Subject: NIH GUIDE - RFA AI-91-10 - V20(25) 06/28/91 - P2/2
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Fri, 28 Jun 91 09:54 EST

Hi Paul,
This is part 3 of 6 of this week's NIH Guide. Please post as:
RFAAI-91-10(P2).910628.
              Thanks, Mary Broaddus
 
$$XID RFA AI9110 AI-91-10 P2O2 *****************************************
investigators.  Most phase III protocols are open to participation by
any ACTU.  phase I/phase II protocols are usually conducted at a limited
number of ACTUs.  Protocols are developed by the investigators, with
substantial involvement of the pertinent TRP Medical Officer, following
jointly determined priorities.
 
The components of the ACTG are described below.
 
1.  The ACTUs
 
An individual ACTU is located at a clinical research institution and
consists of multidisciplinary scientific investigators, medical
clinicians, data managers, and administrative staff necessary to conduct
clinical trials on investigational therapies for HIV infection.  Access
to ancillary non-ACTU services (e.g.,Institutional AIDS Ward, CRC,
designated State AIDS Center) provide useful additional resource
support.  An ACTU may have one or more subunits (sites not located at
the main ACTU that are established by formal administrative and
financial arrangements between institutions).  Each main ACTU is
responsible for the proper functioning of its subunit(s).
 
The Principal Investigator is a physician who has the responsibility for
the guidance and leadership of the ACTU.  The Principal Investigator has
the responsibility for selecting the clinical trials in which the ACTU
participates.
 
The ACTUs conduct all phases of clinical trials research on new and
improved treatment intervention for all aspects of HIV infection,
including associated opportunistic infections, oncological, and
neurological conditions.  However, individual ACTUs vary with respect to
emphasis in scientific area and type of clinical trials conducted at the
site.
 
2.  TRP
 
The Associate Director, TRP, supports clinical trials research by
providing scientific and technical advice; serving as a source of
expertise; facilitating protocol development and implementation;
reviewing protocols to ensure consistency, scientific soundness, and
conformance with FDA requirements for Investigational New Drug (IND)
trials.  The Associate Director, TRP, coordinates the activities
required to develop new agents from initial human trials to their final
FDA approval.  In addition, the Associate Director, TRP, facilitates the
transfer of effective therapies from the research setting to routine
patient care.
 
3.  SDAC and the Operations Office.  See Appendix II Section E. on
SUPPLEMENTARY RESOURCES FUNDED UNDER OTHER MECHANISMS.
 
4.  ACTG Interaction
 
National meetings of the entire ACTG are held three times a year.  The
primary purpose of these meetings is to bring the ACTG together to
review the work of the scientific and resource committees.  This
includes a review of the scientific agendas set forth by the scientific
and resource committees of the group, scientific plenary sessions
covering topics at the leading edge of HIV therapeutics, updates on
protocols, and workshops dealing with the conduct of ACTG studies or
operations.  Invited guests from the FDA, the NIH, and pharmaceutical
industry also participate in these meetings.  The ACTG has a committee
structure consisting of scientific committees, resource committees, and
the Executive Committee.
 
The structure and functioning of the committees and the development of
protocols are described below.
 
a. Committees
 
Scientific Committees
 
There are nine ACTG Scientific Committees:  Primary Infection,
Opportunistic Infection, Oncology, Pharmacology/Pharmacokinetics,
Neurology, Pediatrics, Immunology, Virology, and Women's Health.
 
The scientific committees form the scientific nucleus of the ACTG.  Each
committee has a chair, vice chair, and a core committee made up of are
ACTU investigators.  In addition, ACTU investigators with relevant
expertise and interest in the committee's research area represent the
ACTUs.  Each committee also has a single representative from SDAC, the
DAIDS, and HIV-infected persons and their advocates.  The ACTU
investigators constitute a large majority representation on all ACTG
committees.
 
The role of each Scientific Committee and the Executive Committee is to
develop cooperatively a research agenda and establish research
priorities in a particular scientific area and continually reassess
those priorities in light of new ideas and research opportunities and to
evaluate the conduct and status of active studies in light of current
national priorities for AIDS clinical research.
 
