Request for Proposal Monitoring services to support the conduction of a phase 2/3 trial in Human African Trypanosomiasis Disease Dated: October 8 th 2015 Page 1
Table of Contents 1. PURPOSE... 3 2. RFP INSTRUCTIONS... 3 2.1. General information... 3 2.2. RFP Timelines... 4 2.3. RFP processes and contact information... 4 2.3.1. Instructions... 4 2.3.2. Confirmation of Intent... 4 2.4. Format and content of the proposal... 5 2.5. Conflict of Interest... 5 3. DNDi OVERVIEW... 6 3.1. Mission & objectives... 6 3.2. Project background... 6 3.3. HAT phase 2/3 clinical trial: Key data... 7 4. SCOPE OF WORK... 8 5. CRITERIA FOR SELECTING SERVICE PROVIDERS... 12 6. PROPOSAL REQUIREMENTS, DELIVERABLES & TIMELINES... 12 6.1. RFP deliverables... 12 6.2. Timelines... 13 7. ANNEXES... 13 Page 2
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 Monitoring 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 f. Late submission proposals are subject to rejection 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 Page 3
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 12 November 2015 14 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 Timelines of the RFP 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. Timelines of the RFP 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. Confirmations of intent should be sent by email to Christophine Marty-Moreau (contacts details below) Questions types Contact person 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 Page 4
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 Project team organization to facilitate the staffing structure and monitor efficiently the study. o Firm s experience in conducting/managing HAT or Infectious studies in DRC. 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 2.5 Conflict of Interest The Company shall disclose any actual or potential conflicts of interest in the Intent to Participate letter. Page 5
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. HAT occurs in two clinical stages and is invariably fatal if left untreated. 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 Page 6
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: ideally 6-7 centres, dispersed in remote areas in DRC Nb of subjects 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. o DSMB meetings may occur every 6 months and upon request in case of need Recruitment Plan: o Nb of subjects to be screened: 170 o Nb of subjects to be included: 155 9% of screen failure Page 7
4. SCOPE OF WORK The purpose of this Request for Proposals (RFP) refers to Monitoring services within the context of the development of the pivotal phase 2 /3 study. 4.1 List of main activities DNDi would like to quote the service of clinical monitoring for the participating sites in DRC. 5 to 7 sites are planned, 2 sites have previous experience in clinical trials, a previous collaboration with DNDi as well as a huge expertise in HAT. DNDi expects 1.5 patient included per site per month over 18 months in order to enroll 155 patients. Based on these assumptions, DNDi would like to allocate maximum 2 FTE CRA and 1 FTE lead CRA dedicated for the country. The CRA should be identified based upon therapeutic expertise, experience and geographic location to optimize cost and operational efficiency. The initial monitoring plan is to conduct 100% source document verification (SDV) in inclusion/exclusion criteria and in all variables related to primary and secondary endpoints, including pharmacokinetic (PK) sampling timelines, abnormal laboratory results and also related to AE/SAE in all visits for the first 20 patients included in each site. Then, 100% SDV will be performed for all remaining patients enrolled per site and only in regards to: informed consent form, inclusion/exclusion criteria, primary efficacy endpoint, AE and SAE. 4.2 Responsibilities The CRA will be responsible for the clinical monitoring of the project in RDC in accordance with study specific procedures, applicable SOPs and regulations and will act as DNDi s contact with the assigned clinical sites. Other responsibilities include (but not limited to) informed consent form verification, drug accountability, data collection, medical review and regulatory documentation. The CRA shall report to the lead CRA and to DNDi study manager for any urgent issue and I interact with other study CRAs as part of the sponsor study team. Accompanying visits (comonitoring visits) by the sponsor personnel are foreseen to follow both site and monitor quality and progress. 4.3 Knowledge, Skills and Abilities Proven clinical monitoring skills, working knowledge of Good Clinical Practices and applicable Standard Operating Procedures Demonstrated understanding of medical/therapeutic area knowledge and medical terminology Good oral and written communication skills Good organizational and time management skills Effective interpersonal skills Attention to detail Proven flexibility and adaptability Page 8
Ability to work in a team or independently as required Good computer skills: good knowledge of Microsoft Office Fluency in English and Spanish language and grammar are mandatory. `Portuguese is a plus. 4.4 Other activities The following services should also be considered within the scope of this RFP: Redaction and management of the monitoring plan including, but not limited to: o Monitoring visits preparation, conduction o Monitoring visits reports requirements and timelines o Close-out visits preparation, conduction o Close-out visits reports requirements and timelines o Investigator study file and Trial master file management, specific forms and logs as per DNDi SOPs o Flow and instructions for SAE management as per DNDi SOP and local requirements o IMP accountability and reconciliation Review of the recruitment plan and additional tools to follow / track the recruitment as required Development of the study manual in local language (French) under the supervision of the DNDi project manager CRA should attend monitoring team meetings and / or study team meetings and investigators meetings The scope of this RFP does not include any Project Management activity. These activities and role will be performed by DNDi project manager. Activities related to the study monitoring as well as review and validation of the monitoring visit reports and follow-up letters will be reviewed by the lead CRA. Investigators payment and contracts will also be administered directly by DNDi. 4.5 Monitoring Workload Estimate duration for the Monitoring activities: 30-32 months. Estimate of the CRA workload for the country: Page 9
