RFP No. NIH-NIAID-DMID-96-09 Title: "Clinical Studies of Chronic Lyme Disease" Issued by: Carl R. Henn Contracting Officer NIH/NIAID Contract Management Branch Solar Building, Room 3C07 6003 Executive Boulevard MSC 7610 Bethesda, Maryland 20982-7610 DATE ISSUED: June 15, 1995 PROPOSAL DATE DUE: October 15, 1995, 4:30 P.M. (EST) Ladies and Gentlemen: The National Institute of Allergy and Infectious Diseases (NIAID) invites interested parties to submit competitive offers for evaluation leading to award of a contract for "Clinical Studies of Chronic Lyme Disease". The Government contemplates the award of one (1), five (5) year, cost-reimbursement, level of effort type contract as a result of this RFP. Listed below are the four attachments of this Electronic RFP package. These documents represent all the necessary information required for the submission of a proposal for this acquisition. Following proposal submission and review, additional information (e.g., Representations and Certifications) will be requested by the Contracting Officer from all offerors intended to comprise the competitive range. Although these documents contain sufficient information for you or your organization to submit a proposal, if you or your organization intend to submit a proposal in response to this RFP, IT IS ESSENTIAL THAT YOU IMMEDIATELY NOTIFY CARL HENN OF THE NIAID CONTRACTING OFFICE AT THE FOLLOWING INTERNET ADDRESS: ch24v@nih.gov IF YOU DO NOT NOTIFY THE CONTRACTING OFFICE INDICATED IN THIS DOCUMENT YOU WILL NOT RECEIVE AMENDMENTS TO THE RFP WHICH COULD IMPACT YOUR PROPOSAL PREPARATION. The documents included with this electronic RFP package are as follows: 1. Introduction, Background and Work Statements, dated June 15, 1995 (Attachment A). 2. Reporting Requirements, dated June 15, 1995 (Attachment B). 3. Evaluation Factors for Award, dated June 15, 1995 (Attachment C). 4. Proposal Instructions and Information, dated June 15, 1995 (Attachment D) In addition to the information listed above, a listing of the applicable Government clauses/provisions, sample contract format, and terms and conditions which will be incorporated into the eventual contract document may be obtained either through accessing the NIH Gopher system or by sending a request to Carl Henn, Contract Specialist, using the internet electronic mail address listed above. The original and twenty (20) copies of your technical proposal and the original and five (5) copies of your business proposal must be received by the Contracting Officer no later than October 15, 1995, at 4:30 p.m. local time at the address listed in Attachment D, Item 7. You are reminded that the "Technical Proposal Cover Sheet" must be completed in full detail and used as the cover sheet for each copy of your technical proposal (A copy of this form is contained in this NIH Gopher under the directory entitled "Instructions for Proposal Submission".). New policies require submission of more detailed information than has been previously required. It is important that you list all professional personnel and organizations named in the proposal who have any role in the proposed work, including: staff of the primary organization (offeror), subcontractors, and collaborating organizations; and consultants. Organizational affiliation(s) must be indicated for every person named. You may use additional sheets, as needed, following the format shown in the Technical Proposal Cover Sheet. This information will be used to ensure that there will be no conflict of interest when selecting review committee members. Your attention is further directed to the "Proposal Intent" form contained in the Gopher sub-directory entitled "Forms Required for Proposal Submission". Please complete this form and return it to this office on or before September 10, 1995. Funds are not presently available for this requirement. The Government's obligation under a resulting contract is contingent upon availability of appropriated funds from which payment for contract purposes can be made. If you have any additional questions regarding this RFP, please contact Carl Henn through the internet using the electronic mail address listed above or phone 301/496-0993, fax 301/480-5253. Sincerely, \s\ Carl R. Henn Contract Management Branch National Institute of Allergy and Infectious Diseases Attachments: A-D ***************************************************************** ***************************************************************** RFP-NIH-NIAID-DMID-96-09 ATTACHMENT A 6/15/95 II. RESEARCH AND TECHNICAL OBJECTIVES The purpose of this Request for Proposals (RFP) is to solicit proposals to perform clinical studies in patients with Lyme disease. The emphasis of this solicitation will be on conducting studies to evaluate the effectiveness of curative therapies for chronic Lyme borreliosis. To accomplish this objective the first priority of this solicitation is the study of well-characterized patients with documented Borrelia burgdorferi infection. These studies may be multicenter in design. Background Lyme disease (LD) is the most common tick-borne disease in the United States. The etiologic agent, Borrelia burgdorferi, is a spirochete, and is transmitted to humans and other animals by tick vectors belonging to the genus Ixodes. The natural reservoir for the etiologic agent is rodents; many other types of mammals and some birds may also become infected. Lyme disease is a classic example of an emerging infectious disease. In 1975 it was first identified in association with an arthropathy afflicting a cluster of children in Old Lyme, Connecticut. Only a few hundred cases of LD were reported in the United States through 1985. Since then the number of reported cases of LD in the U.S. has increased, with some 11,144 cases reported to the CDC in 1994. As with many infectious diseases, the clinical manifestations of LD are variable and unpredictable. Early manifestations include a rash (erythema migrans), general malaise, and flu-like symptoms. Chronic manifestations include arthritis, cardiac and neurologic manifestations which have been reported to spontaneously remit and recur even following antibiotic therapy. Recently, the term Post-Lyme Disease Syndrome (PLDS), has been used to describe a condition of chronic or intermittent symptoms which is related to LD. The cause of PLDS is not known, but at least two possibilities have been suggested. The first is that it is the manifestation of a chronic active infection of B. burgdorferi that has escaped control or eradication with the use of conventional antibiotic