Statement of Work_75N95022R00108.pdf

STATEMENT OF WORK

75N95022R00108

“Development and Maintenance of a Multigenotypic Aged Rat Colony”

1. BACKGROUND

Current and projected experiments using rodents to model the aging processes and age-related diseases in humans require animals of defined genotype and controlled environmental and health status. Only with the meticulous, long-term control of genetic and environmental variables is it possible to maintain relevant animal models that may be used to study many of the biological and behavioral processes in aging. Therefore, a continuous supply of genetically defined, well characterized inbred and hybrid laboratory animals is essential for a program of research on aging.

2. OBJECTIVE(S)

The objective is to develop, maintain and distribute a standing colony of aged, genetically defined laboratory rats for use by investigators in studies of aging. This colony is to be developed and maintained within controlled and defined barrier environments where animals are monitored and characterized for disease status and markers of genetic purity.

3. WORK TO BE PERFORMED

Independently, and not as an agent of the government, the Contractor shall furnish all necessary services, qualified personnel, materials, facilities, and equipment not otherwise provided by the Government as needed to perform the work described below.

The Contractor shall develop, maintain, and distribute a standing colony of aged rats of the National Institute on Aging (NIA)-specified genotypes for use by investigators in studies of aging.

The expected duration of this colony, and therefore of this contract, is ten (10) years. During years 1 through 3, animals shall be entered into the colony, but few animals shall be removed from the colony except for the purposes of monitoring health and genetic purity. However, if the need should arise, animals may be distributed from the colony at any time at the direction of the Contracting Officer’s Representative (COR). During years 4 through 7, animals shall continue to be entered into the colony and animals shall be distributed to investigators. This should be a period of stable operation with young animals entering the colony at approximately the same rate as older animals leave the colony due to distribution and normal attrition. The final three-year period, years 8 through 10, will serve as the colony close-out period. Animals shall be maintained and distributed, but entry of animals shall cease at the beginning of year 8 or when entries begin in a renewal contract colony. Thus, the population in this contract colony will decline over the last three-year period to a point of near zero or very few animals at the end of year 10.

The colony population at the end of each year of the ten-year period should be approximately as presented in Table 1:

Table 1. Approximate colony population at year end.

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 4,000 21,000 32,000 38,000 38,000 38,000 38,000 22,000 6,000 Near 0

Task Area 1. Provision of Barrier Environment

a) This animal colony shall be divided into at least two, approximately equal, separate segments. Each segment shall be maintained behind a totally independent barrier, specific pathogen- and parasite free, for the entire contract period. All segments shall specifically be helicobacter negative. The purpose of colony division is to ensure the survival of at least one half of the colony in the event of pathologic breach of a barrier, mechanical failure of environmental maintenance systems, or accidental disaster such as fire or flood. Total independence of colony segments, therefore, means separation of buildings, power systems and back-up systems, environmental controls (heat, air conditioning, and air filtration), and breeding stock. Each barrier shall have an independent back-up generator and alarm system in case of loss of power.

b) The total monthly entry level for each strain shall be divided approximately equally amongst the barriers. Exceptions might be made for strains with very low entry levels, but such exceptions shall require written approval from the COR.

c) Each colony segment shall be maintained solely within its barrier facility without intermingling. Entries are to be divided approximately equally between the two colony segments. Exceptions may be granted but, each exception shall require the prior written approval of the COR.

Task Area 2. Supply of the Rat Genotype

a) Within sixty (60) calendar days of the start date of the associated task order, the Contractor shall acquire, from the Government, cryopreserved embryos of the genotypes (foundation stock) described herein and as directed by the COR. The inbred strains designated to start this colony are F344-CDF (Charles River Derived Fisher 344) and BN/Crl (Brown Norway/Crl). The Government may alter the number of entries of specific genotypes and change genotypes as research demands change during the performance period. Alterations in the number or genotype of rats entered require the specific written approval of the Contracting Officer (CO). Alterations in genotypes might require the Contractor to acquire new foundation stock during the contract period of performance.

b) The foundation stock shall be re-derived by embryo transfer prior to development of the breeding colony. Discrete space within the re-derivation area shall be provided for re-derivation of the rats. No other animals shall be housed within an isolator housing the rats from this contract, other than this contract’s animals and foster mothers. Foster mothers shall be of a strain that is easily distinguished from the subject genotype by color and/or genetic markers. Use of foster mothers with different coat color is preferred when possible. The choice of strain of foster mothers shall require prior approval by the COR.

c) The Contractor shall provide the COR with documentation of the health status and genetic purity of the re-derived stock within one hundred and twenty (120) calendar days after the birth of the re-derived litters (Task 7.a.).

