Contract No: DSTLX- 1000078175
NON-CLINICAL DRUG INTERACTION AND TOXICITY STUDIES (FOx)
Contractor: Information Redacted CONTRACTS-IN-CONFIDENCE Contract NO:
Defence Science and Technology DSTLX- 1000078175 Laboratory, Porton Down SCHEDULE OF REQUIREMENTS FOR Issued on: NON-CLINICAL DRUG INTERACTION Previous Contract No 17 January 2013 AND TOXICITY STUDIES (FOx) (Renewal Cts Only) Table I – Requirements PRICE ITEM NO DESCRIPTION QTY £ (VAT EX) Objective 1 Dstl has a requirement to undertake a programme of Safety Studies using a three-drug combination to support Clinical Studies and a UK Marketing Authorisation Application. The activities described in the attached Statement of Work will form part of these Safety Studies. There is an additional requirement to support the licensure of intravenous administration of HI-6 DMS alone.
2 Tasks The Contractor shall undertake the tasks as detailed in the
Statement of Requirements at Annex A and the Information Redacted Technical Proposal (option 2) attached at Annex B. In the event of task conflict or contradiction, for the purposes of this Contract, the accepted Information Redacted Technical Proposal (option 2) will be used as the method statement. Deliverables 3 Full Rights versions of the following reports: For each Study listed above, a QA Audited Draft Report is required following completion of the experimental work The Draft report is to be up-lifted to a Final report to meet the final Milestone of each Study. Report – The Report shall describe the entire work performed under the Study in sufficient detail to explain comprehensively, the work undertaken and the results achieved to include, inter alia, all relevant technical details and details of any problems encountered. TOTAL PRICE (IN WORDS) TOTAL £1,449,650 One Million, Four Hundred and Forty Nine Thousand, Six Hundred and Fifty Pounds
CONDITIONS OF CONTRACT - The Schedule of Requirements is integral to and subject to the attached Conditions of Contract.
Table II – Packaging Requirements Adjustments* Item No Packaging specifications/special markings etc Qty £ N/A Commercial packaging appropriate for safe and N/A N/A secure transport in accordance with IATA regulations.
* Note: to price per quantity shown in Table I
Table III – Duration of Contract
Start Finish Item No CONDITIONS OF CONTRACT This contract shall commence This Contract is subject to: immediately upon acceptance 17 February 2015
of the Offer (DEFORM10) Section 1 – General Conditions dated 17 January 2013 Section 2 – Special Conditions Section 3 – Annexes and Appendices
CONTENTS
1. CONDITIONS OF CONTRACT
Section 1 – General Conditions
Section 2 – Special Conditions
1. HEADINGS
2. PERIOD OF CONTRACT
3. DATA PROTECTION ACT
4. ACCESS TO THE CONTRACTOR‟S PREMISES
5. PROGRESS REVIEWS AND REPORTS
6. QUALITY ASSURANCE AND CONTROL
7. PAYMENT [Stage Payment Plan To Be Agreed]
8. AMENDMENT TO CONTRACT
9. STATUS OF CONTRACT
10. SUB CONTRACTS
11. DELIVERY
12. DISCLOSURE OF INFORMATION
13. ISSUED PROPERTY
14. CONTRACTOR‟S RECORDS
15. INDEMNITY AND INSURANCE
16. PERFORMANCE
17. WARRANTIES
18. TRANSPARENCY
Appendix to Contract – Addresses and Other Information
Attachment 1 Statement of Requirement
1. Conditions of Contract
Section 1 General Conditions
DEFCON 68 (Edn 05/11) - Supply Of Data For Hazardous Articles, Materials And Substances
DEFCON 92 (Edn 08/90) - Failure of Performance1
DEFCON 501 (Edn 04/04) - Definitions And Interpretations
DEFCON 502 (Edn 06/08) - Specifications
DEFCON 503 (Edn 07/05) - Amendments To Contract
DEFCON 507 (Edn 10/98) - Delivery
DEFCON 509 (Edn 09/97) - Recovery Of Sums Due
DEFCON 513 (Edn 06/10) - Value Added Tax
DEFCON 515 (Edn 10/04) - Bankruptcy And Insolvency
DEFCON 516 (Edn 06/04) - Racial Discrimination
DEFCON 518 (Edn 09/97) - Transfer2
DEFCON 520 (Edn 07/11) - Corrupt Gifts And Payments Of Commission
DEFCON 521 (Edn 10/04) - Sub-Contracting To Supported Employment Enterprises
DEFCON 523 (Edn 03/99) - Payment Of Bills Using The Bankers Automated Clearing Service (BACS) System
DEFCON 524 (Edn 10/98) - Rejection
DEFCON 525 (Edn 10/98) - Acceptance
DEFCON 526 (Edn 08/02) - Notices
DEFCON 527 (Edn 09/97) - Waiver
1 For the purposes of this contract DEFCON 92 shall apply to all services (excluding the supply of Articles) which the Contractor is required under the Contract to perform or to fulfil
