Request for Proposal

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Request for Proposal

Data Management and Biostatistics services

to support the conduction of a

phase 2/3 trial in

Human African Trypanosomiasis Disease

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Table

of

1. PURPOSE

DNDi plans to conduct a phase 2/3 study with SCYX-7158, which is the first oxaborole-based oral drug, for the treatment of late-stage Human African Trypanosomiasis (HAT) due to Trypanosoma brucei gambiense.

This study is aimed to provide safety and efficacy data in order to provide a tool for sustained elimination of HAT as part of WHO’s roadmap for elimination of HAT targeted for 2020 and endorsed by the London Declaration on Neglected Tropical Diseases in January 2012.

2. RFP INSTRUCTIONS

2.1. General information

a. DNDi invites you as a Service Provider to submit a proposal in regards of this RFP for Data Management and Biostatics Services in support for the conduction of the phase 2/3 trial. b. This entire RFP and all the related discussions, meetings, information exchanges and

subsequent negotiations that may occur are subject to the confidentiality terms and conditions of the Intent to Participate attached as Annex 1.

c. All bidders are required to complete and send return the Intent to Participate letter.

d. The issuance of this current Request for Proposal in no way commits DNDi to make an award. DNDi is under no obligation to justify the reasons of its service provider’s choice following the competitive bidding. DNDi could choose not to justify its business decision to the participants of the RFP.

e. DNDI reserves the right to:

 Reject any proposal without any obligation or liability to the potential service provider.

 Withdraw this RFP at any time before or after the submission of bids without any advance notice, explanation or reasons.

 Modify the evaluation procedure described in this RFP

 Accept other proposal than the lowest one

 Award a contract on the basis of initial proposals received without discussions for best and final offers

 Award all services to only one supplier or allocate them to different suppliers according to what DNDi will consider necessary

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g. DNDi reserves the right to request additional data, information, discussions or presentations to support their proposal. All bidders must be available to discuss about details of their proposal during the RFP process

h. All offers should be submitted in an electronic format

i. A proposed time plan set out below indicates the process DNDi intends to follow. If there are changes to this timelines, DNDi will notify you in writing.

2.2. RFP Timelines

Process steps Responsible party Timelines

Launch RFP

Send back the Intent to Participate letter Q&A sent to DNDi

DNDi responses to Q&A Reception of proposals

Notification to Pre-selected Bidders Bid Defense Meetings

Bidder selection Project Start

DNDi

Service Provider Service Provider DNDi

DNDi DNDi DNDi DNDi

Service Provider

08 October2015 15 October 2015 15 October 2015 19 October 2015 20 October 2015 05 November 2015 10 November 2015 13 November 2015 Upon contract signature

2.3.RFP processes and contact information

2.3.1. Instructions

All bidders may request further clarifications in regards of this current RFP, by addressing its questions in writing to the dedicated key contacts identified below. These questions should be submitted to DNDi at the date mentioned in the section 2.2 RFP Timelines.

In order to keep a fair bidding process, questions on the substance will only be answered in a document shared with all the bidders on the date indicated in section 2.2. RFP Timelines. To submit your questions, please use the form attached as Annex 2.

2.3.2. Confirmation of Intent

Please transmit your intent to participate by using and signing the document attached in Annex 1. Each bidder is required to provide DNDi with a written confirmation of intent or decline to participate by the date as indicated in the section 2.2.

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Confirmations of intent should be sent by email to Christophine Marty-Moreau (contacts details below)

Questions types Contactperson Title Contact information

Contractual & Technical aspects

Christophine

MARTY MOREAU

Procurement Manager

15 Chemin Louis Dunant 1202 Geneva Switzerland Phone: +41 22 906 92 61 Email: cmarty@dndi.org

2.4.Format and content of the proposal

Responses to this RFP must be in English and should contain the following information:

 A cover letter including:

o Name and address of the service provider

o Name, title, phone number and email address of the person authorized to commit contractually the service provider

o Name, title, phone number and email address of the person to be contacted in regards of the content of the proposal, if different from above

o Signature of this letter done by a duly authorized representative of the company

o Acceptance of the consultation principles

o Acceptance of DNDi agreement template: Clinical Service Agreement attached as Annex 3

 A technical proposal

o Detailed proposal explaining how your company’s approach will enable DNDi team to perform this study, meet project timelines and ensure quality results.

o Your risk based management approach for this project.

o Some information on your company organization, including how a team might be organized as described to facilitate the staffing structure you would apply to manage and monitor the study.

o Some history of your firm’s experience in conducting/managing HAT or Infectious studies in Africa.