Task Area 3. Development of Breeding Colonies Entries for Each Colony Segment

a. The Contractor shall develop breeding colonies consisting of two or three tiers:

foundation colony, and expansion and/or production colonies, dependent on the entry levels required for the aging colonies. Monthly reports shall be provided during the development of the breeding colony (Task 7.b.). The numbers of breeding rats to be maintained shall be at a level that permits the addition of male and female weanling rats at the rate listed below.

Table 2. Initial Monthly Entry Levels into the Aging Colony for Each Strain

STRAIN SEX TOTAL ENTERED

F344 Male 650 F344 Female 450 BN Male 60 BN Female 20

F344BN F1 Male 365 F344BN F1 Female 250

b. After the foundation stock animals for each colony segment have been re-derived, they shall be entered from isolators into the barrier system without contamination by pathogens or parasites and shall be maintained as such. All offspring, whether part of the breeding colony or the aging colony, shall be considered Government owned property.

Animals shall be removed from the barrier only for shipment to investigators, for monitoring of genetic purity or colony health or for other purposes as directed by the COR. In both colony segments no other types of animals and no other types of activity other than that defined in the work-scope shall be permitted in the barrier rooms used to rear and maintain the rat genotypes specified.

c. Breeding and recording of pedigrees of animals shall conform to the standards established for laboratory rat strains by the Institute for Laboratory Animal Resources (ILAR) "Guide for the Care and Use of Laboratory Animals” https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf.

https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf

d. Litters larger than 8 animals shall have the smallest pups culled within five (5) calendar days of birth to bring the litter size down to 8; animals from litters smaller than 3 shall be excluded from introduction into the aging colony.

e. Rats shall be weaned at three to four (3-4) weeks of age and entered into the aging colony at the levels described in Table 2 above.

f. Mating, isolation, and primary enclosures shall meet or exceed minimum floor space requirements per rat, and population size per cage as stated in the ILAR "Guide for the Care and Use of Laboratory Animals". All primary enclosures shall require the prior approval of the COR. Mating cages shall be numbered consecutively. The type of cage bedding is subject to review and approval by the COR within sixty (60) calendar days of award of contract.

g. Records of date of birth, health, breeding, environment, and colony monitoring shall be maintained by the Contractor. These records shall be supplied to the investigators upon request by the COR.

h. The Contractor shall provide discrete production space for each breeding colony segment within the barrier or isolation area for that segment. This space shall be defined within each unit, and the animals held therein until the scheduled removal or expiration of the animals. Facilities set aside for these colonies shall be provided with all equipment, materials, and supplies necessary to maintain these animals effectively within the barrier enclosure in a stable condition and environment.

i. No animal shall be medicated during any part of the breeding, rearing, or maintenance period except on specific instruction of the COR.

j. The Contractor shall provide for quarterly positive assurance of genetic quality control, including histocompatibility antigen and/or micro-satellite testing, sampling 35% of the breed cages in the nucleus breeding colonies of the inbred strains and 50% of the cages in the production breeding colony of the hybrid strain. Genetic monitoring reports shall be due no more than sixty (60) calendar days after the animals were submitted for testing, and the report shall also be included in the semi-annual progress report. Procedures for genetic quality control are subject to the prior written approval of the COR.

k. Upon obtaining pathologic or other evidence that a barrier has been breached, the Contractor shall notify the COR and the CO by telephone and/or email within four (4) hours of discovery of the breach. A written Report of Unexpected Event shall be provided via email to the CO and the COR within three (3) calendar days of the event. The CO shall arrange a teleconference or meeting of the Contractor's representative, the COR, and the CO as soon as practicable, but in all cases within seven (7) calendar days, to determine an appropriate course of action. Such action may range from medication to reestablishment of the colony in newly constituted barrier facilities. Final determination of the appropriate course of action will be made by the COR, and all associated costs shall be borne by the Contractor. Potentially affected investigators shall be notified by written notice approved by the COR.

Task Area 4. Aging Colony Development

a) The Contractor shall provide discrete production space for each colony segment within the barrier or isolation area for that segment. This space shall be defined within each unit, and the animals held therein until the scheduled removal or expiration of the animals.