2 Any request for a Transfer, which involves a change of Contractor name or entity (a “novation”), shall be forwarded to:
Commercial Services Group - Defence Suppliers Service Ministry of Defence Maple 2B, #22 Abbey Wood Bristol BS34 8JH
Copied to the Dstl Commercial Services Dept identified in the Contract
DEFCON 528 (Edn 10/04) - Overseas Expenditure and Import Licences3
DEFCON 529 (Edn 09/97) - Law (English)
DEFCON 529A (Edn 09/97) - Law (Scots)
DEFCON 530 (Edn 07/04) - Dispute Resolution (English Law)
DEFCON 530A (Edn 07/04) - Dispute Resolution (Scots Law)
DEFCON 531 (Edn 05/05) - Disclosure Of Information
DEFCON 532A (Edn 06/10) - Protection of Personal Data (Where Personal Data is not being processed on behalf of the Authority)
DEFCON 534 (Edn 06/97) - Prompt Payment (Sub-Contracts)
DEFCON 537 (Edn 06/02) - Rights Of Third Parties
DEFCON 538 (Edn 06/02) - Severability
DEFCON 566 (Edn 02/11) - Change Of Control Of Contractor4
DEFCON 601 (Edn 10/04) - Redundant Materiel
DEFCON 602B (Edn 12/06) - Quality Assurance (Without Deliverable Quality Plan)
DEFCON 606 (Edn 10/97) - Change And Configuration Control Procedure
DEFCON 608 (Edn 10/98) - Access And Facilities To Be Provided By The Contractor
DEFCON 609 (Edn 10/98) - Contractor's Records
DEFCON 611 (Edn 07/10) - Issued Property
DEFCON 612 (Edn 10/98) - Loss Of Or Damage To The Articles
DEFCON 621B (Edn 10/04) - Transport (If Contractor Is Responsible For Transport)
DEFCON 625 (Edn 10/98) - Co-Operation on Expiry of Contract
DEFCON 632 (Edn 02/07) - Third Party Intellectual Property - Rights And Restrictions
DEFCON 646 (Edn 10/98) - Law And Jurisdiction (Foreign Suppliers)
DEFCON 656 (Edn 03/06) - Break
3 The Contractor shall, within one month of acceptance of the Contract, notify the Commercial Services Department of details of any overseas sub-contract or order he has placed, or intends to place, in aid of the contract. Details to be provided are: Prime Contract Reference: Country Sub-Contract Placed/to be Placed: Name of Sub-Contractor/Supplier: Full Address: Value of Sub-Contract Order Applicable to Prime Contract: Date Placed/to be Placed: If no overseas orders are to be placed, the Contractor shall advise the Commercial Services Department to this effect in the same timescale. 4 Details of any changes are to be copied to the Commercial Services Department, address as in Box 1 of Appendix to Contract
DEFCON 694 (Edn 02/12) - Accounting For Property Of The Authority
DEFCON 703 (Edn 11/02) - Intellectual Property Rights – Vesting In The Authority
Section 2 Special Conditions
1. HEADINGS
In the following Terms and Conditions of Contract the relative ordering of conditions or the placing of information in Annexes is of no significance. All headings within these Terms and Conditions are generally for convenience only and shall not affect interpretation of the subsequent text or the Contract as a whole. All cross-references are for immediate ease of reference only and are not intended to be either complete or definitive.
2. PERIOD OF CONTRACT
The Contract shall commence immediately upon acceptance of the Offer of Contract and shall continue until 17 February 2015. No work shall be carried out after this date without the prior written approval of the Authority, or his authorised Commercial representative.
On acceptance of the Contract, all work carried out by the Contractor on the requirement prior to the Contract coming into force shall be deemed to have been carried out under the terms and conditions of the Contract.
The Contract shall have deemed to have expired on the completion of all the Studies and on acceptance and payment of all the Deliverables listed in Table 1.
3. DATA PROTECTION ACT
The Contractor warrants that all obligations under the Data Protection Act 1998, which arise in connection with this Contract will be adhered to.
4. ACCESS TO THE CONTRACTOR’S PREMISES
For the purposes of this Contract in addition to the provisions of DEFCON 608 the following shall apply:
The Chief Executive, Dstl, or his authorised representative, shall have the right of access to the premises where the work of the Contract is being undertaken, including those of any subcontractors, and to all information relevant to the Contract for the purpose of keeping in touch with the nature and progress of the work.
