[Federal Register Volume 76, Number 99 (Monday, May 23, 2011)]
[Notices]
[Pages 29752-29754]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-12627]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Nomination of In Vitro Test Methods for Detection and
Quantification of Botulinum Neurotoxins and Detection of Non-Endotoxin
Pyrogens; Data Request for Substances Evaluated by These Test Methods
AGENCY: Division of National Toxicology Program (NTP), National
Institute of Environmental Health Sciences (NIEHS), National Institutes
of Health (NIH).
ACTION: Request for comments and/or data.
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SUMMARY: On behalf of the Interagency Coordinating Committee on the
Validation of Alternative Methods (ICCVAM), the NTP Interagency Center
for the Evaluation of Alternative Toxicological Methods (NICEATM)
requests public comment on nominations received for (1) Three in vitro
test methods proposed for detecting and quantifying botulinum
neurotoxin (BoNT), and (2) an in vitro test method proposed for
detecting non-endotoxin pyrogens. NICEATM seeks data generated using
alternative test methods for detecting and quantifying BoNT, including
but not limited to three test methods nominated by BioSentinel
Pharmaceuticals, Inc. (BioSentinel). Data from the standardized mouse
LD50 assay currently used for these endpoints are requested
for comparison. In addition, NICEATM seeks data generated using
alternative test methods for identifying non-endotoxin pyrogens,
including but not limited to the monocyte activation test (MAT), which
was nominated by Biotest AG. Data on non-endotoxin pyrogens tested in
the rabbit pyrogen test (RPT) are requested for comparison. NICEATM
received nominations for validation studies on each of the above test
methods, which have the potential to reduce or replace animal use for
regulatory testing. At this time, ICCVAM requests public comments on
the appropriateness and relative priority of these activities.
DATES: For consideration by the Scientific Advisory Committee on
Alternative Toxicological Methods (SACATM) at its annual meeting (67 FR
23323), comments and data are
[[Page 29753]]
requested by June 2, 2011. NICEATM and ICCVAM will accept comments and
data for these nominations until July 7, 2011.
FOR FURTHER INFORMATION CONTACT: Dr. Warren Casey, Deputy Director,
NICEATM, NIEHS, P.O. Box 12233, Mail Stop: K2-16, Research Triangle
Park, NC, 27709, (telephone) 919-541-2384, (fax) 919-541-0947, (e-mail)
[email protected]ov. Courier address: NICEATM, NIEHS, Room 2034, 530
Davis Drive, Morrisville, NC 27560.
SUPPLEMENTARY INFORMATION:
Nomination for the Detection and Quantification of BoNTs
In 2006, NICEATM and ICCVAM convened a workshop, Alternative
Methods to Refine, Reduce, or Replace the Mouse LD50 Assay
for Botulinum Toxin Testing, in response to a nomination from the
Humane Society of the United States requesting that ICCVAM assess the
availability of alternative methods to replace the mouse
LD50 assay for BoNT potency testing. Workshop participants
concluded that some of the methods considered could be used, in
specific circumstances or in a tiered-testing strategy, to reduce or
refine the use of mice in current in vivo BoNT testing protocols
(ICCVAM, 2008a). However, none of the reviewed methods was considered
suitable to serve as a complete replacement for the mouse
LD50 assay, either for detection of BoNT or for potency
determination. The workshop participants noted that some of the methods
considered might be useful as replacements for the mouse
LD50 assay in the future given additional development and
validation efforts.
BioSentinel has developed tests for the detection and
quantification of BoNTs. These tests include the in vitro
BoTestTM and BoTestTM Matrix assays and the cell-
based assay BoCeIlTM. Following appropriate validation and
demonstration of adequate performance, these methods may have the
potential to meet regulatory requirements for detection and
quantification of BoNTs in a range of applications.
BioSentinel has forwarded a nomination for these methods to (1)
Facilitate collaboration to develop a validation strategy which could
lead to the regulatory acceptance of the test methods for the detection
and quantification of BoNT contained in suspect substances, the
determination of drug product potency, and/or the clinical diagnosis of
botulism and (2) coordinate and conduct necessary validation studies.
