ResponsestoQuestions.pdf

RFP N01CM07011-68: Preclinical toxicology of drugs developed for cancer and other diseases Question No.

Document Page No.

Paragraph Clause/Citation requiring clarification Question Response

1 RFP 6, 7 Article C.2.a.1 vs.

Article C.2.b.3

Monthly Technical Progress Reports vs. Monthly Status Report for each drug on test

Are these two monthly reports independent of each other or are they referring to the same (i.e., one) monthly report?

These are the same

2 RFP 36 Section L.1.d Estimate of effort

…the Government considers the effort to be approximately 49,000 labor hours (per year).

Is the ~49,000 hours per year meant to be the estimate for each of the anticipated 5 or 6 awardees (i.e., if 5 awardees the total is ~245,000 hours per year combined for the 5 contractors) or the total estimate for all contract awardees (i.e., if 5 awardees then ~9,800 hours per year per contractor)

This is the award total and these hours are only estimates. The offer or should focus on providing accurate labor hours for each protocol. The numbers of studies of any given type per year (and therefore the numbers of hours per year) is dynamically determined by the needs of our program and our portfolio. Please note this is a WA-based contract.

3 RFP 47, 48 Section L.2.b Sharing of Model Organisms for Biomedical Research, paragraph 2

Offerors must include in their technical proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH finding …., OR provide appropriate reasons why such sharing is restricted or not possible.

As unique model organisms will not be generated under this contract, is it appropriate to state that sharing is not possible as no such organisms will be generated?

Provide appropriate reasons why such sharing is not Applicable.

Attachment3, SOW

1 Section 1.a.

Analytical Phase

Drug identity analysis…, validation of the procedures supplied by the NCI for dose concentration analyses….

It is unclear if dose formulation preparation itself is part of the SOW that the offeror should include labor and materials costs for or if the prepared dose formulations will be supplied to the awardee for use on study, perhaps by the “ANALYSIS OF

ANTI-CANCER CHEMICALS

The offeror should provide labor estimates that include concentration analysis post-dosing and/or pre-dose. For example, if a measure is taken pre-dose on a prep made daily, this measure need not be repeated post dosing on subsequent days. If however the prep is made on day one for a 5-day administration from a single prep a post dose (5 days) measure may be needed. The study design will determine the need for such.

5 Attachment3

, SOW

2 Section 2.e.

General areas of work

Assess cardiotoxicity, in rodents, beagle, dogs and/or non-human primates as specified by the PO.

Will the assessment of cardiotoxicity be by routine safety pharmacology studies, such as using telemetered animals to measure BP, heart rate, ECG, and body temperature, as well as an in vitro assessment of QT prolongation potential for assessment of the cardiovascular system ?

Yes

4 con’t AND PHARMACEUTICAL FORMULATIONS” project (Project Numbers

N02CM722001, N02CM722002,

or N02CM722003).

Please clarify the scope of the formulation and analytical chemistry procedures that will be the responsibility of the awardee, and thus should be budgeted for in this proposal:

1) Bulk chemical Identity analysis (using one or two methods) with or without an assessment of purity?

2) Concentration analysis post-dosing or just pre-dose?

3) Dose formulation preparation?

Also, please provide a list of the possible vehicles anticipated for use on this contract AND types of test articles (i.e., mainly new chemical entities or mainly biologics such as monoclonal antibodies, peptides, siRNAs, microRNAs, etc).

Dose formulation preparation- The Awardee will not be provided pre-made dose preps, but will be expected to prepare the molecule as instructed.

We will not provide a list of vehicles. The contractor should have sufficient experience in administering test articles in various vehicles.

6 Attachment3

, SOW

2 Section 2.e.

General areas of work

Assess neurotoxicity in rodents, beagle, dogs and/or non-human primates as specified by the PO

Will the assessment of neurotoxicity be by routine safety pharmacology studies such as conducting functional observational battery studies (e.g., the modified Irwin study in rodents) for assessment of the central nervous system?