5. PROGRESS REVIEWS AND REPORTS
For the purposes of this Contract in addition to the provisions of DEFCON 604 and DEFCON 642 the following shall apply:
5.1 Progress Reviews
Progress Reviews will be held on a quarterly basis or as required by the Dstl Project Manager (as shown at Box 2 of the Appendix to Contract).
The Contractor is to supply a Minutes Secretary and produce minutes of the meetings if necessary.
The front page of any Minutes produced as a result of any Meeting between the Authority and the Contractor shall state: “Nothing in these Minutes shall be construed as giving authority to proceed on work beyond that provided in the Contract or vary the terms and conditions of the Contract.”
5.2 Reports
The Contractor shall prepare and submit Reports in the manner stated below and in accordance with Clause 11 (Delivery) of this contract:
Reports shall be signed on the Contractor‟s behalf by a person authorised to commit the Contractor.
All Reports shall be to the requirements and acceptance of the Dstl Project Manager (as at Box 2 of the Appendix to Contract).
The title page of all reports shall be annotated as follows: The investigation, which is the subject of this Report, was initiated by the Chief Executive, Dstl and was carried out under the terms of Contract No – [DSTLX- 1000078175].
Distribution of Minutes and Reports shall be as follows: Reports Minutes
Project Management Branch TWO* ONE Commercial Services Department NIL ONE
*One Hard copy and one electronic
6. QUALITY ASSURANCE AND CONTROL
In addition to the provisions of DEFCON 602B the following shall apply:
6.1 The Contractor shall ensure that the Contract is performed in accordance with the Quality requirements specified below:
Good Laboratory Practice (GLP) International Conference on Harmonisation (ICH) Guidelines
6.3 The Contractor shall be responsible for the Quality Control and Quality Assurance of all work carried out on the Contract. The necessary control shall be exercised by the Contractor‟s own Quality organisation to the satisfaction of the Authority.
7. PAYMENT
7.1 Payment shall be made in accordance with the Payment Plan set out below:
Dstlx-1000078175 Non-Clinical Drug Interaction and Toxicity Studies Milestone Payment Plan ANNEX C
* The Stage Payment Plan is to be clarified as part of the Contract Start up Meeting and subsequently incorporated in to the Contract through Contract Amendment. 7.2 Payments for each stage under the Stage Payment Scheme shall be made when: 7.2.1 the Contractor shall have completed all work comprised in the stage for which the advance is sought and the authority shall have certified completion of that stage in accordance with the contract.
7.2.2 the stages shall have been completed sequentially unless otherwise agreed between the parties.
7.2.3 the Contractor shall have complied with all its contractual obligations that impinge on progress of work including, where required under the Contract, the provision of information required by the Authority for the purposes of assessing contractual performance provided that the Authority shall not be obliged to make a payment to the Contractor in respect of a completed stage if:
7.2.3.1 the Authority shall have reasonable cause to believe that the Contractor will be unlikely to render complete performance of his obligations in respect of the contract.
7.3 Where the Authority intends to rely on clause 7.2.3.1 as the basis for rejecting any claim for an advance payment which the Contractor may make in accordance with clause 7.5, the Authority shall give to the Contractor reasonable notice in writing of its intention together with the Authority's reasons for the rejection.
7.4 Save as hereby provided the entitlement of the Contractor to retain all advance payments is conditional on complete performance of items to of the contract. Where the Authority terminates the contract otherwise than in accordance with DEFCON 656, the Authority shall without prejudice to any other right/remedy of either party be entitled to recover in full all advance stage payments made before termination, except where articles/services have been delivered/rendered in accordance with the contract schedule and acceptance has occurred.
7.5 All requests for Payment shall be submitted using a Commercial Invoice to the Authority‟s Bill Paying Branch as set out in the Appendix to Contract and below. A copy, such as a photocopy or fax, is not acceptable.
7.6 Invoices should be submitted as follows: Invoice for payment shall be sent to: Dstl Ledgers Processing Team, PO Box 325, Dstl Portsdown West, Portsdown Hill Road, FAREHAM. Hampshire. PO14 9HL To ensure prompt payment, the Contractor shall issue a copy of the invoice (clearly marked “COPY, NOT FOR PAYMENT”) to the Project Management Branch (Box 2 of the Appendix to Contract) at the same time as the original invoice is submitted to Dstl Accounts Payable.
7.7 The Authority shall pay all valid, properly completed claims for payment within 30 days of receipt in its Bill Paying Branch. Claims for payment must include, inter alia, the Contract or Purchase Order number. Only one invoice is to be submitted per Milestone.
7.8 Notwithstanding any statement to the contrary on the Contractor‟s Commercial Invoice, payment shall not be construed as acceptance by the Authority of the satisfactory performance of the Contractor's obligations nor as a waiver of its rights and remedies either under the Contract or otherwise.