regimens. A second possibility is that PLDS may be due to permanent damage caused by the original infectious process. An October 18, 1994 meeting at the National Institute of Allergy and Infectious Diseases (NIAID) reviewed our current understanding of chronic Lyme disease and examined a number of possible clinical approaches to studying chronic LD. It was clear from the meeting that a scientific approach to the problem will require treatment studies in human subjects. The purpose of this solicitation is to develop the research infrastructure needed to address two essential issues--the evaluation of therapeutic approaches to treat patients with chronic Lyme disease and the pathological basis/bases of this condition. It is expected that one contract will be awarded. However, this RFP does not commit the government to make an award. STATEMENT OF WORK Independently and not as an agent of the Government, the Contractor shall exert its best efforts to furnish all necessary services, qualified professional and technical personnel, patients, materials, equipment, and facilities, not otherwise provided by the Government under the terms of this contract as needed to perform the work set forth below. Specifically, the Contractor shall: 1. Conduct clinical studies in patients with documented and well-defined chronic Lyme disease. The major focus of these studies shall be on therapeutic effects of antimicrobial agents in chronic Lyme disease. Assessments of the sensitivity and specificity of laboratory tests shall also be undertaken as part of the therapeutic evaluation. Assessments of the pharmacologic properties of drugs used singly or in combination with other therapeutic medications shall, when necessary and appropriate, also be included. Pilot studies of treatments (antimicrobial and/or other therapies) for other manifestations or infections associated with Lyme disease which may enhance our understanding of chronic Lyme disease may also be proposed. All studies are subject to Project Officer approval. [NOTE 1 TO OFFEROR: The Offeror shall submit with this proposal one detailed protocol for a controlled phase III study. The Offeror may also submit with this proposal protocols (if appropriate) for up to two pilot studies as well. It is anticipated that a phase III study would require 150-300 patients, a phase II study would require 30- 60 patients.] [NOTE 2 TO OFFEROR: Proposed antimicrobial treatment regimens for chronic Lyme disease and pilot studies of chronic Lyme disease should be thoroughly described and justified. Sample protocols and consent forms should be submitted with the proposal and should demonstrate that the Offeror thoroughly understands the issues associated with therapeutic management of patients with chronic Lyme disease. See Attachment A.1 for standardized Protocol Schema.] A. Prepare protocols, consent forms, and other IND information for submission to the Project Officer and the local Institutional Review Board (IRB) for approval and, when appropriate, for NIAID to submit to the FDA as part of an Investigational New Drug (IND) package. Amend as necessary after comments by the Project Officer, the DMID Clinical and Regulatory Affairs Branch, local IRB, and regulatory authorities. B. Organize and administer the research activities of the contract as follows: 1) Design and implement the proposed clinical studies. This shall include developing the specifics of experimental design, receiving and shipping of reagents and samples, coding of patients, reagents, and samples, and coordinating all of the subcontractors' activities (if applicable). This shall also include conducting all clinical studies in compliance with DMID/ NIAID policy and in coordination with the Clinical and Regulatory Affairs Branch, DMID/NIAID. Prepare a list of responsibilities delineating the role of Industry, the collaborative group, and the NIAID in the implementation of each trial. The list of responsibilities shall be submitted for review and approval by the Project Officer prior to each trial initiation. [NOTE 3 TO OFFEROR: Regardless of who holds the IND, a list of responsibilities is to be included with any protocol(s) submitted. A sample list is given in Attachment A.2.] [NOTE 4 TO OFFEROR: Offeror must clarify arrangements with potential drug sponsors in the proposals (Attachment A.3). Offeror should list proposed sources for any necessary drugs or biologics and document the proposed sponsor's enthusiasm for the study and willingness to participate.] 2) Supervise, coordinate, and perform the studies. [NOTE 5 TO OFFEROR: Offeror should describe the clinical and research backgrounds of the Principal Investigator (P.I.), co-investigators, statistical staff, nurses, etc. with respect to; professional experience with Lyme disease and other infectious diseases, clinical trial design and management, and data management. Two-page biosketches, with a summary of relevant training, experience and recent publications, of all proposed professional personnel should be included in the proposal.] [NOTE 6 TO OFFEROR: If a multicenter trial is proposed, the Offeror shall include a detailed description of the proposed mechanisms for ensuring uniformity in: patient enrollment, diagnosis, data management; adherence to protocols; and other quality control issues directly affecting the conduct and outcome of the therapy trials.] 3) Manage the information generated, including collection, transmission, storage, confidentiality, retrieval, validation, analysis, and publication. C. Ensure compliance with monitoring and interim analyses required by the NIAID. Develop a detailed plan and prepare ongoing reports for the monitoring of major safety and efficacy endpoints for an independent Data and Safety Monitoring Board (Attachment A.4) and NIAID. All plans shall be submitted to and approved by the Project Officer prior to study implementation. 2. Analyze clinical specimens in a central laboratory. These analyses shall include, but are not necessarily limited, to: determinations of immunologic responses to borrelial antigens; determinations of the presence of Borrelia burgdorferi or borrelial antigens in clinical materials; determinations of borrelial nucleic acids through techniques such as the polymerase chain reaction (PCR); immunogenetic background of patients; other laboratory tests relevant to borrelial infection; co-infecting agents, particularly babesia and ehrlichia. [NOTE 7 TO OFFEROR: A detailed description of the assays to be used to assess infection and patient immune responses, and data or references demonstrating the efficacy of these assays in the Offeror's hands shall be provided.] 