 A financial proposal

o Budget template to be completed and attached as Annex 4

o Your approach to minimize expenses

 Administrative information

o Business Company information: directors and officers, creation date, corporate headquarters, locations, business turnover of the past 3 years (global and in the field of service provided), headcounts (global and in the field of service provided), general services provided, customer’s reference, pricing strategy for NGOs.

o Any other relevant information enabling DNDi to assess the opportunity of contracting with your company

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2.5.Conflict of Interest

The Company shall disclose any actual or potential conflicts of interest in the Intent to Participate letter.

3. DNDi OVERVIEW

3.1.Mission & objectives

Neglected tropical diseases continue to cause significant morbidity and mortality in the developing world. Yet, of the 1,556 new drugs approved between 1975 and

2004, only 21 (1.3%) were specifically developed for tropical diseases and tuberculosis, even though these diseases account for 11.4% of the global disease burden.

Founded in 2003 to address the needs of patients with the most neglected diseases, DNDi is a collaborative, patient’s needs driven, not for profit drug R&D organization.

Acting in the public interest, DNDi bridges existing R&D gaps in essential drugs for these diseases by initiating and coordinating drug R&D projects in collaboration with the international research community, the public sector, the pharmaceutical industry, and other relevant partners. DNDi’s primary focus has been the development of drugs for the most neglected diseases, such as Human African Trypanosomiasis (HAT, or sleeping sickness), visceral leishmaniasis (kala-azar), and Chagas disease, while considering engagement in R&D projects for other neglected diseases to address unmet needs that others are unable or unwilling to address.

The primary objective of DNDi is to deliver a total of 11 to 13 new treatments by

2018 for leishmaniasis, sleeping sickness, Chagas disease, malaria, paediatric HIV, and specific helminth infections and to establish a strong R&D portfolio that addresses patient needs. Expanding upon R&D networks built on South-South and North-South collaborations, DNDi aims to bring medical innovation to neglected patients by developing field-adapted treatments. In doing this, DNDi has two further objectives:

 Use and strengthen existing capacities in disease-endemic countries via project implementation

 Raise awareness about the need to develop new drugs for neglected diseases and advocate for increased public responsibility.

For more information, please visit DNDi website: http://www.dndi.org/

3.2.Project background

Human African trypanosomiasis (HAT) is a life-threatening disease caused by the protozoan parasites Trypanosoma brucei (T.b.) gambiense and T.b. rhodesiense, which typically occurs in Sub-Saharan Africa where the vector, the tsetse fly, is endemic. Democratic Republic of Congo (DRC) accounts for 75% of all reported cases.

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SCYX-7158 is expected to be administered as a single oral dose treatment for both stages of HAT due to T. b. gambiense, dramatically simplifying the current prescription of the treatment. A phase 1 program in healthy volunteers of sub-Saharan origin was completed and DNDi is starting a pivotal phase 2/3 trial that should form the basis for evaluation of the efficacy and safety in late stage or stage 2 HAT. Note that DNDi has sought the European Medicines Agency (EMA)’s Scientific advice under article 58 of Regulation 726/2004 on the design of the pivotal phase 2/3 trial and that EMA feedback is expected by November 2015.

3.3.HAT phase 2/3 clinical trial: Key data

 Indication: Late stage Human African trypanosomiasis due to T.b gambiense

 Study design: Open, multicentric, pivotal using historical controls as comparator

 Participating country: 1 country (DRC), ideally 6-7 centers dispersed in remote areas

 Number of patient planned per site: 1-2 patients per site per month.

 Timelines:

o Draft Protocol: November 2015

o Final protocol: December 2015

o CA/EC Submission: December 2015

o Investigator Meeting: March 2016

o First Patient In by 31 March 2016

o Futility analysis: From September to November 2016

o Enrollment period = 18 months

o Last Patient Out by 31 Mar 2019

o Interim (12 month endpoint) Database Lock: November 2018

o Interim (12 month endpoint) TLF: December 2018

o Interim (12 month end-point) CSR: March 2019

o Art 58 submission (12 month data end-point + available 18 month data): July 2019

o 18 month endpoint DataBase lock: May 2019

o 18 month endpoint TLF: June 2019

o Final CSR: September 2019

 Analyses:

o A futility analysis will be performed on the first 20 patients after end of hospitalization. Results of this futility analysis are expected around November 2016 but recruitment will not stop until results are disclosed by the DSMB.

o As the primary endpoint is composed of an early primary endpoint (12 month) and a final primary endpoint (18 month) that will prevail over the 12 month endpoint, interim analyses and interim clinical study reports will be done once all patients will have reached the 12 month visit while the study will continue until the 18 month visit is completed. All available 18 month data at the time of submission might be used.