7.9 Where the Authority is responsible for arranging all or any part of the transportation of Articles to be supplied under the Contract the Authority shall be deemed not to have received the Relevant Form until either: a. the consignee has physically received the Articles; or b. 5 days after the Articles are ready for collection as notified to the Authority's Transport Office. whichever occurs first. Wherever possible, the Contractor shall inform the Authority's Transport Office at least 2 days in advance of the date upon which the Articles shall be ready for collection.
7.10 Where and to the extent that the debt would otherwise be a "qualifying debt" under the Late Payment of Commercial Debts (Interest) Act 1998 ("the Act") “qualifying contractors” may claim simple interest at the prevailing rate of statutory interest (as defined in the Act) as a contractual remedy. No interest shall be payable for any period of delay attributable to the conduct of the Contractor. All claims for interest made pursuant to this Condition shall be notified in writing to the Commercial Services Department shown in the Appendix to Contract.
8. AMENDMENT TO CONTRACT For the purposes of this Contract in addition to the provisions of DEFCON 503 and DEFCON 606 the following shall apply:
Any technical or other proposal from the Contractor, which would involve an amendment to the Contract, including the Schedule of Requirements, shall be submitted in writing to the Authority for
consideration. If the Authority agrees, these proposals shall be promulgated by Contract amendment.
9. STATUS OF CONTRACT
Nothing in the Contract shall be construed as creating a partnership, a Contract of employment or a relationship of principal and agent between Authority and the Contractor.
10. SUB CONTRACTS
10.1 The Contractor shall not place any sub-contracts for work under the Contract without the prior written approval of the Commercial Services Department.
10.3 The Contractor shall be responsible for the management of sub-contractors or agents and accept responsibility for the delivery of their required outputs.
10.4 No sub-contracting by the Contractor shall in any way relieve the Contractor of any of his responsibilities under this Contract.
11. DELIVERY
For the purposes of this Contract in addition to the provisions of DEFCON 507 the following shall apply:
11.1 The Deliverables as at Table I – Schedule of Requirements are to be consigned to the address in Box 2 of the Appendix to Contract.
12. DISCLOSURE OF INFORMATION
12.1 In this Condition, the definition of Information shall be that set out in DEFCON 531 (Edn 10/97).
12.2 The Authority shall not be in breach of the Contract where it can show that any disclosure of Information is made solely and to the extent necessary to comply with the Freedom of Information Act 2000 or the Environmental Information Regulations 2004.
13. ISSUED PROPERTY
13.1 In accordance with the provisions of DEFCON 611 the following items shall be issued to the Contractor in support of the Contract:
13.1.1 Government Furnished Assets (GFA)
The following item of GFA will be issued as a Contract Work Item (CWI) –
Qty of HI-6 DMS and other drug substances TBC Supporting Information TBC The GFA detail is to be advised by Dstl following the Contract start up meeting and subsequently incorporated into the Contract through Contract Amendment. 13.2 All GFA shall be issued on Loan for the period of the Contract and shall be used solely for the execution of the Contract.
13.3 Any surplus GFA remaining at the end of the Contract shall either be returned to Dstl or destroyed in accordance with agreed written disposal instructions issued in accordance with DEFCON 601 (Redundant Material).
13.4 All GFA shall be issued to support the execution of this Contract. It is the Contractor‟s responsibility to review all GFA on receipt to ensure its adequacy to complete the specified Contract
Tasks. Any concerns should be reported to the Authority at the earliest opportunity and before work commences.
14. CONTRACTOR’S RECORDS
14.1 For the purposes of this Contract the Contractor‟s Records to be maintained and made available to Dstl if required under DEFCON 609 are as follows:
All Contract Records (Study Files) to be retained for a period of 4 Years from the Contract End Date. 14.2 The Contractor should contact the Project Manager (as shown at Box 2 of the Appendix to Contract) at the end of the 4 Year period for formal disposal instructions.
15. INDEMNITY AND INSURANCE
15.1 Without prejudice to any rights or remedies of the Authority the Contractor shall indemnify the Authority and the Crown against all actions, suits, claims, demands, losses, charges, costs and expenses which the Authority or the Crown may suffer or incur as a result of or in connection with any damage to property or in respect of any injury (whether fatal or otherwise) to any person which may result directly or indirectly from any defect in the Articles or the negligent or wrongful act or omission of the Contractor. 15.2 The Contractor shall effect with a reputable insurance company a policy or policies of insurance covering all the matters which are the subject of indemnities under these Conditions and shall at the request of the Authority produce the relevant policy or policies together with receipts or other evidence of payment of the latest premium due thereunder.