In addition to providing general expertise, the Scientific Committees
(Immunology, Virology, and Pharmacology) also have responsibility for
developing and recommending laboratory quality assurance policies in the
areas of flow cytometry, viral assays, marker evaluation, and
pharmacological assays.  The Committees meet during each ACTG meeting.
In addition, committees meet and/or are in contact at times other than
ACTG meetings.
 
Resource Committees
 
Resource Committees were formed to provide technical expertise and
practical advice to the ACTG.  There are three ACTG Resource Committees:
Site and Data Management Committee (SDMC), Patient Care Committee, and
the Community Constituency Group.  With the exception of the advisory
Community Constituency Group (see below), a majority of the membership
of the SDMC and the Patient Care Committee are ACTU investigators or
ACTU professional staff.  The Chief, Operations and Data Management
Branch, represents TRP on the SDMC and the Chief, Clinical Research
Management Branch, represents TRP on the Patient Care Committee.  The
Community Constituency Group is comprised solely of HIV-infected persons
and patient advocates and is strictly advisory to the ACTG Executive
Committee.
 
The Executive Committee
 
The Executive Committee develops general ACTG policies concerning
committee structure and membership, committee operations, publications,
access to data, interim data monitoring, agendas for group meetings,
competing protocols, and the evaluation of ACTU performance and ACTG
meetings.  In addition, the Executive Committee establishes scientific
priorities for the ACTG and assures equal access to trials for all
patient populations.  The majority of the 12-member Executive Committee
are representatives from the ACTUs.  The Executive Committee also
includes the Associate Director, TRP, two representatives from the
Community Constituency Group (including HIV-infected individuals), and
one representative from the SDAC.
 
b. Protocol Development
 
Ideas for individual studies may be introduced from any source, although
most come from ACTU investigators.  Proposed studies are summarized in
the form of a "concept sheet" that includes the study's rationale,
objectives, design, eligibility criteria, treatment regimen, and sample
size estimates.
 
The concept sheets are reviewed by TRP (Medical Officer and Clinical
Trials Review Committee).  The appropriate Scientific Core Committee and
the Executive Committee review, approve, and prioritize concept sheets.
Approved concept sheets are developed into protocols by a team composed
of a protocol chair (an ACTU investigator); TRP representatives (Medical
Officer and a Regulatory Affairs representative); one SDAC statistician;
one Operations Office representative; and an ACTU investigator
immunologist, virologist, or pharmacologist, as required.  The final
draft of the protocol is forwarded to the FDA.  After FDA approval and
notification from the pharmaceutical company that the investigational
agent is available in sufficient quantity, the protocol is opened for
enrollment.
 
Once a protocol has been activated, the protocol chair is responsible
for the overall conduct of the study, for its ongoing performance, and
is expected to take the lead in dissemination of study results,
including publications.  Safety and toxicity studies (phase I/phase II
trials) usually involve the participation of a limited number of ACTUs;
whereas, large-scale phase III efficacy studies involve multiple ACTUs.
Because most ACTG clinical trials are conducted under an IND held by the
DAIDS/NIAID, regulatory requirements mandate review and approval of
protocols by the NIAID Clinical Trials Review Committee (composed of
DAIDS staff) prior to their initiation.
 
C. Major Strengths and Accomplishments of the ACTG
 
The ACTG has established the capability to conduct all phases of
clinical trials, including large-scale, multicenter trials, within the
framework of investigator-initiated research involving scientists from
many disciplines.  Over 170 ACTG protocols have been conducted and more
than 14,000 persons have been enrolled in ACTG clinical trials.
Considerable advances have been made in antiretroviral drug therapy
(including the extension of life-prolonging therapy to early stages of
the disease), and in the area of prophylaxis of opportunistic
infections.  Noteworthy ACTG protocols include:
 
o Protocol 002, a study of 574 persons with AIDS, showed that a lower
dose of zidovudine (AZT) from the earlier approved dose was equally
beneficial in the treatment of AIDS;
 
o Protocol 016, a double-blind, placebo-controlled study of 713 patients
with AIDS-related complex, demonstrated a beneficial effect of AZT; and
 
o Protocol 019, a double-blind, placebo-controlled study of 3,207
persons with asymptomatic HIV infection, revealed a beneficial effect of
AZT.  This latter study, especially, has had enormous implications for
the thousands of asymptomatic persons who are HIV infected.
 