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 Recruitment Plan:

 Nb of subjects to be screened: 170

 Nb of subjects to be included: 155 – 9% screen failure rate

4. SCOPE OF WORK

The purpose of this Request for Proposals (RFP) refers to Data Management and Biostatistics services within the context of the development of the pivotal phase 2 /3 study.

4.1.CRF and Data Management

4.1.1 General Information

DNDi would like an easy collection and a rapid transmission of study data in remote centers where internet access might be limited. Site monitoring visits will occur on a monthly or a

minima on a bi-monthly basis and remote monitoring is to be performed by monitors on a

monthly basis. Therefore, DNDi would like the CRO to propose a solution to get on going access to both study data: some row data (not monitored) from the site during the patient hospitalization period, for safety purposes, and clean SDV data, knowing that a 90% level of data-cleaning is expected at any time. Please propose and quote on different options for data collection/transmission with arguments for each system, including strengths/weaknesses of systems such as connectivity issues, time impact at initiation and site closure, cost impact….knowing that in case of paper CRF, electronic transmission of the scanned monitored CRF pages to Data Management is to be performed by CRAs within max 5 days and turn-around time for query resolution might not exceed 5 days.

4.1.2 CRF Design (assumptions)

 Electronic or paper CRF in French

 Total number of unique CRFs pages per patient: estimated 70-90 pages

o 1 screening visit (screening period and pre-treatment - Eligibility -Informed Consent signed here): estimated 6 pages per visit

o 5 visits (Baseline, D1, D5, D11, D15). Estimated 6 pages per visit

o 8 FU visits maximum (M1, M2, M3, M4, M5, M6, M12, M18) + 1 unscheduled: estimated 6 pages per visit

o Number of AE pages: estimated 2 x 3 pages (during hospitalization and during follow-up)

o Number of SAE pages: estimated 3 pages

o Number of Concomitant treatment pages: estimated 2 x 2 pages (during hospitalization and during follow-up)

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o Number of queries per patient: estimated 2 per visit

o Number of edit checks (automatic queries): estimated 4500

o Medical Coding per Enrolled Patient: estimated 40

 User Acceptance Tests as appropriate

 To support the study management and follow-up

o Edit and send (study team + investigator) electronic visit calendar for each patient included.

o Send reminder for FU visits (study team + investigator) (6 month, 12 month and 18 month visits)

 Send reminder for missing visits (study team + investigator)

 Possibility of off-line access to study data (clean and row data) allowing rremote monitoring or whatever system that allows “immediate” access to study data

 Reports:

- Query reports to CRAs and investigators: listings of queries sent to CRAs and investigators before monitoring visits.

- Monthly reports on study data to DNDi Project Management. Reports can be suggested by the vendor, according to current practice. It is preferred that the reports can be generated and exported by the sponsor study team (as many times as needed). Example of reports: study and site enrollment, population set, reason for non-inclusion, demographics, medical history, concomitant medication, abnormal laboratory values, AE and SAE... Reports should be ready for

implementation since first patient in order to follow the study progress. Ensure flexibility for unscheduled demands.

- Activity report (metrics such as: enrollment status, data entry and data cleaning status, query status, protocol deviation listing,…)

- Patient profiles (criteria to be later defined) and data listings edited for DSMB and interim locks

 Communication:

- Weekly (until end of futility) and then monthly TC with DNDi project management is expected (CRO to organize, prepare and send the agenda and minutes). Plus ad-hoc meetings as needed.

- Quarterly TC with DNDi Project Management and Monitoring team (CRAs + Project Management) (DNDi to lead and organize),

4.1.3 Additional Information / requirement

DNDi would like a draft CRF to be available for the EC submission planned in December 2015.

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4.2 Data Management Services

Data management systems must be compliant with 21 CFR Part 11 and C-DISC compliant. For screen failures, demographics and data justifying the non inclusion will be captured (to be further precised).

4.2.2 Main activities

A summary of the main activities is detailed above (list not exhaustive)

 Site Hardware qualification if EDC

 Electronic or paper CRF development and management (including shipment for paper CRF) and tracking

 CRF completion guideline development and management

 Database set-up and deployment including UAT if needed

 “Hybrid” data entry: “immediate” for CRF pages used as source document and a later data entry for CRF pages monitored by CRAs. Detail the workflow of data entry and how DNDi, sites and monitors will have access to study data.

