

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