HIV-associated malignancies are becoming an increasing problem as the
epidemic matures.  Patients are living longer with improved therapy of
the primary infection and opportunistic infections, thus increasing the
likelihood that a given patient will develop an HIV-related malignancy.
In addition, it is becoming apparent that treatment of non-Hodgkin's
lymphoma (NHL) in HIV-infected patients can improve survival in some
cases.  New modes of therapy for Kaposi's sarcoma, such as angiogenesis
inhibitors, are nearing readiness for human trials and will require
large-scale clinical trials in order to evaluate their effectiveness.
In addition, the number of women with HIV infection is increasing.
These patients are at increased risk for cervical neoplasia associated
with human papilloma virus.
 
The ACTG Oncology Committee has carried out a program of phase I, II,
and III trials of agents and regimens for therapy of Kaposi's sarcoma
and NHL.  A large phase III trial comparing two regimens for NHL started
late in 1990.  A large phase II trial, which includes chemotherapy
induction and maintenance with an antiretroviral combined with
interferon, is in development.  Several phase I trials are ongoing and
in development.  There is also a single trial in development for
Hodgkin's disease.
 
Neurologic complications are an important component of the spectrum of
HIV infection.  Studies on the identification, treatment, and possible
prophylaxis of these complications are an important ACTG objective.
 
In addition, the ACTG is currently collaborating with more than 10
pharmaceutical firms with antiretroviral drugs in development.
 
The recompeted ACTG system will retain the exemplary features of the
current system (including primary emphasis on high-quality,
multidisciplinary, investigator-initiated research in all phases of
clinical trials) and incorporate the changes required to meet the
challenges imposed by the evolution the AIDS epidemic.  Increased
emphasis will be placed on linking funding to performance coupled with
the flexibility to allocate resources as clinical trials research
priorities require.
 
D. Community Program for Clinical Research on AIDS (CPCRA)
 
The NIAID national program of community-based clinical research on the
treatment of HIV infection and its complications is also sponsored by
TRP.  The purpose of the CPCRA is to develop the capability to conduct
scientifically sound research in community settings in order to expand
HIV-related research opportunities and broaden the base of persons
involved in NIAID-sponsored projects.  These projects, supported by
contracts, extend research opportunities to clinicians in primary care
settings by providing administrative and technical support.  CPCRA sites
are especially effective in targeting HIV-infected persons from minority
populations, women at risk for HIV infection, and persons who are drug
users.
 
Eighteen contracts were awarded in October 1989.  The recipients of
these contracts are primary care providers in a wide diversity of
clinical settings across the country and currently care for 30,000
persons with HIV infection.  The coexistence of an ACTU and a CPCRA site
in the same Standard Metropolitan Statistical Area (SMSA) results in
providing the HIV-infected person with the full range of NIAID-sponsored
clinical trials.  NIAID requires that CPCRA sites establish formal
communication links with ACTUs in the same SMSA.  Adult ACTUs likewise
will be required to establish a communication with a CPCRA site in the
same SMSA as part of the application in response to this RFA.
 
E. Supplementary Resources Funded Through Other Mechanisms
 
1.  Statistical and Data Analysis Center (SDAC)
 
The purpose of the SDAC contract is to provide extensive biostatistical
expertise and data management coordination to the ACTG.  The award was
made to the Harvard School of Public Health in September 1989.
 
At the request of the Executive Committee, the SDAC assists the ACTUs in
the statistical analysis and data management of data emanating from all
the participating ACTUs conducting studies.  These responsibilities,
include:  (1) statistical design and proposed analyses of an ACTG
clinical trial; (2) the development of forms for clinical trials data
collection; (3) the routing of such data to the central data management
center; and (4) a complex series of quality control measures designed to
ensure the accuracy and timeliness of the submitted information.  A
senior SDAC statistician serves as an advisor to the ACTG scientific
committees and the Executive Committee.
 