3. Provide sufficient numbers of patients from appropriate populations as required for the described clinical studies. The target population for most studies is well-defined chronic Lyme disease patients. [NOTE 8 TO OFFEROR: The availability of appropriate populations is critical. A Patient recruitment, retention and entry criteria for therapeutic studies shall be described in detail.] [NOTE 9 TO OFFEROR: INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 9, 1994 (FR 59 11146-11151), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Offerors may obtain copies from these sources or from the contact person listed in the RFP.] 4. Disseminate the scientific and clinical results of the proposed studies and coordinate the preparation of all manuscripts and presentations involving data from multicenter sites. A publication policy shall be established to address coordination of the writing and revising of manuscripts (and abstracts) as well as how the order of authorship is to be determined. All publications shall acknowledge NIAID support. The Project Officer shall have access to all data generated with the support of this contract and shall review, recommend changes, and provide clearance for publication/disclosure of these data in manuscripts, abstracts and presentations. No presentation of primary results from any study may be made without the approval of the Contractor. 5. Attend and participate in one meeting per year in Bethesda to discuss clinical trial coordination, and regulatory issues related to clinical trials. [NOTE 10 TO OFFEROR: Travel, lodging and meal costs for the individual serving as the research nurse coordinator or clinical trial coordinator and one other staff member to attend this meeting should be included in the business proposal.] 6. Organize and attend one meeting per year in Bethesda, Md. for purposes of protocol and study development and/or evaluation. [NOTE 11 TO OFFEROR: The Offeror shall budget for the cost of this meeting in the proposal. Travel, lodging, meal and honoraria costs for five external scientific protocol/study developers/evaluators to attend this meeting should be included in the business proposal.] 7. Organize and attend one DSMB meeting per year. [NOTE 12 TO OFFEROR: The Offeror shall budget for the cost of this meeting in the proposal. For purposes of budget planning assume four (4) members; one each from Western, Midwest, Northeast and Southern regions of the United States.] 8. Report to the DMID Clinical and Regulatory Affairs Branch, the Project Officer and the Data Safety and Monitoring Board (DSMB) all adverse reactions to comply with FDA regulations. [GENERAL NOTES TO OFFEROR: 1. Award of a contract does not commit the Government to approve any of the studies presented in the proposal. The Project Officer will determine which studies are actually undertaken. The Project Officer will also determine the necessity of arranging and attending meetings related to contract activities.] 2. Subcontracting agreements are encouraged to accomplish the work outlined in this solicitation. The proposal should describe in detail the study plan and its relationship to the overall proposal, complete descriptions of facilities, professional backgrounds and numbers of personnel, and costs. 3. Disclosure of any and all patents or patent applications of materials, reagents, or procedures filed in or outside of the U.S. by the Offerors and/or listed personnel or collaborators must be made at the time of proposal submission.] ATTACHMENT A.1 Schema for Chronic Lyme Disease Protocols Study Number: Title: Drug: (Dosage and Duration) P.I.(s): IND Holder: (Specify if NIAID or Pharmaceutical Company) Study Objectives: Statement of Hypothesis to be Tested: Study Design: (Randomized? Masked?) Randomization: Enrollment: (Estimated: date of initiation date of completion patients per month number of sites) Data Analyses: (Give dates and patient increments for interim analyses; parties responsible for data management; for data analysis) Study Population: (age, sex, serology, etc.) Endpoints: (primary study outcome definition; method of assessment; concise definition of success and failure) Attachment A.2 Sample List of Responsibilities The Contractor shall prepare for approval by the Project Officer a list of responsibilities to indicate who will: generate consent forms approve consent forms distribute consent forms to sites* conduct site assessment/orientation/start-up visits* collect pre-study regulatory documents sponsor IND submit protocol and regulatory documents to FDA ship study medication to repository or sites* generate randomization codes hold randomization codes perform CRF/drug supply/regulatory site monitoring* perform QA monitoring report serious adverse events to FDA -3 & 10 day reports -annual safety reports monthly update of enrollment, ADE's, and waivers harvest completed CRFs conduct secondary review of CRFs log in CRFs, generate queries to investigators perform data entry and logic checks resolve all queries and ensure audit trail submit annual IND report to FDA submit any protocol revisions, updated 1572s to FDA obtain copies of annual IRB renewals from the sites design CRF print CRF distribute CRFs to sites* maintain lab samples (serum/isolate) in a repository serve as central lab facility for drug levels/susceptibilities analyze data present data to DSMB *Note: Intended for multicenter studies. ATTACHMENT A.3 NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES CLINICAL TRIALS AGREEMENT FOR STUDIES DONE WITH THE DAIDS/DMID/DAIT Based on Protocol ________ (TITLE) In Collaboration With (Pharmaceutical Company) DRAFT (Date) The Division of _______, NIAID, and (Pharmaceutical Company), located at (address), have agreed to cooperate on the conduct of a clinical trial whose designation is Protocol ____ for (Drug), entitled " ." The (Division), NIAID believes that this multi-center clinical trial can be most efficiently conducted by taking advantage of the established clinical trial site network, (relevant clinical trial network) which is uniquely positioned to coordinate the efforts of a staff of program and data managers, scientists, physicians, statisticians and regulatory experts (please see Attachment 1 describing the ____). Thus, the agreement whose terms and conditions under which the protocol will be conducted and which are outlined below reflects this belief. The understanding by both parties to the agreement is as follows: 1. INVESTIGATIONAL