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 


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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.




*****************************************************************
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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.

                                              
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*****************************************************************

  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.