2.  The Operations Office
 
A new five-year contract for the Operations Office was awarded to Social
and Scientific Systems (SSS) on March 1, 1991.  Activities required
under the new contract include:  provision of services necessary to
establish and maintain a system for the receipt and review of concepts
for new clinical trials; development of systems and procedures required
to coordinate all activities related to the implementation/conduct and
completion of ACTG studies; provision of technical and administrative
support for meetings of protocol teams, and ACTG committees; provision
of scientific information specialists support for the medical branch of
TRP; development and implementation of a microcomputer-based management
information system to track the progress of clinical trials from concept
stage through protocol implementation and completion; and development
and maintenance of an ACTG Standard Operating Procedures (SOP) manual
documenting all standard SOPs approved by the Executive Committee with
respect to ACTG activities.  At the request of the ACTG Committees
(Executive and Scientific), the Operations Office assists in the
functions described above to facilitate protocol development, protocol
implementation, and logistical information management for the clinical
trials at the ACTUs.
 
3.  Monitoring
 
a. Clinical Site Monitoring
 
In July 1990, a contract was awarded by the TRP to Pharmaceutical
Products Development, Inc. (PPD) in Wilmington, NC, to provide site
monitoring for ACTUs and CPCRA sites.  This contractor, at the request
of the ACTG Executive Committee, conducts routine site monitoring
visits, special mail and on-site audits to assess the quality of the
data collected at each ACTU, and conformance to FDA and DAIDS policies
and procedures.
 
All ACTUs are responsible for the quality of the research records at
their unit and are expected to provide complete and accurate research
records.  Although ACTUs differ in the way they ensure that research
records are accurate and complete, each ACTU is expected to institute an
internal quality assurance program supervised by a clinician.  External
review of the QA at each ACTU is be provided by PPD periodic on-site
monitor visits (approximately four per year).
 
b. Laboratory Quality Assurance
 
All ACTU flow cytometry, virology, and pharmacology laboratories are
required to participate in quality assurance programs established by the
ACTU Executive Committee.  All ACTU hematology laboratories are required
to furnish documentation demonstrating their ongoing participation and
certification by an external hematology proficiency testing program,
such as that administered by the College of American Pathologists.  This
documentation shall be collected as part of the site registration
process.
 
4.  NIAID Clinical Research Products Repository (CRPR)
 
DAIDS has established a CRPR, through a contract with ERC Bioservices
Corporation, for the storage and distribution of drugs used in clinical
investigations sponsored by DAIDS.  This contract is managed by the
Pharmaceutical and Regulatory Affairs Branch of TRP.  At the request of
the ACTU Principal Investigators, the contractor performs the following:
receives drugs from a variety of sources and stores them at their
required conditions; ships and distributes drugs upon receipt of an
appropriate order form from a site pharmacist for an authorized
investigator; manages the inventory by performing physical inventories
and monitors usage rates of drugs; disposes of returned drugs as
required by local, State, and Federal regulations; and establishes a
computerized management information system to maintain drug inventories
and distribution records.
 
5.  AIDS Clinical Trials Information Service (ACTIS)
 
The ACTIS is a central resource providing information on NIH-and
industry-sponsored clinical trials for individuals infected with HIV.
This is a free service for users and is jointly sponsored by the NIAID,
National Library of Medicine, and the FDA in collaboration with and
through an inter-agency agreement with the CDC through their contractor
Aspen Systems Corporation.  The DAIDS, through the Operations Office,
provides a weekly update to ACTIS including information about all
DAIDS-sponsored protocols including copies of new protocols, weekly
accrual lists, information regarding protocol changes, and lists of
participation sites.
 