NEW DRUG APPLICATION (IND) SPONSORSHIP The NIAID shall be responsible for the submission of an IND covering Protocol _________. The IND shall satisfy all of the requirements of the United States Food and Drug Administration (U.S. FDA). A letter granting cross reference to (Pharmaceutical Company)'s FDA files which pertain to (Drug) shall be supplied by (Pharmaceutical Company), and, in return, the NIAID will also supply a letter, if requested, granting cross reference to the NIAID'S IND to (Pharmaceutical Company). OR The Company shall be responsible for the submission of an IND covering Protocol _________. The IND shall satisfy all of the requirements of the United States Food and Drug Administration (U.S. FDA). A letter granting cross reference to NIAID's FDA files which pertain to (Drug) shall be supplied by NIAID and, in return, the Company will also supply a letter, if requested, granting cross reference to the Company's IND to NIAID. A. Monitoring The IND Holder shall be responsible for clinical site monitoring and the quality assurance of all data. Monitoring shall be done in compliance with U.S. FDA Good Clinical Practices Guidelines. B. Adverse Experience Reporting Adverse experience reports shall be collected by the IND Holder according to the procedures outlined in the protocol. The IND holder shall assume total responsibility for the reporting of such adverse events to the FDA with a copy to (Pharmaceutical Company). The IND holder shall report all serious and life threatening adverse events observed in this clinical trial to other Parties to this Agreement on a timely basis consistent with Federal Regulations 21 CFR 312.32. All other adverse experiences shall be reported by IND holder to other Parties to this Agreement on a timely basis consistent with Federal Regulations 21 CFR 312.33 for the Annual Report. Specific provisions for reporting adverse experiences to agencies outside the U.S. shall be provided for as required. (Pharmaceutical Company) shall, in a timely manner and during the term of this trial, provide the (Division),NIAID with any information it now has or may obtain in the future regarding the safety and/or the toxicity of (Drug). 2. PROTOCOL TEAM Development and management of the protocol, evaluation of data, proposal of amendments, recommendations for early termination, etc. shall be the responsibility of the Protocol Team. The membership shall include the study chair (a _______investigator), a protocol specialist, and representatives from (Pharmaceutical Company), other ______sites, the NIAID, and the persons involved with statistical and data analysis from the study, respectively. The number of company representatives will be agreed upon between the company and the NIAID and will take into account any special requirements of the protocol design. While the (Division), NIAID will endeavor to control the distribution of the protocol document itself, (Pharmaceutical Company) acknowledges that a list of all protocols which are open to patient enrollment are available (with abstracts) to the public under the Freedom of Information Act. 3. STUDY SITES The (Division), NIAID will utilize trial sites under Government Contract or Cooperative Agreement (Clinical Trial Sites) for the studies described in the protocol. The NIAID will ensure that the protocol will be conducted at Clinical Trial Sites according to the U.S. FDA Good Clinical Practices Guidelines. (Pharmaceutical Company) agrees to limit the conducting of the protocol to ______sites so long as mutually agreed accrual targets are met. However, this commitment does not prohibit (Pharmaceutical Company) from conducting, at its own expense, additional clinical trials with (Drug) at non- NIAID sites. 4. CASE REPORT FORM (CRF) DEVELOPMENT The (Division), NIAID shall assume responsibility for the development and subsequent revisions, if any, of CRFs with appropriate review and approval by the Protocol Team. 5. DATA COLLECTION, MANAGEMENT, ANALYSIS AND REPORTING The (Division), NIAID shall assume responsibility for the collection, management, analysis, and initial reporting of all data obtained from the trial. (Pharmaceutical Company) may utilize data and reports from this study for any legitimate business or regulatory purpose. Information which may be released to the public or which may have significant impact on (Pharmaceutical Company)'s approval of (Drug) for commercial sale shall not be released without prior discussion of the information with (Pharmaceutical Company) except to the extent required Federal Law. (Pharmaceutical Company), after appropriate consultation with the (Division), NIAID, may provide information regarding the trial to governmental organizations (e.g., FDA, SEC, etc.). 6. DRUG SUPPLY AND DISTRIBUTION The (Division),NIAID shall provide (Pharmaceutical Company) with an estimate of the quantity of (Drug) that will be required to complete the protocol. (Pharmaceutical Company) shall provide this quantity of drug and placebo if appropriate to the (Division), NIAID without charge. The NIAID shall be responsible for distributing (Drug), as well as any other drug used in the trial to the trial sites. Drug shall be shipped to repository or study sites as mutually agreed upon. (Pharmaceutical Company) shall provide the (Division), NIAID with the necessary Material Safety Data Sheet (MSDS) for (Drug) together with any specific storage or shipping instructions. 7. CONFIDENTIAL/PROPRIETARY INFORMATION The (Division), NIAID shall treat as confidential/proprietary any preclinical, clinical, or formulation data that (Pharmaceutical Company) marks "Confidential" including but not limited to the Investigator's Brochure and the protocol. Such information is the sole and exclusive property of (Pharmaceutical Company) during the period of this Agreement and subsequent thereto. Likewise, all information which is disclosed visually or orally and subsequently confirmed as Confidential Information in writing within ten (10) working days after first disclosure will be held as Confidential Information. Confidential/Proprietary Information means confidential scientific, business, or financial information provided that such information: is not publicly known or available from other sources who are not under a confidentiality obligation to the source of the information; has not been made available by its owners to others without a confidentiality obligation; is not already known by or available to the receiving Party without a confidentiality obligation; or does not relate to potential hazards