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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Review Memo - PREA

REVIEW MEMO

Re PREA study + labeling changes
IND/BLA BN070012
From Laurence Landow MD, Medical Officer
To Dov Golding MD, Director, Division of Hematology
Through Toby Silverman MD, Chief, Clinical Review Branch
Sponsor Fresenius Kabi Deutschland GmbH
Product 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride
Indication Treatment and prophylaxis of hypovolemia
RPM Franklin Stephenson
Receipt Date 6-MAR-2007
Review Completion Date 5-OCT-2007
Action Due Date 28-DEC-2007

Proposed Trial
Background

In response to a recommendation from the Pediatric Review Committee and conveyed to the sponsor in a teleconference on 14 December 2007, the sponsor has submitted the protocol for a proposed study to be conducted in children 2-12 y to support dosing of the product: "Efficacy and safety of 6% hydroxyethyl starch 130/0.4 vs 5% HSA in volume substitution therapy during open heart surgery in 2 to 12 year old pediatric patients." As indicated by the Committee, support for dosing instructions already exists for the (a) 0-2 y subpopulation based on results of study HS-13-27-DE and (b) 12-18 y subpopulation based on extrapolation from studies conducted in adults.

Proposed trial

This will be a Phase 3, randomized, controlled (5% albumin), multicenter trial in children (N=60) undergoing open heart surgery. Several non-IND studies in this population have been published in peer-reviewed journals.

The primary objective is show equivalence between 6% hydroxyethyl starch 130/0.4 and 5% HSA with respect to total volume of colloid solution (mL/kg) required for perioperative volume therapy (defined as induction of anesthesia until 24 h after wound closure). Success will be declared if the ratio (means) of investigational colloid /control colloid is in the range 0.55 - 1.82 (same ratio as used in the US Phase 3 orthopedic trial). Assuming a coefficient of variation of 0.363 (observed common mean ± SD in a prior published study: 39.95 ± 14.5 mL/kg body weight), power of 90%, and type 1 error rate of 0.05, 10 subjects per treatment arm would need to be enrolled (this trial will enroll 60 subjects).

A secondary objective is to compare hemodynamics, laboratory parameters, estimated blood loss, and adverse events between the two treatment arms. No colloid other than the investigational product or control will be permitted until 24 h after wound closure, after which only 5% HSA will be permitted. A transfusion trigger has yet to be defined.

Inclusion criteria include the following:

  • Male and female, 2 to 12 year old pediatric patients undergoing elective open-heart surgery requiring plasma volume substitution
  • Signed parental written informed consent and patient assent where achievable (e.g. patients > 6 years)
  • No participation in a clinical drug trial within the last two months or concomitantly

Exclusion criteria include the following

  • Known or suspected allergy to hydroxyethyl starch (such as rash), including its ingredients (inclusive corn) and related drugs
  • Known bleeding disorders or increased tendency to bleed in Medical History, e.g. hypofibrinogenemia, thrombocytopenia, or hemorraghic diathesis
  • Renal disease with oliguria or anuria not related to hypovolemia
  • Known pregnancy

PMC

The sponsor also has submitted the following PMC language:

"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."

Labeling Changes

Paragraph 2.2 ("Pediatric Dose") has been amended as follows (strikeouts and additions to the labeling as indicated in green font as per the sponsor):

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Conclusions

  1. The sponsor has submitted a proposed protocol in outline form that appears to meet the concerns of the Pediatric Review Committee in terms of dosing instructions for the 2-12 y age cohort.

     

     

  2. The proposed timelines are acceptable.

     

     

  3. The proposed labeling changes are acceptable contextually but the last sentence could be improved as follows:

     

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Recommendation

Approval.

 

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