Facilities set aside for these colonies shall be provided with all equipment, materials, and supplies necessary to maintain these animals effectively within the barrier enclosure in a stable condition and environment. The weanling rats shall be from barrier-maintained parents and shall be maintained within the barrier until scheduled for removal (shipment or sacrifice) or natural expiration of the animal. The numbers of rats of each strain that shall be entered into the aging colony during the contract base period are provided in Table 2 under Task 3.a. No change in the entry level shall be made without written authorization from the CO.

b) All cages of rats shall be permanently identified by their genotypes, sex, and age. Age shall be denoted as month/year of birth with the additional notation on the cage card of the week of the month when born, such as week 1, week 2, and so on. Recombination or consolidation of cages is prohibited.

c) Each rat shall be permanently marked by tail tattoo to identify month (2 digits) and year (2 digits) of birth (a rat born in August of 2022 would receive the tattoo ‘0822’).

d) No animal shall be medicated during any part of the breeding, rearing, or maintenance period except on specific instruction of the COR.

e) Routine monitoring for disease and postmortem examinations shall be performed by either an independent laboratory approved by the COR or the Contractor if Contractor plans, personnel, and facilities are approved by the COR. Selection of animals for monitoring shall be evenly divided between colony segments and represent all genotypes and sexes which are maintained in each segment. Numbers of each genotype and sex submitted for monitoring shall reflect the proportion of that genotype/sex in the colony.

Sixty (60) rats per quarter or twenty (20) rats per month shall be submitted for routine health monitoring, unless otherwise specified by the COR. Rats to be submitted for routine monitoring shall be a minimum of four (4) months old. Approximately half of the rats tested each quarter shall be 4-12 months old and the other half 12-20 months old.

The schedule for removal shall be developed by the Contractor and shall require the approval of the COR.

f) In addition to conducting routine in-house health monitoring, the Contractor shall periodically submit up to sixty (60) rats per quarter for independent health evaluation by a qualified animal diagnostic laboratory designated by the COR. Shipping costs shall be charged to the contract.

g) Routine clinical and postmortem evaluation shall include:

1. Descriptive clinical condition of the animals including general condition, weight, and visible lesions and symptoms;

2. Gross pathologic observations of body tissues and organs;

3. Microbial, parasitological, and serological evaluation necessary and approved by the

COR to monitor effectiveness of the barrier system and animal health;

4. Histopathology of major organs and systems.

h) In addition, serology on pooled samples from up to eight (8) breeders being retired from the breeding colony shall be performed monthly using a prevalent agents panel, and environmental swabs from each barrier shall be tested by PCR monthly using a prevalent agents panel.

i) Rats shall be monitored for wounds and open lesions caused by fighting or excessive scratching and for visible tumors. Rats shall be euthanized when wounds, age-related decline or tumors are extreme enough to cause pain, wasting or decreased mobility in the animal. Rats shall be euthanized when a tumor reaches 1 cm in diameter regardless of its impact on mobility or behavior. Unless the COR instructs the Contractor to perform necropsies on animals that are euthanized, the Contractor is free to dispose of the carcasses in any manner they deem appropriate, including donation to raptor rescue groups or zoos and contribution of the carcasses to academic researchers for research purposes.

j) All spontaneous deaths in the aging colony shall be reported in table form by strain, sex, and age in the semiannual progress reports (Task 7.c.) and on the weekly inventory report (Task 7.d.). Necropsies shall not be performed on rats unless there is an unusual pattern of animal deaths or upon the direction of the COR. Postmortem findings in such cases shall be tabulated, summarized, and provided to the COR within sixty (60) calendar days of the death. Primary and secondary lesions possibly attributable to cause of death are to be described. Differences in strain specific or colony wide findings between colony segments shall be identified and reported in the semiannual progress report. Unless the COR instructs the Contractor to perform necropsies on animals that are found dead in the cages, the Contractor is free to dispose of the carcasses in any manner they deem appropriate, including donation to raptor rescue groups or zoos and contribution of the carcasses to academic researchers for research purposes.

k) Upon obtaining pathologic or other evidence that a barrier has been breached, the

Contractor shall notify the COR and the CO by telephone and/or email within four (4) hours of discovery of the breach. The CO shall arrange a teleconference or meeting of the Contractor's representative, the COR, and the CO as soon as practicable, but in all cases within two (2) business days, to determine an appropriate course of action. Such action may range from medication to reestablishment of the colony in newly constituted barrier facilities. Final determination of the appropriate course of action will be made by the COR.

