[Federal Register Volume 73, Number 227 (Monday, November 24, 2008)]
[Notices]
[Pages 71003-71004]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-27790]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


National Toxicology Program (NTP); NTP Interagency Center for the 
Evaluation of Alternative Toxicological Methods (NICEATM); Availability 
of the Interagency Coordinating Committee on the Validation of 
Alternative Methods (ICCVAM) Test Method Evaluation Report: Validation 
Status of Five In Vitro Test Methods Proposed for Assessing Potential 
Pyrogenicity of Pharmaceuticals and Other Products and Final Background 
Review Document: Validation Status of Five In Vitro Test Methods 
Proposed for Assessing Potential Pyrogenicity of Pharmaceuticals and 
Other Products; Notice of Transmittal of ICCVAM Test Method 
Recommendations to Federal Agencies

AGENCY: National Institute of Environmental Health Sciences (NIEHS), 
National Institutes of Health (NIH)

ACTION: Availability of the ICCVAM Test Method Evaluation Report and 
Final Background Review Document.

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SUMMARY: NICEATM announces availability of the ICCVAM Test Method 
Evaluation Report: Validation Status of Five In Vitro Test Methods 
Proposed for Assessing Potential Pyrogenicity of Pharmaceuticals and 
Other Products (NIH Publication 08-6392). The test method evaluation 
report (TMER) describes five in vitro pyrogen test methods that can be 
used for detecting Gram-negative endotoxin in human parenteral 
pharmaceuticals. The report includes ICCVAM's (a) Recommendations on 
uses and limitations for each test method, (b) recommendations for 
standardized protocols, (c) recommendations for future studies, and (d) 
recommendations for the development of performance standards.
    ICCVAM concludes that none of these test methods can be considered 
as a complete replacement for the rabbit pyrogen test (RPT) for all 
testing situations for the detection of Gram-negative endotoxin. 
However, ICCVAM recommends that they can be considered for use on a 
case-by-case basis to detect Gram-negative endotoxin in human 
parenteral drugs, subject to product-specific validation to demonstrate 
equivalence to the RPT, in accordance with applicable U.S. Food and 
Drug Administration regulations. When used in this manner, these 
methods can reduce the number of animals needed for pyrogenicity 
testing. The report also recommends that these

[[Page 71004]]

and other in vitro alternative test methods be considered prior to in 
vivo pyrogenicity testing, where determined appropriate for a specific 
testing situation.
    NICEATM also announces availability of the final ICCVAM Background 
Review Document: Validation Status of Five In Vitro Test Methods 
Proposed for Assessing Potential Pyrogenicity of Pharmaceuticals and 
Other Products (NIH Publication 08-6391). The final background review 
document (BRD) provides the data and analyses used to assess the 
current validation status of these five in vitro test methods.
    The ICCVAM TMER and supporting BRDs have been forwarded to U.S. 
Federal agencies for regulatory and other acceptance consideration, 
where applicable. Responses received will be posted on the NICEATM-
ICCVAM Web site.

ADDRESSES: Electronic copies of the ICCVAM TMER and final BRD are 
available from the NICEATM-ICCVAM Web site at http://iccvam.niehs.nih.gov or by contacting NICEATM (see FOR FURTHER 
INFORMATION CONTACT).

FOR FURTHER INFORMATION CONTACT: Dr. William S. Stokes, Director, 
NICEATM, NIEHS, P.O. Box 12233, MD EC-17, Research Triangle Park, NC 
27709, (telephone) 919-541-2384, (fax) 919-541-0947, (e-mail) 
[email protected] Courier address: NICEATM, NIEHS, 79 T.W. 
Alexander Drive, Building 4401, Room 3128, Research Triangle Park, NC 
27709.