                        APPENDIX II
 
               CORE BUDGET FOR PEDIATRIC ACTUS
 
USE INFORMATION BELOW TO COMPLETE PAGE 4 OF SECTION 1
OF FORM PHS 398
 
NIAID GUIDELINES BASED ON PROJECTED ACCRUAL OF NEW PATIENTS
 
                                                NEW PTS
                                                25 - 50
------------------------------------------------------------
Personnel
 
Principal Investigator                          10 -  30%
 
Co-investigator(s)                              70 - 100%
 
Study Coordinator                               100%
 
RNs/PAs/Nurse Practitioners                     200 - 400%
Clinical Assistant                              100 - 200%
 
Nerologist/Developmentalist/Psych               20% minimum
 
Data Manager/QA Coordinator                     50 - 100%
 
Data Entry Clerk                                50 - 100%
 
Pharmacist                                      50 - 100%
 
Social Worker                                   50 - 100%
 
Administrative Support                          100 - 150%
 
Laboratory Technician                           25 -  50%
 
                        APPENDIX III
 
   PROPOSED PEDIATRIC ACTU COST/PATIENT/PROTOCOL/UNIT TIME
 
                    FOR TWO ACTG PROTOCOLS
 
Attach this form to page ____ of Section ____ of form PHS 398.
 
THIS SECTION WILL FEATURE A NARRATIVE OF ASSUMPTIONS TO BE
USED TO CALCULATE COSTS OF THE TWO PROTOCOLS DESCRIBED.
COPIES OF THE VERSIONS OF THE INDIVIDUAL PROTOCOLS ARE
AVAILABLE ON REQUEST FROM THE OPERATIONS OFFICE.
 
                  Protocol 128 (version 3.0)
 
"A Randomized Blinded Trial to Evaluate the Safety and
Tolerance of High Versus Low Dose Zidovudine Administered to
Children with Human Immunodeficiency Virus"
 
Phase III, multicenter, randomized, blinded, outpatient
study
 
Time Period Analyzed:  104 weeks on treatment
 
Assumptions
 
-     Screening charges are not included.
 
-     Optional tests and procedures are not included.
 
-     Prophylaxis for PCP is not included.
 
-     Clinical procedures and laboratory tests for endpoint
      determinations are not included.
 
-     Supplemental tests and procedures for children with
      LIP are not included.
 
-     The PI time and effort is estimated at 2 hours; this
      is exclusive of MD time for patient visits.
 
Required Laboratory Tests
 
hematology:     CBC with WBC differential, mean corpuscular
volume, platelet count, reticulocyte count
 
chemistry:      serum creatinine, BUN, total bilirubin,
SGOT, SGPT, LDH
 
immunology:     quantitative immunoglobulin levels
(IgA, IgG, IgM); absolute T cells, absolute CD4+ count,
absolute CD8+ count
 
virology:  serum HIV antigen levels (p24), HIV culture
(blood)
 
                  COST OF CLINICAL TRIALS
               COST/PROTOCOL/PATIENT/UNIT TIME
 
Protocol 128 (version 3.0)
 
------------------------------------------------------------
H&P (full):  MD = 1/2 hour      $      x 14 = $    3COMMENTS
             RN = 2 1/2 hours   $      x 14 = $    3
H&P (abbrev) MD = 1/4 hour      $      x 16 = $    3
             RN = 2 hours       $      x 16 = $    3
neuropsychological testing                         3
   psychologist = 3 hours       $      x  5 = $    3
pharmacy: set up fee            $      x  1 = $    3
          pharmacist = 1/2 hour $      x 29 = $    3
data mgmt: data mgr = 1/4 hour  $      x 30 = $    3
laboratory: hematology (5 tests)$      x 30 = $    3
            chemistry (6 tests) $      x 27 = $    3
            immunology (6 tests)$      x 10 = $    3
            virology (p24 ag)   $      x 10 = $    3
            HIV culture (blood) $      x  3 = $    3
chest x-ray                     $      x  5 = $    3
echocardiogram                  $      x  3 = $    3
EKG                             $      x  3 = $    3
PI analysis = 2 hours               $              3
Overhead                            $              3
Total for the study (104 weeks) =   $              3
--------------------------------------------------
 
            Protocol 139 (amended 12/6/90)
 
"A Phase I Study of the Safety and Pharmacokinetics of
Recombinant CD4 Immunoglobulin G (rCD4-IgG) in Infants and
Children with Documented HIV-1 Infection"
 
Phase I, pharmacokinetics, open label, dose escalating study
 
Time Period Analyzed:  12 weeks on treatment; 1 month post
therapy follow-up
 
Assumptions
 
-     Maintenance therapy after the 12-week treatment period
      is not included.
 