Potentially affected investigators shall be notified by written notice approved by the COR.

Task Area 5. Environmental and Husbandry Requirements

a) Weaned rats assigned to the aging colony shall receive a laboratory animal feed, the formulation of which is consistent with NIH31 (Rader et al., 1986, J. Nutrition 116:1777-88) diet with regard to ingredients, both in kind and amount. The kind of ingredients shall be absolute; the percentage of the kinds of ingredients may vary dependent on nutrient content provided the final formulation remains consistent with NIH31 diet. The laboratory animal feed formulation shall be reviewed and approved by the COR.

b) The barrier system or isolation room shall be operated and constructed to effectively exclude pathogens, ecto-, endo-parasites as well as vermin. Personnel shall follow the sanitary and/or sterile practices and techniques that have been established for the maintenance of barrier-sustained animals as described in the ILAR "Guide for the Care and Use of Laboratory Animals" https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf.

c) The following items shall be controlled within the ranges specified: temperature (68-74oF), humidity (40-70%), light cycles (12/12 hours), air circulation (0.25m/hr/animal) and filtration (HEPA), and water chlorination and acidification (water shall be chlorinated and the pH controlled so as to not exceed pH 7.3 and 7-8 PPM chlorination at discharge end). A maximum of 25% re-circulated air within the barrier is allowed. The COR shall be notified immediately if the ambient temperature remains outside the above noted temperature range for a period in excess of four (4) hours or if there is a loss of animals due to a breakdown of environmental controls.

d) Current ILAR https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf and Department of Health and Human Services (DHHS) guidelines http://grants.nih.gov/grants/olaw/references/phspol.htm for breeding, care and maintenance of laboratory rats shall apply where specifications have not been detailed.

Task Area 6. Shipment of Animals to Investigators

a) Animals from the aging rat colony shall be distributed to investigators or laboratories only as specified by the COR or the designated representative of the COR. A copy of the most recent Health Evaluation Summary for the animals prepared under Task 4.g. shall be sent with each order.

b) The aged rats shall be shipped in containers:

1. Made of new materials that are non-reusable and non-returnable;

2. The design and fabrication of which are approved by the COR;

3. With filters for ventilation openings of a type approved by the COR; and

4. Designed so that stacking will not interfere with normal circulation of air through the https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf http://grants.nih.gov/grants/olaw/references/phspol.htm container; and

5. Containing food and a water source in each compartment; aged rats should be shipped with excess food.

c) The number of rats per container shall not exceed six (6) animals. If animals from different cages are shipped in the same container, the container shall be sub-divided into compartments, each of which contains only cage-mates, and all compartments in the crates shall be of the same age and sex. Special provisions may be specified by the COR as needed, such as shipping singly in individual compartments.

d) The Contractor shall report to the COR or the designated representative of the COR within twelve (12) hours of expected delivery time if there are delays in the shipment of animals.

e) Shipment via dedicated, climate-controlled truck is the preferred method. The Contractor shall be responsible for the cost of replacing orders not filled correctly according to the instructions provided by the COR or the representative designated by the COR.

f) When shipment by dedicated, climate-controlled truck is not possible, air freight shall be used. The Contractor shall take all necessary precautions to assure expedient delivery of animals shipped by air freight, by advising the recipient of expected arrival time, mode of transport and carrier number, and any responsibility the consignee has for pick-up at the point of arrival. When the consignee is notified that they are required to meet animals at point of arrival, late or delayed pick up of animals shall constitute neglect by recipient and Contractor is relieved of all replacement or reimbursement obligations.

g) Rats produced under this contract shall be made available to investigators under conditions as stated herein or as otherwise specified by the COR. The contract shall bear all costs associated with delivery of the rats to the investigators, including crates, enclosures, and freight charges.