Yes

7 Attachment3

, SOW

2 Section 2.e.

General areas of work

Assess immunotoxicity in rodents, beagle, dogs and/or non-human primates as specified by the PO

Does the assessment of immunotoxicity refer to organ weight and histopathology of immune tissues (e.g., spleen, thymus, lymph nodes) in the 28 day repeat-dose general toxicity studies, or is there an expectation for additional assays, including, but not limited to, immunophenotyping of WBCs, T-dependent antibody responses, or host resistance?

Yes and there may be a need for additional assays, including, but not limited to, immunophenotyping of WBCs, T-dependent antibody responses, or host resistance?

8 Attachment3

, SOW

7 Section 12. Level of effort Paragraph 3

This set of protocols would theoretically be the basis for the complete evaluation of one anticancer and one anti-HIV drug per year….

Please clarify the number of studies that should be budgeted for a single year.

Should the offeror propose conducting one of each study design per year (total 7 or 8 studies), or two of each study (one for an anticancer drug and one for an anti-HIV drug) per year (total of 14 or 16 studies depending on the answer to the above question)?

The offer or should focus on providing accurate labor hours for each protocol. The numbers of studies of any given type per year (and therefore the numbers of hours per year) is dynamically determined by the needs of our program and our portfolio. Please note this is a WA-based contract.

9 Attachment3

, SOW

8 Section 13. Travel requirements

Plan on payment of registration fee, one day per diem and one-half of the air fare for this meeting.

Would the NCI please clarify the level of support NCI plans on providing for travel?

Is the intent of this statement that the NCI will pay the specified expenses, leaving the offeror to pay for the remaining associated travel expenses, or that the offeror will pay for these specified expenses and NCI will fund the balance?

The Principle Investigator and/or a Senior Scientist may attend one national scientific meeting per year. The registration fee will be paid; one day of per diem will be paid; and one half of the air fare will be paid. If two people attend any remaining expenses will be paid by the offeror. If only one person attends, the Contracting Officer must approve any requested expenses, other than those identified above.

10 Attachment 12, Sample Work Assignment

Pages 1, 2, and 4 of multi-dose toxicity of (X) in rats

Title, Section I (Objective), and Section II.C.4 (Dosing Procedure) in Daily

X 4-RAT.TOX

study protocol

Title, pg 1: Multi-Dose Toxicity of (X) in Rats

Objective, pg 2: …following a single intravenous dose of…

Dosing Prodecure, pg 4: On day one, each rat…will receive a single intravenous dose of….

Would the NCI please clarify if this protocol should be for a single dose on Day 1 as indicated on pg 2 and pg 4 or if this is to be daily IV injections on Days 1-4 as implied by the title on pg 1?

This is to be daily IV injections on Days 1-4

The revised rat protocol is attached to this amendment.

11 Attachment 12, Sample Work Assignment

Page 4 of multi-dose toxicity of (X) in rats

Section II.B.6.

(Animal Identification)

All animals will be given a unique identification for this study by ear tag or other approved method.

Please clarify what are considered other approved methods (e.g. implantable miciochips) and whether the methods are acceptable for any/all of the rat toxicity studies.

There are several IACUC approved methods used to identify rodents. Each method has both advantages and disadvantages. In long-term studies it is important to choose a method that is permanent and easily read.

12 Attachment 12, Sample Work Assignment

Page 4 of multi-dose toxicity of (X) in rats

Section II.C.2.

(Group Assignments) on Page 4 of Daily X 4-RAT.TOX study protocol

After randomization, 40 male rats (5/dose group) will be assigned to three dose groups and a vehicle control group (VCTL).

Would the NCI please clarify if this should be 40 male rats (10/dose group), 20 male rats (5/dose group), or 40 rats (20 males and 20 females with 5/sex/group) as the text does not coincide with the table below the text?

40 rats (20 males and 20 females with 5/sex/group)

Attachment 12, Sample

Page 6 of

Section II.C.5.d (Necropsy

Half of the rats (5 males and 5 females) from each group will be sacrificed on study

Please clarify if there are 80 rats on study with 40 rats (5

40 rats (20 males and 20 females with 5/sex/group);

13 con’t Work Assignment multi-dose toxicity of (X) in rats

Procedure) Paragraph 1 day 4 and the surviving rats will be sacrificed on study day 29.

male and 5 females per group) being sacrificed on each of two days of necropsy (days 4 and 29) or if there is only one day of sacrifice and necropsy (day

4) of either 20 or 40 male rats? The table on pg 4 (Section C.2.) does not indicate a necropsy on Day 29.