 Data Cleaning. Please detail how you plan to clean the data (eg: by allocating time continuously or when you have the full patient profile)

 Edit trail

 On going medical review

 Data validation

 Data Imports from External Vendors (laboratory including lab reference ranges, PK…)

 Data Transfers (please detail the format of data)

 Coding set-up (latest versions of MedDRA and WHODrug + updates)

 Coding of adverse events, concomitant medications and medical history

 SAE Reconciliation (at least 3)

 PK reconciliation

 ECG reconciliation

 Monthly Study report (population set, demography, medical history, conc med, AE, SAE…)

 Patient profile generation

 Preparation and review of data prior to the database locks and DSMB meetings

 Data Management Plan development and maintenance

 Data Validation Plan development and maintenance

 Soft interim database locks (2 to 3)

 Final DataBase lock

 Delivery of the submission package 4.2.3 Other activities and requirements

 Possibility to print and distribute study forms from other vendor (eg: IMP logs) in triplicate

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 Data Safety Monitoring Board (DSMB):

o Charter development

o Schedule and coordinate DSMB meetings (at least 3 meetings planned with the possibility to call for any DSMB meeting in case of need or any 6 months in case of longer study duration):

- To coordinate meeting logistics (travel, hotel, catering etc.) as needed

- To prepare tables and listings to incorporate into the DSMB review packets

- To prepare electronic meeting review packets for DSMB members

- To prepare the meeting minutes (open and closed session) and to distribute the meeting minutes and recommendations in accordance to Charter requirements DNDi will be responsible for DSMB member selection and payment management and this is not part of the scope of the DM activity. Although safety services and medical monitoring are not under the scope of this RFP, at least 2 reconciliations between Safety Database and Clinical Database are planned and must be considered.

 Participation to investigator meeting.

 Site, CRA and sponsor training on CRF completion and database management.

4.3 Biostatistics

Biostatistic system must be C-DISC compliant. 4.3.2 Main activities

A summary of the main activities is detailed above (list not exhaustive):

 Statistical analysis plan (SAP) development and maintenance

 Data definition and Analysis dataset programming

 Programming of mock tables, listings and figures

 Interim analysis (at least 2)

 Final statistical analysis

 Production of statistical tables, listings and figures for interim and final analysis

 DSMB data listings as well as SAE listings (see sections 4.2.2 and 4.2.3)

 Lists, Tables and Figures*, as follows (not exhaustive)

o Nb of unique Tables: estimated 10

o Nb of repeated tables: estimated 30

o Nb of individual data Listings estimated: 35

o Nb of Figures estimated: 5

 Interim statistical report

 Statistical collaboration on final report including pdf integration

 Final database transfer

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4.3.3 Additional information

DNDi would like Statistical Analysis Plan to be developed in parallel with study protocol development (from study protocol draft 3)

5. CRITERIA FOR SELECTING SERVICE PROVIDERS

The decision to award any contract as a result of this RFP process will be based on Service Providers’ responses and any subsequent negotiations or discussions. The decision making process will consider the ability of each service provider to fulfil DNDi’s requirements as outlined within this RFP and the cost of the offer.

Proposals will be assessed against the main following criteria but not limited to:

 Technical criteria

o Project approach, methodology and planning

o Experiences/skills, level of company representatives assigned to this project

o Quality and applicability of proposal presentation

o Customer references / Experience in related therapeutic area and DRC

 Capacity to deliver

o Reasonable timelines

o Data quality

o Project management capabilities (including “out of the box” thinking)

o Risk management approach for this project

o Past experience with similar work

o Profile of staff involved ( CVs)

 Financial criteria

o Realistic costing of the proposal with NGO rates when possible

o Approach to minimize expenses

o

6. PROPOSAL REQUIREMENTS, DELIVERABLES &

TIMELINES

6.1 RFP deliverables

Given DNDi’s requirements, describe how your approach and staff will enable your team to meet study timelines, insure quality results, and minimize expenses. Please be sure to include the following information in your proposal:

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o Management Board, History, Locations, and contact

o Key figures (Revenue, headcounts, Locations)

o General services provided and specific expertise

o Similar projects / experience in related area

 Project approach for required services, especially on off-line monitoring

 Project management plan

o Proposed timelines and organizational structure

o Deliverables (tools & reports that you intend to supply)

o Associated services (maintenance, support, helpdesk, etc.)

o Proposed method and communication plan

 Risk Management Plan to mitigate risks

 Budget with full details of your offer including fixed costs and Pass-Through Costs.

Activities performed by subcontractors should be clearly indicated (as well as company names). We recommend the use of DNDi template inserted as Annex 4

 Project team involved

 List of tasks and responsibilities

 Any other relevant information

6.2 Timelines

Beginning of services planned for Q4 2015 Completion of activities planned for Q4 2019

7. ANNEXES

Annex 1: Intent to Participate letter Annex 2: Q & A Form

Annex 3: Clinical Service related Services Agreement template Annex 4: Budget template

Request for Proposal