16. PERFORMANCE
16.1 The Project Management Branch (Box 2 of Appendix to Contract) shall be responsible for monitoring the technical performance of the Contractor. 16.2 The Services which the Contractor is required under the Contract to perform or to fulfil and any Articles which the Contractor is required under the Contract to supply shall be to the reasonable satisfaction of the Authority and shall conform in all respect with any particulars specified in the Contract. 16.3 The Services which the Contractor is required under the Contract to perform or to fulfil and any Articles which the Contractor is required under the Contract to supply shall be fit and sufficient for the purpose for which such Articles are ordinarily used and for and any particular purpose made known to the Contractor by the Authority. 16.4 The Services which the Contractor is required under the Contract to perform or to fulfil and any Articles which the Contractor is required under the Contract to supply shall conform in all respects with the requirements of any applicable legislation, statutes, orders, regulations or bye-laws from time to time in force. 16.5 The Authority relies on the expertise, skill and judgement of the Contractor in the performance of the Contract.
17. WARRANTIES
17.1 It shall be a condition of the Contract that the Contractor warrants, represents and undertakes to the Authority that: 17.1.1 For the duration of the Contract it shall guarantee the provision of the levels of service and performance specified in the Contract; 17.1.2 For the duration of the Contract it shall at all times have full capacity, capability and authority to perform the Contract; 17.1.3 For the duration of the Contract it has and shall continue to hold all necessary (if any) regulatory approvals necessary to perform the Contractor‟s obligations under the Contract
17.1.4 For the duration of the Contract it has and shall continue to provide and maintain an organisation having the necessary facilities to undertake the work specified in the Contract.
18. TRANSPARENCY 18.1 For the purpose of this Condition the expressions: a. “Transparency Information” shall mean the content of this Contract in its entirety, including from time to time agreed changes to the Contract, and details of any payments made by the Authority to the Contractor under the Contract;
b. Contractor Commercially Sensitive Information” shall mean the information listed in the Contractor Commercial Sensitive Information Annex to the Contract being information notified by the Contractor to the Authority which is acknowledged by the Authority as being commercially sensitive information. 18.2 Notwithstanding any other term of this Contract, including DEFCON 531 where applicable, the Contractor understands that the Authority may publish the Transparency Information to the general public. The Contractor shall assist and cooperate with the Authority to enable the Authority to publish the Transparency Information. 18.3 Before publishing the Transparency Information to the general public in accordance with clause 2 above, the Authority shall redact any information that would be exempt from disclosure if it was the subject of a request for information under the Freedom of Information Act 2000 (“the Act”) or the Environmental Information Regulations 2004 (“the Regulations”), including the Contractor Commercially Sensitive Information. 18.4 The Authority may consult with the Contractor before redacting any information from the Transparency Information in accordance with clause 3 above. The Contractor acknowledges and accepts that its representations on redactions during consultation may not be determinative and that the decision whether to redact information is a matter in which the Authority shall exercise its own discretion, subject always to the provisions of the Act or the Regulations. 18.5 For the avoidance of doubt, nothing in this Condition shall affect the Contractor‟s rights at law.
Appendix to Contract Addresses and Other Information
1. Commercial Department: 5. Bill Paying Branch:
Information Redacted Dstl Ledgers Processing Team S&T Sourcing Team PO Box 325 G02-D Building 5 Dstl Portsdown West Dstl Porton Down Portsdown Hill Road SALISBURY Fareham Wiltshire SP4 0JQ PO14 9HL Information Redacted Telephone: 02392 532444 (Generic)
2. Project Management Branch: 6. Consignment Instructions: Information Redacted The items are to be consigned as follows: Biomedical Sciences Dstl Porton Down Main Stores SALISBURY Dstl Porton Down Wiltshire SP4 0JQ Salisbury Information Redacted Wiltshire SP4 0JQ
3. Drawings/Specification are available from: 7. Forms and Documentation are available from:
N/A Ministry of Defence, Forms and Pubns Commodity Management PO Box 2, Building C16, C Site Lower Arncott Bicester, OX25 1LP
DSDA Operations Customer Services (DOCS): Civ: +44 (0) 1869 256052 Fax: +44 (0) 1869 256026 e-mail: [email protected] By post - A self-addressed label should be sent with each application.
The DEFCONs are available on the Internet at: www.aof.mod.uk/aofcontent/tactical/toolkit/index.htm
4. Quality Assurance Authority: 8. Notes:
VAT (Where DEFCON 513 applies). The To the satisfaction of the Chief Executive, Dstl, or Contractor is responsible for the determination of his authorised representative. VAT liability. The Contractor should consult his In addition to the General Conditions, the local VAT office (and not the Commercial Services following Quality Assurance requirements apply: Department) in cases of doubt. The Contractor N/A should notify the Commercial Services Department of his VAT liability under the Contract. AQAPS and DEFSTANS are available from Stan
1, Kentigern House, 65 Brown Street, Glasgow, G2 8EX. a self-addressed label should be sent with each application.