There is only one day of sacrifice and necropsy (day 4 or 5)

14 Attachment 12, Sample Work Assignment

Page 6 of multi-dose toxicity of (X) in rats

Section II.C.5.d (Necrospy Procedure)

All tissues listed below will be examined, sampled, and fixed in cold, buffered neutral10% formalin.

For all protocols (rat and dog) with a necropsy, the tissue list indicates that the testes will be fixed in 10% neutral formalin. However, literature suggests that the optimal fixative for the testis is modified Davidson’s solution or Bouins’ fluid (LL Lanning et. al., 2002.

Toxicologic Pathology 30:507-520).

Please clarify if the testes should be fixed in 10% neutral buffered- formalin or an alternative fixative.

Please use optimal fixatives for select tissues when these optimized choices deviate from common fixation techniques.

Work Assignment

Page 7 of multi-dose toxicity of (X) in rats

Section II.C.5.e (Microscopic Pathology) Paragraph 1

Sections of the above tissues marked with an asterisk (*) will be cut approximately 5 microns thick and stained….

Please verify that no tissues are to be sectioned and stained for microscopic examination as no tissues are marked with an asterisk.

The asterisks were left off. Please see the attached amended protocol

*Adrenal glands (2) *Bone (femur) *Bone marrow (femur) Brain Cecum *Colon

15 con’t *Duodenum Epididymides Esophagus Eyes (2) *Gonads - Testes/ovaries (2) Gross lesions *Heart Ileum Jejunum *Kidneys (2) *Liver

*Lungs (infuse with formalin) Lymph nodes (mandibular and mesenteric) Mammary gland (when present in regular abdominal skin section) *Pancreas Parathyroid gland (when present in regular thyroid section) Pituitary gland Salivary glands (mandibular, sublingual, and parotid) *Sciatic nerve *Skeletal muscle Skin (1. ventral abdomen 2. injection site) Spinal Cord (thoracolumbar segment for routine section or spinal cord if neurological signs indicate cord involvement) *Spleen Stomach (forestomach and glandular) Thymus Thyroid glands Trachea Urinary Bladder *Uterine horn (2)

Page 1 of

Sections A and B Compatibility and

These tests are to be initiated before initial dosing of dogs.

Please clarify if testing for compatibility and hemolytic

Dogs only.

16 con’t Work Assignment

Appen dix A of PK and

DRF

of (X) in Dogs

Hemolytic Potential potential should also be conducted prior to dosing of rats via the intravenous route of if this testing is only to be done prior to initial dosing of dogs.

Work Assignment

Page 7 of Single dose toxicity of (X) in rats

Section II.C.5.e (Microscopic Pathology) Paragraph 1

Sections of the above tissues marked with an asterisk (*) will be cut approximately 5 microns thick and stained….

Please verify that no tissues are to be sectioned and stained for microscopic examination as no tissues are marked with an asterisk.

The asterisks were left off. Please see the attached amended protocol

*Adrenal glands (2) *Bone (femur) *Bone marrow (femur) Brain Cecum *Colon *Duodenum Epididymides Esophagus Eyes (2) *Gonads - Testes/ovaries (2) Gross lesions *Heart Ileum Jejunum *Kidneys (2) *Liver

*Lungs (infuse with formalin) Lymph nodes (mandibular and mesenteric) Mammary gland (when present in regular abdominal skin section) *Pancreas Parathyroid gland (when present in regular thyroid section) Pituitary gland Salivary glands (mandibular, sublingual, and parotid)

17 con’t *Sciatic nerve *Skeletal muscle Skin (1. ventral abdomen 2. injection site) Spinal Cord (thoracolumbar segment for routine section or spinal cord if neurological signs indicate cord involvement) *Spleen Stomach (forestomach and glandular) Thymus Thyroid glands Trachea Urinary Bladder *Uterine horn (2)

18 Attachment

Work Assignment

Pages 6 and 7 of 28- Day toxicity of (X) in rats

Section II.C.5.c (Clinical Pathology) vs.