or cautionary warnings associated with the production, handling, or use of the subject matter of this Agreement 8. TRIAL DATA All raw data obtained from the trial shall be the property of the Clinical Trial Site that produces the data. These data shall not be released to the public except to the extent required by law. No persons or party other than (Pharmaceutical Company), its contractor, and/or its designate shall have any rights to review and/or use the raw data obtained from the trial for purposes of filing an NDA without the permission of (Pharmaceutical Company). Where applicable, the grouped data shall be controlled by the NIAID and shall not be released to the public without appropriate consultation with (Pharmaceutical Company). However, (Pharmaceutical Company) retains the right to access and utilize the data for all legitimate business or regulatory purposes. Upon completion of the study, the pharmaceutical company will be provided with a copy of the complete analysis data set and other raw data as required in a machine-readable format to be determined jointly. 9. FDA MEETINGS With respect to any discussions with FDA involving data obtained from this trial, IND holder shall take the initiative in arranging meetings with the FDA. Formal meetings with the FDA concerning the trial data shall be discussed and agreed upon by (Pharmaceutical Company) and the (Division), NIAID in advance. 10. PUBLICATIONS POLICY Any publications based on the results of the trial shall conform to the applicable NIAID publication policy for _________ responsible for the study. (Pharmaceutical Company) shall receive copies of any abstract or manuscript prior to their submission for publication with sufficient time for review. Recognizing that (Pharmaceutical Company) scientists may play an important role in the design, analysis, and interpretation of the findings of the trial, consideration shall be given by the Principal Scientists at the Clinical Trial Sites under Government Contract or Cooperative Agreement and the NIAID to include appropriate individuals from (Pharmaceutical Company) in the authorship of publications based on the trial. 11. INDEMNIFICATION AND DISPUTES No indemnification for damages is provided for under this agreement. Each party shall be liable for damages it incurs as a result of its own activities under this agreement. Any dispute arising under this Agreement which is not disposed of by agreement of the parties shall be submitted jointly to the signatories of this Agreement. If the signatories are unable to jointly resolve the dispute within thirty (30) days after notification thereof, the Assistant Secretary of Health (or his/her designee) shall propose a resolution. Nothing in this section shall prevent any Party from pursuing any and all administrative and/or judicial remedies which may be available. 12. ENDORSEMENT (Pharmaceutical Company) acknowledges that the involvement of the (Division), NIAID in the trial shall not be construed as an endorsement by the (Division), NIAID or the National Institutes of Health (NIH) for (Drug). However, this does not prohibit (Pharmaceutical Company) to reference or use publications and reports based on the trial for legitimate business and regulatory purposes. 13. PROVISION OF FINANCIAL SUPPORT TO NIAID CLINICAL TRIAL SITES (Pharmaceutical Company) shall not provide separate funding to any sites participating in the trial for any aspect of the study without the prior written approval of the (Division), NIAID. 14. UNILATERAL TERMINATION Either (Division), NIAID or the Collaborator may unilaterally terminate this entire Agreement at any time by giving written notice at least thirty (30) days prior to the desired termination date. The Parties agree that should this Agreement be terminated, the Protocol will nonetheless be completed if medically appropriate. If you agree with the terms of this Clinical Trials Agreement for Protocol ______________entitled "_______________________________________," please have your authorized representative sign below. An additional signed original is enclosed for your records. (Signature) (Date) Division Director National Institute of Allergy and Infectious Diseases National Institutes of Health (Signature) (Date) (Type in Name) (Title) (Pharmaceutical Company) Attachment A.4 DMID GUIDELINES, DATA AND SAFETY MONITORING BOARDS (April 21, 1993) The independent Data and Safety Monitoring Board (DSMB) plays a crucial role in ensuring the safety and welfare of patients enrolled in randomized, comparative clinical trials. The following outline summarizes DMID guidelines concerning the establishment, responsibilities and operating procedures of a DSMB. Although these guidelines represent DMID standard operating policy for DSMBs, it is recognized that special circumstances may require occasional deviation from these policies. These deviations should be brought to the attention of the DMID Clinical Studies Group. Which Clinical Trials? An independent DSMB should be established for any clinical study in which there is a perceived potential for toxicity or early determination of efficacy. All Phase III studies and masked Phase I/II therapeutic studies should normally be supported by a DSMB. Procedures for the safety monitoring of all Phase I trials, Phase I/II vaccine trials and any clinical studies for which the degree of risk to the subject is considered minimal are established at the direction and discretion of the program officer and may or may not include a DSMB. Membership: The membership of the DSMB reflects the disciplines and medical specialties necessary to interpret the data from the clinical trials. The selection of DSMB members is the responsibility of the Project Officer who will normally solicit recommendations for proposed members from many sources, including study investigators. The program officer will also select one member to serve as the chair of the DSMB. The proposed membership will be submitted to the FDA as part of the IND application. The DSMB typically consists of 3-6 members and should include: a) Experts in the clinical aspects of the disease/population being studied. b) One or more biostatisticians. c) Investigators with experience in the conduct of randomized controlled clinical studies (this category will likely overlap with a). d) Other scientists as required (e.g., persons with special expertise in relevant areas). In some trials, especially any involving special circumstances or populations, for example prisoners, it may be desirable to include a medical ethicist. DMID