IMPORTANT NOTICE DSTL DOES NOT ACCEPT RESPONSIBILITY FOR THE TIMELY PAYMENT OF INVOICES WHICH ARE NOT SUBMITTED TO THE PRECISE ADDRESS STATED IN BOX 5 OF THE APPENDIX TO CONTRACT AND STRICTLY IN ACCORDANCE WITH THE ARRANGEMENTS DETAILED IN THIS CONTRACT ANNEX A to Contract No DSTLX-1000078175
STATEMENT OF REQUIREMENT
Summary statement
Dstl has developed a new drug combination therapy for intramuscular administration against nerve agent poisoning consisting HI-6 dimethane sulphonate (DMS), Atropine sulphate and Avizafone (known as „Triple Therapy‟). Dstl has a requirement to undertake a programme of Safety Studies using this three-drug combination to support clinical studies and a UK Marketing Authorisation Application. The activities described will form part of these Safety Studies. Dstl has an additional requirement to support the licensure of intravenous administration of HI-6 DMS alone. The Studies must comply with Good Laboratory Practice (GLP) and meet the International Conference on Harmonisation (ICH) guidelines on Pharmaceuticals for Human Use.
Statement of requirements 1. Drug interaction studies 2. Protein binding studies 3. General toxicity studies (HI-6 DMS i.v. only) 4. Development toxicity studies (both products) 5. Phase II environmental risk assessment (HI-6 DMS i.v. only)
Information on the two drug products Triple Therapy (intramuscular injection) The purpose of the triple therapy is to act as an emergency treatment following nerve agent exposure. The posology for the triple therapy will be one injection on detecting symptoms of nerve agent exposure, a second injection if symptoms persist and, depending on clinical condition, a third injection after the second injection. These injections will be by intramuscular administration via an autoinjector. The maximum total doses of each of the three components delivered to one subject for the purposes of non-clinical evaluation will be regarded as a single dose, are shown below.
Table 1. Proposed clinical and non-clinical doses of triple therapy drug substances
Clinical dose Non-clinical dose
Drug substance total dose (total dose scaled) (3 x single) *
Avizafone 30 mg 0.43 mg.kg-1 **
Atropine sulphate 6 mg 0.09 mg.kg-1
HI-6 DMS 1908 mg 27.27 mg.kg-1
Water for Injection -1 6 ml 0.09 ml.kg ***
* Based on a body weight of 70kg ** Approximately equivalent to 0.22mg/kg diazepam
*** used to make solution up to total volume and include citrate buffer (pH 3-4)
For the purposes of this work programme 3 auto-injectors (maximum in man) are to be treated as equivalent to a single therapeutic dose and then scaled from a 70kg man using a mg/kg ratio.
HI-6 DMS is a new active substance in the EU and has not been approved in any Marketing Authorisation. Avizafone was approved as part of the UK Marketing Authorisation for ComboPen in 1996 (Autoject (ComboPen ) auto-injector L4A1, PL 04537/004) however, there is no UK Marketing Authorisation containing avizafone alone and it is not listed in the British National Formulary (BNF). Atropine sulphate does have a UK Marketing Authorisation and is listed in the BNF. HI-6 DMS, atropine sulphate and avizafone will be supplied by Dstl.
The objective of the non-clinical programme will be to generate and/or compile sufficient preclinical data to support Phase I clinical studies in healthy volunteers. Testing will be conducted using the combination of active ingredients employed in the triple therapy at the ratios intended for use in the product. General toxicity studies have already taken place for the triple therapy (further information can be found in Annex A).
Intravenous administration of HI-6 DMS The posology for HI-6 DMS will be intravenous administration by trained medical personnel to casualties following nerve agent exposure. For the purposes of this work programme the single therapeutic dose will be determined by ascertaining the maximum tolerated dose or a maximum practical dose when administered by i.v. continuous infusion in the range-finding study. As HI-6 DMS is unstable at room temperature in aqueous solution, this necessitates reconstitution of the product on the day of administration.
It is proposed that use will be made of relevant existing data from the triple therapy to assist in determination of dose levels in animal models. Some of the studies carried out as part of the pre-clinical programme for the triple therapy can be used as a means of limiting the extent of the pre-clinical programme for this product. Therefore no safety pharmacology or mutagenicity studies will be required. The objective of the non-clinical programme will be to generate sufficient non-clinical data to support Phase I clinical studies in healthy volunteers.