Nomination for the Detection of Non-Endotoxin Pyrogens
ICCVAM previously evaluated the validation status of five in vitro
test methods proposed for assessing the potential pyrogenicity (i.e.,
ability to induce fever) of pharmaceuticals and other products, as
potential replacements for the RPT. Subsequent to this evaluation,
ICCVAM recommended that, although none of the test methods should be
considered as a complete replacement for the RPT for the detection of
Gram-negative endotoxin, they can be considered for use to detect Gram-
negative endotoxin in human parenteral drugs on a case-by-case basis,
subject to product-specific validation to demonstrate equivalence to
the RPT, in accordance with applicable U.S. Federal regulations
(ICCVAM, 2008b). ICCVAM recognized that these test methods could be
applicable for detection of a wider range of pyrogens, including non-
endotoxin pyrogens, and made recommendations for future studies that
could expand their applicability. In response to these recommendations,
Biotest AG recently nominated a commercialized version of one of these
tests (i.e., MAT), which uses cryopreserved human blood and quantitates
the induction of interleukin (IL)-1[beta], for additional validation
studies to evaluate its usefulness for identifying non-endotoxin
pyrogens.
Draft ICCVAM Conclusions and Recommendations
Based on the information provided by the test method sponsors,
ICCVAM concludes that the nominated activities are of sufficient
interest and applicability to warrant further evaluation. ICCVAM's
preliminary recommendation is that both nominations should have a high
priority for further discussion to assess what information is needed to
adequately characterize the usefulness and limitations of the proposed
test methods, and any other similar in vitro test methods, for these
endpoints. These assessments will identify what data are needed and
what studies are required to fill any data gaps that are identified.
Studies identified as necessary to adequately characterize the
validation status for regulatory testing purposes are proposed to have
a high priority.
As part of the nomination review process, NICEATM invites public
comments on these nominations and the appropriateness and relative
priority assigned by ICCVAM to the nominated activities. ICCVAM will
finalize its recommendations on the priority of these nominations after
considering comments received from the public and SACATM, which will
comment on the ICCVAM draft recommendations at its meeting on June 16-
17, 2011.
Background Information on ICCVAM, NICEATM, and SACATM
ICCVAM is an interagency committee composed of representatives from
15 Federal regulatory and research agencies that require, use,
generate, or disseminate toxicological and safety testing information.
ICCVAM conducts technical evaluations of new, revised, and alternative
safety testing methods with regulatory applicability and promotes the
scientific validation and regulatory acceptance of toxicological and
safety testing methods that more accurately assess the safety and
hazards of chemicals and products and that reduce, refine (decrease or
eliminate pain and distress), or replace animal use. The ICCVAM
Authorization Act of 2000 (42 U.S.C. 285l-3) established ICCVAM as a
permanent interagency committee of the NIEHS under NICEATM. NICEATM
administers ICCVAM, provides scientific and operational support for
ICCVAM-related activities, and conducts independent validation studies
to assess the usefulness and limitations of new, revised, and
alternative test methods and strategies. NICEATM and ICCVAM work
collaboratively to evaluate new and improved test methods and
strategies applicable to the needs of U.S. Federal agencies. NICEATM
and ICCVAM welcome the public nomination of new, revised, and
alternative test methods and strategies for validation studies and
technical evaluations. Additional information about ICCVAM and NICEATM
can be found on the NICEATM-ICCVAM Web site (http://iccvam.niehs.vnih.gov).
SACATM was established in response to the ICCVAM Authorization Act
(Section 285l-3(d)) and is composed of scientists from the public and
private sectors. SACATM advises ICCVAM, NICEATM, and the Director of
the NIEHS and NTP regarding statutorily mandated duties of ICCVAM and
activities of NICEATM. SACATM provides advice on priorities and
activities related to the development, validation, scientific review,
regulatory acceptance, implementation, and national and international
harmonization of new, revised, and alternative toxicological test
methods. Additional information about SACATM, including the charter,
roster, and records of past meetings, can be found at http://ntp.niehs.nih.gov/go/167.
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References
ICCVAM. 2008a. ICCVAM-NICEATM/ECVAM Scientific Workshop on
Alternative Methods to Refine, Reduce, or Replace the Mouse
LD50 Assay for Botulinum Toxin Testing. NIH Publication
No. 08-6416. Research Triangle Park, NC: NIEHS. Available: http://iccvam.niehs.nih.gov/docs/biologics-docs/BoNTwkshprept.pdf.
ICCVAM. 2008b. ICCVAM Test Method Evaluation Report: Validation
Status of Five In Vitro Test Methods Proposed for Assessing
Pyrogenicity of Pharmaceuticals and Other Products. NIH Publication
No. 08- 6392. Research Triangle Park, NC: NIEHS. Available: http://iccvam.niehs.nih.gov/methods/pyrogen/pyr_tmer.htm.
Dated: May 16, 2011.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2011-12627 Filed 5-20-11; 8:45 am]
BILLING CODE 4140-01-P