staff may be members of the DSMB, but no Committee member should have direct involvement with the conduct of the trial other than in advisory or review activities. In addition, all DSMB members shall confirm that they have no financial interest in the outcome of the study. This may be accomplished by including a phrase such as "Acceptance of this invitation to serve on the [study name] DSMB confirms that I do not have any financial interest or other conflict of interest with any of the collaborating pharmaceutical firms" in the letter of invitation to DSMB members and orally by program staff or the DSMB chair at the DSMB meetings. Representatives of the manufacturer(s) of the test substance(s) are not eligible to serve on the DSMB. Responsibilities. At periodic intervals during the course of each trial, the DSMB examines the accumulated data on safety and, if appropriate, efficacy, in order to make recommendations to DMID concerning continuation, termination, or other modifications of the trial based on the observed beneficial or adverse effects of the treatments or vaccines under study. Interim analyses of efficacy are to be conducted in accordance with stopping rules which are clearly defined in advance of data analysis and have the approval of the DMID, the FDA, and the DSMB. Preferably, these, and operating procedures for the DSMB, are agreed upon at a DSMB meeting held prior to initiation of enrollment and are included in the protocol. Finally, the DSMB may review the general progress of the study and assist DMID by commenting on any apparent problems with study conduct, enrollment, sample size and/or data collection. Meetings: At intervals during the course of each trial, the DSMB examines the accumulated data on safety and, if appropriate, efficacy, in order to make recommendations to DMID concerning continuation, termination, or other modifications of the trial based on the observed beneficial or adverse effects of the treatments, vaccines, or other interventions under study. In addition, the DSMB may review the general progress of the study and assist DMID in resolving any problems that may arise. Ideally, the DSMB should first meet before the start of the trial to discuss the protocol and to establish guidelines for monitoring the study. At this initial meeting DMID staff will generally take the opportunity to discuss DMID's goals for the study. Other interested parties may be invited to attend DSMB sessions as considered appropriate by the DSMB and DMID. The Committee's decisions should be made by consensus whenever possible and otherwise by majority vote. Meetings may be convened as conference calls as well as in person, although it is recommended that the initial meeting as well as meetings for interim analyses be conducted in person. On rare occasions, a committee member who can not attend a meeting may receive a copy of the confidential report to the DSMB and may provide written comments to the DSMB chair for consideration at the meeting. Similarly, on rare occasions a DSMB member may be allowed to participate in a face-to-face meeting by conference call. The agenda for each meeting is generally developed by DMID staff in conjunction with the DSMB Chair. One recommended model for conducting the business of the DSMB is as follows: x Open Sessions: These may be attended by any study investigator or industry representative, but should always include the lead investigator and the study biostatistician. Appropriate DMID program and regulatory staff should also attend. At an Open session, issues relating to the general conduct and progress of the study are discussed. Such issues include accrual, degree of comparability of groups with respect to baseline factors, quality control, compliance with protocol, currency of follow-up, etc. These data should be presented in such a way that identification of the specific treatment group is not possible. x Closed Sessions: These are normally attended only by voting committee members and DMID staff members invited by the study program officer. However, the committee may request the participation of other individuals for part or the entirety of the session. At this session safety data and, if appropriate, efficacy endpoint data (including interim analyses) are reviewed. Data may be presented by coded treatment arm, with the codes accessible by the DSMB, if desired. This may be accomplished by providing a sealed envelope to the DSMB chairman which contains the code. The decision to reveal the code is the responsibility of the DSMB chairman. Meeting Reports A. Interim reports are generally prepared by the study statistician(s) and distributed to the DSMB, preferably at least 3 days prior to a scheduled meeting. These interim reports are numbered and provided in sealed envelopes within an express mailing package. The contents of the report are determined by the DMID and the DSMB. Additions and other modifications to these reports may be directed by the DSMB on a one-time or continuing basis. Interim data reports generally consist of two parts. Part 1 (Open Session Report) provides information on study aspects such as accrual, baseline characteristics, and other general information on study status. Part 2 (Closed Session Report) may contain data on study outcomes, including safety data and depending on the study, perhaps efficacy data. The Closed Session Report is considered confidential. Copies distributed prior to and during a meeting are collected by the study statistician(s) following the meeting. Data files to be used for interim analyses should have undergone established editing procedures to the extent possible. Interim analyses of efficacy data are performed only if they are specified and approved in advance and criteria for possible stopping are clearly defined. B. Reports from the DSMB. At the conclusion of, or shortly after, each meeting the DSMB chair will prepare a report summarizing the recommendations of the DSMB for DMID staff. This report will not contain confidential information presented at the meeting (e.g., data separated by treatment group). This report will normally be provided to the Division Director, the chair of the Clinical Studies Group, the FDA (as an amendment to the IND), the principle investigator and to co-sponsoring pharmaceutical firms. In addition, a report of unblinded data concerning the safety of an agent may be provided to the sponsor of that agent. (If two or more agents are being evaluated, each co-sponsor may receive safety data on its compound only). Unblinded efficacy data are not