Task Area 7. Reporting Requirements and Other Deliverables

All electronic reports submitted shall be compliant with Section 508 of the Rehabilitation Act of 1973. Additional information about testing documents for Section 508 compliance, including guidance and specific checklists, by application, can be found at:

http://www.hhs.gov/web/508/index.html under “Making Files Accessible.”

a) Post-re-derivation Health and Genetic Monitoring Report. The Contractor shall provide to the COR a report documenting the health status and genetic purity of the re-derived foundation stock within one hundred and twenty (120) calendar days after the birth of the re-derived litters.

b) Breeding Colony Development Report. Monthly reports shall be provided during the development of the breeding colony, providing the date the foundation stock was received, updates on the re-derivation progress, the numbers of rats produced each http://www.hhs.gov/web/508/index.html month for the breeding colony for each strain and the target number of breeder rats for each strain, any problems encountered with breeding the rats or litter size/survival, and the anticipated date for entries into the aging colony to begin and how that estimate has changed since the previous month’s report. Any change in the trajectory for the breeding colony development that has cost implications for the contract shall be noted in the report. The breeding colony development report shall be provided to the COR by email within seven (7) calendar days from the end of the reporting period. The first reporting period for the breeding colony development report shall be the first full month after the associated task order award and the reports shall continue until all strains have begun entries into the aging colony.

c) Semi-Annual Progress Reports. Semi-annual progress reports shall include the number of rats shipped from each barrier during the reporting period, the number of mortalities in each barrier, and any problems involving the colony, colony health, genetic monitoring, environment, or environmental control. The report shall include the results of routine genetic monitoring and all laboratory tests executed either by Contractor as a routine part of the protocol or results from tests that have direct implication for colony health or development. All deaths or sacrifices from the colony shall be accounted for by strain, gender and age of the animal sacrificed or expired. Unusual problems with the potential to impact colony health or genetic purity shall be reported to the COR immediately. Semi-annual progress reports shall be submitted to the CO and COR within thirty (30) calendar days of the end of each reporting period of the associated task order. The initial report shall be submitted for the first full six (6) months of the contract performance including any fractional part of the initial month. Thereafter, the reporting period shall consist of six (6) full calendar months. A semi-annual progress report will not be required for the period when the final report is due. Electronic transmission of progress reports is acceptable as long as they contain the Principal Investigator’s signature (ex. .PDF format).

d) Weekly Inventory Report. A weekly inventory report shall be submitted to the COR in accordance with a format approved by the COR. Electronic transfer of the inventory in Excel spreadsheet format is the preferred means. The weekly inventory report is due to the COR no later than one (1) week (seven (7) calendar days) from date of inventory.

Access to a “real-time” electronic inventory would take the place of the weekly census report subject to approval by the COR.

e) Quarterly Health Monitoring Reports. Quarterly health monitoring reports shall be submitted to the COR no later than three (3) months from the date the animals were submitted for evaluation. Semiannual summaries of these reports shall be furnished as a part of 7.c above. Real time access to the health monitoring reports as the results come in is an acceptable alternative for these reports.

f) Quarterly Genetic Monitoring Reports. Results of the quarterly genetic monitoring of the breeding colonies shall be reported to the COR no later than sixty (60) calendar days from the date the animals were submitted for evaluation. Semiannual summaries of these reports shall be furnished as a part of 7.c above. Real time access to the genetic monitoring reports as the results come in is an acceptable alternative for these reports.

g) Monthly Environmental Reports. Results of the monthly environmental monitoring shall be submitted to the COR no later than three (3) months from the date of sampling.

Semiannual summaries of these reports shall be furnished as a part of 7.c above.

h) Individual Postmortem Reports. Complete postmortem reports on individual animals chosen for additional health monitoring independent of the quarterly health monitoring shall be submitted to the COR no later than sixty (60) calendar days from the date of death.

i) Final Report. A final report shall be submitted to the CO and COR on or before the completion date of the associated task order. The final report shall include a summation of the work performed and results obtained for the entire associated task order period of performance. This report shall be submitted on or before the associated task order completion/expiration date.

j) Summary of Salient Results. The Contractor shall submit, with the Final Report, a summary (not to exceed 200 words) of salient results achieved during the performance of the associated task order.

k) Contract Closeout. In accordance with FAR 4.804, within sixty (60) calendar days of the contract task order expiration/completion, the Contractor shall be responsible for and provide the following items:

1. Indirect cost rate proposals for all years (in which a proposal was not previously submitted);

2. Final property inventory (excluding intellectual property) and Standard Forms

1428 and 1429 (if applicable);

3. Settling all subcontract costs and any issues thereunder;

4. Subcontracting compliance reports for all years to the electronic subcontract reporting system at http://www.esrs.gov (if applicable);

5. Final patent and royalty reports;

6. A contractor’s release of claims, i.e., contractor’s closing statement; Contractor’s

Assignment of Refunds, Rebates, and Credits; and

7. A final invoice or completion voucher.

http://www.esrs.gov/

“Development and Maintenance of a Multigenotypic Aged Rat Colony”