Details of Studies Required 1. Drug interaction studies a) Studies to assess the potential of HI-6 DMS, atropine sulphate and avizafone (individually and in combination with each other) to induce hepatic drug metabolising enzymes in freshly isolated human hepatocytes. b) Studies to investigate the potential of HI-6 DMS, atropine sulphate and avizafone (individually and in combination with each other) to inhibit the major human forms of cytochrome P450 (CYP) including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 (testosterone 6β-hydroxylase and midazolam 1‟-hydroxylase).
It is assumed that the route of administration of the final products do not influence the test methodology. Therefore these studies will be applicable to both the triple therapy (human route i.m.) and HI-6 DMS alone (human i.v. route).
Transporter assay (Additional Work if required) A transporter assay may be required to investigate the potential of HI-6 DMS to interact as a substrate and an inhibitor of P-glycoprotein (P-gp) efflux transporter. This may assist in prediction of potential drug-drug interactions in human. This assay is optional and the
requirement for this assay will be based on results from the drug interaction studies. (If/when this additional work is required, a quotation will be requested by Dstl from the Contractor.)
2. Protein binding of HI-6 DMS Protein binding studies for HI-6 DMS have already been carried out using human and dog plasma by ultra-filtration. These studies are also required to be conducted in rat, rabbit, marmoset and guinea pig plasma. This will assess species differences and indicate whether plasma unbound drug concentration is an appropriate measure of exposure. These studies will be applicable to both products. Dstl will be able to supply marmoset plasma if required. 3. Development toxicity Developmental toxicity studies are required for both the triple therapy (i.m.) and for i.v. administration of HI-6 DMS. The proposal to address the developmental toxicity aspect is a four part approach in both rabbit and rat for each product. The supporting assays for formulation analysis and bioanalytical analysis in rat studies will be made available for validation. The toxicity programme will need to include development and validation of these assays for rabbit. Part 1 Establish the maximum tolerated dose (MTD) in each species in non-pregnant females. Part 2 7-day repeat dosing at the MTD in non-pregnant females in each species to show that cumulative toxicity does not occur on repeated exposure. Limited formulation analysis and toxicokinetic analysis will need to be included in these studies. Part 3 A small-scale development study with a limited number of animals to check that the selected dose levels are tolerated in pregnant animals and to collect the toxicokinetic data necessary. Part 4 A developmental toxicity study which complies with ICH Guidelines. Tenders will be evaluated on the basis of a study programme that is compliant with this proposal; however tenders are invited to offer alternative approaches.
4. General Toxicity (required for the i.v. administration of HI-6 DMS only) The supporting assays for formulation analysis and bioanalytical analysis in dog will be made available for validation. General toxicity in beagle dogs: a) Range-finding toxicity studies The tolerance to i.v. administration of HI-6 DMS will be assessed in dose range-finding study in the beagle dog. The human therapeutic dose is currently undefined, but is likely to be as high as can be tolerated. The dose of HI-6 DMS will be titrated upwards until either the maximum tolerated dose or the maximum practical dose is achieved when administered by i.v. infusion. The i.v. infusion doses in the dog will need to be delivered to animals which are ambulatory which will mean the use of CADD pumps, Baxter infusers or some similar technology. The identified maximum tolerated dose will then be administered to naïve dogs for at least 7 consecutive days. Toxicokinetic evaluation will provide information on exposure and confirm the analytical methodology for bioanalysis of HI-6 DMS. b) 14 day repeat dose & 14 day recovery A 14 day repeated dose toxicity study to be conducted by the i.v. route in the dog will include provision for a post treatment observation period in sub-groups of control and high dose animals. Six-lead electrocardiograms will be recorded prior to dosing and during the final week of treatment (at a time post dose to be determined depending on toxicokinetic data obtained on Day 1) and evaluated. Respiratory rate will also be
recorded prior to dosing and during the final week of treatment at the time post dose selected for ECG recording. Heart rate, QT, PR, and QRS intervals will be measured from the representative ECG waveform at each time point during ECG evaluation. The RR interval will be calculated and reported from the measured heart rate. QTc will be calculated based on the QT interval and heart rate measured from representative ECG waveforms using the Fridericia correction. The study protocol will include provision for analysis of HI-6 DMS in the formulation on Day 1 and during the final week of treatment. Blood samples from animals exposed to HI-6 DMS or the vehicle on Day 1 and during the final week of treatment will be obtained at 1, 2, 4, 8 and 12 and 24 hours post dose and analysed for the HI-6 DMS. Toxicokinetic analysis will be undertaken to assess exposure. Full haematology, blood and urine chemistry analyses will be conducted prior to termination of the study. A full post mortem examination will be carried out, and a spectrum of organs examined (weight etc.). All tissues from at least the controls and high dose group will be examined histopathologically. Particular attention would be given to histopathological examination of the testis and ovary.