normally provided to either DMID or any co-sponsoring pharmaceutical firms. (see below). Preferably, all plans for data sharing should be specified in the protocol. C. Mailings to the DSMB. On a regular basis blinded safety data should be communicated to all DSMB members or to the one member who serves as the designated safety officer. Any concerns noted should be brought to the attention of DMID staff who will take appropriate action. D. DSMB meetings for which no interim analyses or discussion of controversial issues are planned may commonly be held by conference call. Access to Interim Data Access to the accumulating endpoint data should be limited to as small a group as possible. This principle stems from the difficulty in completing a trial once apparent differences begin to emerge and are publicized. Even when small statistically non- significant differences are properly understood to be non- definitive, awareness of such differences may make investigators reluctant to enter patients on the trial, or to limit entry to a certain subset of patients, or to encourage patients to withdraw if they suspect they are assigned to what they may perceive as the inferior treatment. Such tendencies may diminish the reliability of the data or even preclude the completion of the trial. Limiting the access to interim data to the DSMB relieves the investigators of the burden of deciding whether it is ethical to continue to randomize patients and helps protect the study from bias in patient entry and/or evaluation. However, as described above, it is generally acceptable to release unblinded interim safety data, on its product only, to a concerned drug sponsor. International clinical trials. Procedures for the monitoring of international clinical trials may be modified to accommodate the policies and regulations of the concerned host country. ***************************************************************** ***************************************************************** RFP-NIH-NIAID-DMID-96-09 ATTACHMENT B 6/15/95 REPORTING REQUIREMENTS As part of the work to be performed under this contract, the Contractor shall prepare and deliver the following reports to the Project Officer, with one additional copy to the Contracting Officer: 1. Progress Reports The Contractor shall submit to the Contracting Officer (1 copy) and the Project Officer (1 copy) progress reports covering the work accomplished during each reporting period. These reports shall be prepared according to the following format: Semi-annual Progress Reports - The Contractors shall submit 2 copies at the end of each semi-annual performance period. Each report shall include the following: (a) Face page to include contract number, title, period of performance being reported, Contractor's name and address, telephone and fax numbers, Internet address(es), and date of submission. (b) An executive summary, to include: 1. A statement of intended work for the reporting period; 2. A brief overview of the work that was completed for the reporting period and/or justification for intended work that was not completed or unintended work undertaken; 3. A brief overview of the activities that occurred during the current reporting period and any problems (technical or financial) that have occurred during the current reporting period; 4. The advances made in relation to any of the specific aims set forth in the proposal; 5. A brief discussion of the relevance and impact any advances may have on clinical practice; 6. A brief overview of related research from other laboratories including important presentations of data, abstracts and publications; and the impact these data have/will have on the direction and progress of the contract; (c) A full description of: 1. The work performed during the reporting period; 2. The status of patient accruals; 3. The relation of the accomplishments to the goals and objectives of the proposal; 4. A full discussion of the results and their relevance; explanations of any differences between planned and actual progress, and, if necessary, what corrective steps are planned. (d) A full description of data pertaining to: 1. The work performed during the reporting period; 2. The materials and methods pertaining to the proposed work; 3. The relationship of the accomplishments to the goals and objectives of the proposal; (e) Problems encountered and their resolution. (f) Conclusions resulting from analysis and scientific evaluation of data accumulated to date under the project. (g) A summary of activities planned for the next reporting period. (h) Results of Quality Control, Quality Analysis and environmental testing when it pertains. (i) Copies of manuscripts (published or unpublished) derived from research under the contract and copies of all abstracts, manuscripts, preprints and publications that resulted from work conducted or any protocol or method developed specifically under this contract during the performance period. (j) A full disclosure of intent to file patent applications in the U.S. or outside of the U.S. on materials, reagents or procedures derived or established by the work supported under this contract; full disclosure of patent applications filed in the U.S. or outside of the U.S. as well as copies of patent applications. 2. Final Report The Contractor shall submit two (2) copies of the Final report which documents and summarizes the results of the entire contract work for the entire contract period of performance. The following format shall be followed: (a) Face page to include contract number, title, period of performance being reported, Contractor's name and address, telephone and fax numbers, Internet address, and date of submission. (b) An executive summary, to include the advances made in relation to each of the specific aims set forth in the proposal; (c) A detailed description of the work performed, the results obtained, and a discussion of the relevance of the results and their relation to work being conducted in the area by other groups. This report shall be in sufficient detail to explain comprehensively the results achieved, particularly, figures and tables shall be clearly labeled to describe the data presented. The final report shall be submitted by the completion date of the contract. A semi-annual report shall not be required for the period when the final report is due. 3. Reports submitted to the Government shall not include any identifier of subjects, i.e., volunteers, patients, involved in these studies. 