Section C.5.e (Necropsy Procedure, Paragraph 3)

Pg 6. Blood should be drawn from each rat for clinical pathology determinations on study days 5, 15, 25, 35, and 45… Pg 7. All rats will have final body weights taken and will be bled for clinical pathology determinations prior to termination.

Since the final day of dosing is Day 29, with plasma drug level determination and necropsy to be conducted on 1/3 of the animals at that time, is it correct that clinical pathology samples should be collected on Day 29 although not mentioned in Section C.5.c on page 6?

This will affect pricing.

We should consider the collection of Clin.

Path. on day 29 in the pricing although this may not be applied to all study protocols.

19 Attachment 12, Sample Work Assignment

Final page of all study protoc ols

Protocol Approvals:

Signature lines provided for the Study Director, Principal Investigator, and Project Officer

Is it acceptable to the NCI for the Principal Investigator to also act as the Study Director on any/all of the protocols?

Yes, the Principle Investigator may also act as the study director on any/all of the protocols.

20 Throughout

SOW

Does Contracting Officer’s Technical Representative (COTR) replace Project Officer (PO) in all instances?

Yes, once contracts are awarded COTR replaces the PO designation.

Work

Page 3 of all study

Section II.B.1 (Species, Strain, Supplier and Test

F344 rats supplied by the DTP, DCTDC, NCI will be used in this study.

OR

Would the NCI please clarify what costs, if any, should be included for the animals that

It is rare that the NCI will supply F344 rats or dogs for studies. All budgets should include animal costs.

21 con’t Assignment protoc ols

System Justification)

Purebred beagles supplied by the DTP, DCTDC, NCI will be used in this study.

the NCI supplies? Is there a unit cost for each rat and dog? Are there associated shipping fees? Or should budgets not include animal costs?

22 Attachment 12, Sample Work Assignment

Page 1 of Admin

WA

Part I.B.7 Preparation of pathology materials for shipment to archive.

Would the NCI please clarify archiving requirements? Are all of the following to be sent from the contractor to the NCI for archiving: original signed protocol and protocol amendments, raw data, documentation, specimens (blocks, slides, wet tissues), and the original signed final report? If so, should all archiving activity for each accounted for under the Admin WA or only the pathology materials (blocks, slides, and wet tissues)?

All of the following should be sent, but not as stated.

1. To be sent from the contractor to the NCI

• Original signed protocol and protocol amendments, raw data documentation (electronic)

2. To Archive as directed_

• Specimens (blocks, slides)

• Archiving activity for each study can be accounted for by a single sheet with the final study report.

RFP 36 The 49,000 hours per-year seems excessive to us for the 8 protocols and 1 administrative work assignment.

The effort to be approximately 49,000 labor hours (per year). Also, the “revised” Statement of Work states for proposal purposes, offerors are request to submit cost proposal on each of the eight (8) protocols and the administrative work assignment contained in Appendix A.

Therefore, can NCI offer any guidance as to whether we propose each study more

These hours are only estimates. The offeror should focus on providing accurate labor hours for each protocol. The number of studies of any given type per year; and therefore the numbers of hours per year; is dynamically determined by the needs of our program and our portfolio. Please note this is a WA-Based contract.

23 con’t than once or how to calculate the 49,000 labor hours per-year?

24 Federal Business Opportunities

N/A Protocol 9 will not open. Please send this protocol to us.

This protocol is available at the OA Website http://rcb.cancer.gov/rcb-internet/appl/rfp/published_rfps.jsp Additionally this protocol has been reloaded in Federal Business Opportunities.

25 RFP N/A N/A I just want to know if the referenced RFP is open to toxicology laboratories outside the U.S. (our facilities are in China).

What specific qualifications are required for facilities outside the U.S.?

The Contractor must be in compliance with FDA GLP regulations (www.fda.gov/ora/compliance_ref/bimo/glp/87f inalrule.htm ).

The Contractor must have an animal welfare assurance (http://grants.nih.gov/grants/olaw/references/p hspol.htm ).

The OLAW website is http://grants.nih.gov/grants/olaw/olaw.htm NIH requires that prior to awarding funds for a contract for animal use, and assurance statement must be on file with OPRR.