5. Phase II Environmental Risk Assessment (for the i.v. administration of HI-6 DMS only) A Phase II Environmental Risk Assessment will be required for the i.v. administration of HI-6 DMS. This is based on the requirements of CHMP (Committee for Medicinal Products for Human Use) Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00) adopted by CHMP 01 June 2006. Note: It is assumed that only Tier A will be required.
Historical studies on drug substances These previous studies with HI-6 are referring to all studies regardless of their salt structure (i.e. DMS, dichloride etc.) Acute toxicity 1. HI-6 dichloride HI-6 dichloride i.m. dog (Beagle) – mortalities occurred at doses ≥ 610 mg/kg.
2. Atropine sulphate No data are available in the dog. Atropine sulphate: LD50 rat i.m. - 920 mg/kg. A 30x multiple of the proposed human single dose is 2.7 mg/kg, hence atropine sulphate toxicity in the dog is unlikely to be a limiting factor in dose selection. 3. Avizafone Single i.m. administration of avizafone to rat resulted in toxic effects above 40 mg/kg although no mortality was reported at levels up to 610 mg/kg during the 12 day recovery period. No acute i.m. toxicity data for diazepam were identified. The acute p.o. LD50 of diazepam in rats is 710 mg/kg. A 10x multiple of the proposed human single i.m. dose is 4.3 mg/kg (a 30x multiple of the proposed human single dose is 12.9 mg/kg), hence avizafone toxicity is unlikely to be a limiting factor in dose selection in the dog. 4. Safety pharmacology No relevant, GLP-compliant safety pharmacology data on HI-6 dichloride have been identified in the preclinical gap analysis of existing HI-6 dichloride data. No safety pharmacology data specific to either atropine sulphate or avizafone were identified in literature searches.
Mutagenicity 1. HI-6 dichloride
Available data which are GLP-compliant indicate the following results: a. Ames test: Dose levels 33 to 333 g/ml in the absence and presence of S9 in TA1535, TA1537, TA1538, TA98 and TA100. Single assay by plate incorporation, triplicate plates. Negative in all strains both in absence and presence of S9. b. L5178Y TK +/- mouse lymphoma assay: Dose levels selected for analysis: absence of S9 - 100 to 1000 µg/ml; presence of S9 - 60 to 450 µg/ml. Equivocal response in the presence of S9, negative response in the absence of S9. c. HGPRT Locus in CHO cells: Dose levels in absence of S9 - 312.5, 625, 1250, 2500 and 5000 µg/ml. Presence of S9 - 625, 1250, 2500, 3750 and 5000 µg/ml. Negative both in absence and presence of S9. d. Chromosomal aberrations in CHO cells: Dose levels both in absence and presence of S9 - 190, 380, 750, 1500 and 3000 µg/ml, 16 hours treatment in the absence of S9, 2 hours treatment in the presence of S9. Harvested at 18 hours. 3000 µg/ml caused complete mitotic inhibition and toxicity both in absence and presence of S9 and was not evaluated. Statistically significant, dose-related increase in chromosome aberrations in the absence of S9 and a statistically significant increase at 1500 µg/ml only in the presence of S9. e. Chromosomal aberrations in human peripheral lymphocytes: Dose levels in the absence of S9: 80, 160, 320, 630, 1250 and 2500 µg/ml. Dose levels in the presence of S9: 630, 1250, 2500 and 5000 µg/ml. Twenty-four hours treatment in the absence of S9 and 4 hours treatment in the presence of S9. Cells harvested 26 hours after treatment. Statistically significant, dose-related increases in chromosome aberrations in both the absence and presence of S9. 2. Avizafone a. Ames test: Dose levels: 33.3 g to 10 mg per plate in the absence and presence of S9 in strains TA98, TA100, TA1535, TA1537 and TA1538. No evidence of mutagenic potential in TA1535, TA1537 or TA100 at dose levels up to 10 mg/plate. There was a suspicion of a mutagenic effect in TA98 and TA1538 in the presence of S9, but this was not confirmed on re- test at dose levels up to 10 mg/plate. Toxic effects observed in all strains in the presence of S9 at 10 mg/plate and in the absence of S9 in strains TA98 and TA100 at 10 mg/plate. 3. Atropine sulphate No recent, GLP-compliant data have been identified.
Non-clinical development of triple therapy (HI-6 DMS, Atropine sulphate and Avizafone) The following studies have been undertaken in compliance with GLP.
Summary of completed toxicology studies with HI-6-DMS, Atropine sulphate and Avizafone combination
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ANNEX B to Contract No DSTLX-1000078175
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Annex B references the Information Redacted Technical Proposal Option 2 Reference No: EN53367 Version No: v2 as submitted in the detailed Tender response dated: 22/10/12 and is incorporated into the Contract through reference.