SUPPLEMENTARY INFORMATION: 

Background

    In 2005, the European Centre for the Validation of Alternative 
Methods (ECVAM), a unit of the Institute for Health and Consumer 
Protection at the European Commission's Joint Research Centre, 
submitted BRDs for five in vitro pyrogen test methods proposed as 
replacements for the RPT to ICCVAM for formal evaluation of their 
scientific validity for regulatory testing purposes. ICCVAM unanimously 
agreed that the five submitted in vitro pyrogen test methods should 
have high priority for evaluation. On December 16, 2005, NICEATM 
published a Federal Register notice (Vol. 70, No. 241, pages 74833-
74834), requesting public comments on the appropriateness and relative 
priority of convening an independent peer review panel (Panel) to 
evaluate the validation status of the five in vitro pyrogen test 
methods, the nomination of scientists to serve on the Panel, and the 
submission of data from in vivo and in vitro pyrogenicity testing. 
Based on the ECVAM BRDs as well as data and information submitted in 
response to the aforementioned Federal Register notice, NICEATM 
subsequently compiled a comprehensive draft BRD on the five in vitro 
pyrogen test methods and released it for public comment on December 12, 
2006 (Vol. 71, No. 238, pages 74533-74534).
    On February 6, 2007, NICEATM and ICCVAM convened a Panel to review 
the ICCVAM draft BRD for errors and omissions and to evaluate the 
validation status of the five in vitro pyrogen test methods. The Panel 
also reviewed the extent that the information contained in the ICCVAM 
draft BRD supported the ICCVAM draft test method recommendations for 
proposed test method uses, standardized protocols, test method 
performance standards, and additional studies. The Panel considered 
public comments made at the Panel meeting, as well as public comments 
submitted in advance of the meeting, before concluding their 
deliberations. NICEATM made the Panel's report available in May 2007 
(Vol. 72, No. 89, pages 26395-26396). The ICCVAM draft BRD and draft 
recommendations, the Panel's report, and all public comments were made 
available to the Scientific Advisory Committee on Alternative 
Toxicological Methods (SACATM) for review and comment at their meeting 
on June 12, 2007 (Vol. 72, No. 83, pages 23831-23832).
    ICCVAM considered the Panel's report, all public comments, and the 
comments of SACATM in finalizing its recommendations on the use of 
these five in vitro test methods proposed for assessing potential 
pyrogenicity of pharmaceuticals and other products. The ICCVAM TMER 
includes the ICCVAM recommendations on uses and limitations for each 
test method, standardized protocols, future studies, and the 
development of performance standards, as well as the Panel's report and 
Federal Register notices. The final BRD, which provides the supporting 
documentation for this report, is available as a separate document. 
ICCVAM forwarded the ICCVAM TMER and the supporting final BRD to U.S. 
Federal agencies for consideration, in accordance with the ICCVAM 
Authorization Act of 2000 (42 U.S.C. 285l-3). Agency responses to the 
ICCVAM test method recommendations will be made available on the 
NICEATM-ICCVAM Web site as they are received.

Background Information on ICCVAM, NICEATM, and SACATM

    ICCVAM is an interagency committee composed of representatives from 
15 Federal regulatory and research agencies that use, generate, or 
disseminate toxicological information. ICCVAM conducts technical 
evaluations of new, revised, and alternative methods with regulatory 
applicability and promotes the scientific validation and regulatory 
acceptance of toxicological test methods that more accurately assess 
the safety and hazards of chemicals and products and that refine, 
reduce, and replace animal use. The ICCVAM Authorization Act of 2000 
established ICCVAM as a permanent interagency committee of the NIEHS 
under NICEATM. NICEATM administers ICCVAM and provides scientific and 
operational support for ICCVAM-related activities. NICEATM and ICCVAM 
work collaboratively to evaluate new and improved test methods 
applicable to the needs of U.S. Federal agencies. Additional 
information about ICCVAM and NICEATM can be found at http://www.iccvam.niehs.nih.gov.
    SACATM was established January 9, 2002 (Vol. 67, No. 49, page 
11358), and is composed of scientists from the public and private 
sectors. SACATM provides advice to the Director of the NIEHS, to 
ICCVAM, and to NICEATM regarding the statutorily mandated duties of 
ICCVAM and activities of NICEATM. Additional information about SACATM, 
including the charter, roster, and records of past meetings, can be 
found at http://ntp.niehs.nih.gov/go/167.

    Dated: November 7, 2008.
Samuel H. Wilson,
Acting Director, National Institute of Environmental Health Sciences 
and National Toxicology Program.
[FR Doc. E8-27790 Filed 11-21-08; 8:45 am]
BILLING CODE 4140-01-P