Initiation Visits Number of visits 6 Number of hours on site 5 Number of hours preparation and Fup 4 Monitoring Visits (per site) Number of visits 30 Number of hours on site (may vary 12 according to site recruitment, performance and monitoring frequency) Number of hours preparation and Fup 4 Monitoring visit interval Every 4 6 weeks Close-out Visits Number of visits 6 Number of hours on site 4 Number of hours preparation and Fup 4 Study TC (with sponsor) Number of TC (Lead CRA + Sponsor) Weekly Number of TC (CRAs + lead CRA) Monthly Study TC (CRA+ lead CRA with other vendors) Number of TC Quarterly 4.6 Additional information DNDi is interested in entering into cooperative relationships with the vendor; where a smaller, dedicated core team works on the project and staff are incentivized for flexibility and creative approaches to problem solving. Therefore, DNDi would like an agile team organization who is able to react promptly and avoid a long decision process. DNDi PM and associated staff would work together with the CRO team under common system and with open communication line. Some of the key characteristics CRO organization that we feel will be successful, and which we would like included in the proposal are: o Limited number of french speaker, dedicated local CRAs (1-2 max per center), covering more than 1 site, so as to keep the CRAs engaged and knowledgeable about the study; who will work closely and pro-actively with: o DNDi: direct contact with DNDi project Manager, especially during monitoring visit (such as extemporaneous issue/major deviations) o CRO in charge of the Data Management (specific CRA task to be further defined) o the site, by performing off-line monitoring and ensuring regular contacts, as appropriate o Lead CRA (1 layer max) that works seamlessly with: Page 10
o DNDi Project Manager, according to DNDi requirements, providing transparent access to data and information for an efficient study monitoring: in example: Patient recruitment strategy and retention, Monitoring progress (visit planning, monitoring visit report supervision, contact report supervision), overall data cleaning status, issue escalation, follow-up of study deviations and their resolution, Trial Master File status, Budget follow-up, ). o Communication: o 1 weekly TC (organized by the CRO) with participation of the lead CRA o 1 monthly TC (organized by the CRO) with participation of Lead CRA and CRAs. o 1 quarterly TC (organized and lead by DNDi) with other involved CROs (eg: data management). The likelihood of patients not returning to all follow-up visits exists, that is a major risk for the study. Therefore, site monitoring must be performed on a monthly or a minima on a bimonthly basis by local monitors. The first visit to the site is expected within 3-5 days following the end of hospitalization of the first included patient. Then, patient s visit attendance should be closely and proactively followed up with the investigator, a minima on a monthly basis. In any case, remote monitoring is to be performed on a monthly basis to ensure a close study monitoring. Either e-crf (off-line) or paper CRF will be used. In both cases, data cleaning level on SDV data should reach 90% at any time. Therefore, if paper CRF is used, DNDi would like electronic transmissions of the scanned monitored CRF pages to Data Management within max 5 days. Queries might also be sent electronically to investigators/cras, answered on paper and scanned within maximum 5 days DNDi would like a risk based monitoring approach with remote monitoring before the visit and a medical review performed during the monitoring visit. Draft monitoring visit reports are expected within maximum 5 days after the visit. DNDi would like a monthly report on activities that will be used as a basis for budget tracking. Page 11
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 (including vendor internal review timelines) o Data quality o Project management capabilities (including out of the box thinking and adaptability capacity) 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 (caped pass-through costs, reasonable and realistic staff allocation, payments on deliverables upon expected quality and timelines ) 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: Overall Company profile o Management Board, History, Locations, and contact o Key figures (Revenue, headcounts, Locations) o General services provided and specific expertise Page 12
o Similar projects / experience in related area Project approach for required services Project management plan o Proposed timelines and organizational structure o Deliverables (tools & templates reports that you intend to supply) o Proposed method and communication plan Project team involved, with details of team involved (CRA as core staff or consultant, subcontracted CRO or affiliate, location of CRA..) 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 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 Trial related Service Agreement template Annex 4: Budget template Annex 5: Schedule of Events Page 13