4. Scientific Publications The Contractor shall submit one (1) copy of all scientific publications which result from this contract. (See Item 4 on manuscript writing.) 5. Technical Report Distribution Copies of the technical reports shall be submitted as follows: Type of # of Report Copies Addressee Due Dates ______ ______ _________ _________ Semi- 1 Project Officer Semi-Annually Annual DMID, NIAID, NIH (Dates to be Progress Solar Building, Room ____ specified 6003 Executive Blvd. MSC 7630 in contract) Bethesda, MD 20892-7630 Semi- 1 Contracting Officer Same as above Annual CMB, NIAID, NIH Progress Solar Building, Room 3C07 6003 Executive Blvd. MSC 7610 Bethesda, MD 20892-7610 Annual 1 Same as P.O. above Annually (Dates to be specified in contract) Annual 1 Same as C.O. above Same as above Final 4 Same as P.O. above Expiration date Final 1 Same as C.O. above Same as above ***************************************************************** ***************************************************************** RFP-NIH-NIAID-DMID-96-09 ATTACHMENT C 6/15/95 PROPOSAL EVALUATION CRITERIA 1. COMPARATIVE IMPORTANCE OF PROPOSALS You are advised that paramount consideration shall be given to the evaluation of the technical proposals, but not to the exclusion of cost considerations. In the event that the technical evaluation reveals that two or more Offerors are approximately equal in technical ability, then the estimated cost of performance will become paramount. In any event, the Government reserves the right to make an award to the best advantage of the Government, cost and other factors considered. 2. GENERAL The technical proposal will receive paramount consideration in the selection of the Contractor for this acquisition. The evaluation will be based on the demonstrated capabilities of the prospective contractors in relation to the needs of the project as set forth in the RFP. The merit of each proposal will be evaluated carefully, based on responsiveness to the RFP and thoroughness and feasibility of the technical approach taken. Offerors must submit information sufficient to evaluate their proposals based on the detailed criteria listed below. Failure to provide the information required to evaluate the proposal may result in rejection of that proposal without further consideration. 3. TECHNICAL EVALUATION CRITERIA Proposals submitted in response to this RFP will be evaluated based on the following factors which are listed and weighted in order of their relative importance. Proposals will be judged solely on the written material provided by the Offerors. CRITERION WEIGHT % A. Scientific and Technical Approach 50% 1) Quality, originality and feasibility of the proposed methods and approaches to meet the objectives of the solicitation; including plans for recruiting, retaining and following appropriate patient populations. (30%) 2) Clinical importance of the proposed treatment(s) to current problems in treating chronic Lyme disease. (20%) B. Personnel 25% 1) Documented background and expertise of the Principal Investigator and other critical study personnel in conducting clinical studies relevant to chronic Lyme disease. (15%) 2) Documented background and expertise of the Principal Investigator and other project personnel in conducting statistical and laboratory studies relevant to chronic Lyme disease. (10%) C. Facilities/Resources 25% Documented availability of sufficient space, equipment, clinical facilities and access to sufficient numbers of appropriate patients to support the proposed trial, diagnostic testing, and data collection and management. (25%) Total Possible Score: 100% E. EVALUATION OF MINORITY GROUP AND GENDER REPRESENTATION (NIH 3185) (JUL 1994) This research project involves human subjects. NIH Policy requires that woman and members of minority groups and their subpopulations must be included in the study population of research involving human subjects, unless a clear and compelling rationale and justification is provided with respect to the health of the subjects or the purpose of the research. Where inclusion of women and minority populations is not feasible, a detailed rationale and justification for exclusion of one or both groups from the study population must be submitted with the technical proposal. The NIH will review the exclusion rationale to determine if it is appropriate with respect to the health of the subjects and/or the purpose of the research. If the rationale is not considered acceptable by the Government and you are included in the competitive range, you will be afforded the opportunity to further discuss and/or clarify your position during discussions or include women and minorities in your best and final (BAFO). If your exclusion position is still considered unacceptable by the Government after discussions, your proposal may not be considered further for award. ***************************************************************** ***************************************************************** RFP-NIH-NIAID-DMID-96-09 ATTACHMENT D 6/15/95 PROPOSAL INSTRUCTIONS AND INFORMATION _____________________________________ NOTICE TO OFFERORS: This attachment contains proposal instructions and information which is specifically related to this acquisition. The information provided below is only a portion of the instructions and notices required for the submission of a proposal. Additional, more general, information and forms regarding proposal preparation are contained in the NIH Gopher directory entitled "Instructions for Proposal Submission". 1. 52.216-1 TYPE OF CONTRACT (APR 1984) The Government contemplates award of a cost-reimbursement contract resulting from this solicitation. 2. SIC CODE AND SMALL BUSINESS SIZE STANDARD (NIH 3150) (JUN 1988) (a) The standard industrial classification (SIC) code for this acquisition is 8733. (b) (1) The small business size standard is $5.0 million dollars. (2) The small business size standard for a concern which submits an offer in its own name, other than on a construction or service contract, but which proposes to furnish a product which it did not itself manufacture, is 500 employees. (c) This requirement is NOT Set-Aside for Small Business. However, the Federal Acquisition Regulation (FAR) requires in every solicitation (except for foreign acquisitions) the inclusion of the Standard Industrial Classification (SIC) Code and corresponding size standard which best describes the nature of the requirement in the solicitation. 3. NUMBER AND TYPE OF AWARD(S) (NIH 2980) (APR 1984) It is anticipated that 1 award will be made from this solicitation and that award will be made on or about June 30, 1996.