-     Screening charges are not included.
 
-     Required immunizations are not included.
 
-     Optional tests and procedures are not included.
 
-     All laboratory tests are sent to outside laboratories;
      charges are for sample collection, storage, and
      shipping.
 
-     The PI time and effort is estimated at 1 hour; this is
      exclusive of MD time for patient visits.
 
Required Laboratory Tests
 
hematology:     0.5 ml whole blood/sample
 
chemistry:      1.0 ml whole blood/sample
 
coagulation:    1.0 ml frozen serum/sample
 
urinalysis
 
pharmacokinetics: 0.25 ml serum/time point
 
immunology:     T cells - 1.0 ml whole blood/sample
                anti-CD4 - 0.25 ml serum/sample
                antibody to DT and polio vaccines - 1.5 ml
                  serum/sample
                antibody to hepatitis B vaccine - 0.5 ml
                  serum/sample
                lymphocyte proliferation - 5.0 ml whole
                  blood/sample
                quantitative immunoglobulin levels - 0.5 ml
                  serum/sample
 
virology:       HIV antigen levels (p24) - 1.5 ml
                  serum/sample
                HIV culture - 2.0 ml whole blood/sample
 
serum bank:     0.25 ml serum/sample
 
                  COST OF CLINICAL TRIALS
               COST/PROTOCOL/PATIENT/UNIT TIME
 
Protocol 139 (amended 12/6/90)
 
-------------------------------------------------------------
H&P:         MD = 1/2 hour      $      x 14 = $    3COMMENTS
             RN = 1 hour        $      x 14 = $    3
drug administration:  RN=1 1/2 hrs$      x 23 = $    3
pharmacokinetics: RN = 1/2 hour $      x 15 = $    3
pharmacy: set-up fee            $      x  1 = $    3
          IV preparation        $      x 23 = $    3
data mgmt: data mgr = 1/2 hour  $      x  1 = $    3
laboratory: hematology          $      x  5 = $    3
            coagulation         $      x  2 = $    3
            chemistry           $      x  5 = $    3
            urinalysis          $      x  5 = $    3
            pharmacokinetics    $      x 15 = $    3
            T cells             $      x  4 = $    3
            anti-CD4            $      x  4 = $    3
            antibody to DT/polio$      x  3 = $    3
            antibody to hepatitis$     x  4 = $    3
            lycyte proliferation$      x  2 = $    3
            immunoglobulin level$      x  2 = $    3
            HIV antigen level   $      x  4 = $    3
            HIV culture         $      x  4 = $    3
            serum bank          $      x  4 = $    3
chest x-ray                     $      x  2 = $    3
echocardiogram                  $      x  2 = $    3
PI analysis = 1 hour                $              3
Overhead                            $              3
Total for the study (16 weeks) =    $              3
---------------------------------------------------
 
                        APPENDIX IV
         ACTG PROTOCOLS OPEN TO ENROLLMENT (5/2/91)
 
PROTOCOL NUMBER            PROTOCOL TITLE
 
ACTG 082                   A Phase I Trial to Evaluate AZT
                           in HIV-1 Infected Pregnant Women
                           and Their Offspring and a Phase I
                           Pharmacokinetic and Safety Trial
                           of AZT in Laboring Women and
                           Their Offspring
 
ACTG 091                   A Phase I Study of Safety and
                           Pharmacokinetics of 2', 3'-
                           Dideoxyinosine (ddI) Administered
                           Twice Daily to Infants and
                           Children with Symptomatic HIV
                           Infection or AIDS
 
ACTG 103                   A Randomized Trial to Evaluate
                           the Impact of Maintaining Steady-
                           State Concentrations of AZT
                           Versus an Intermittent Schedule
                           of AZT Delivery Versus
                           Intermittent ddI in Children with
                           Symptomatic HIV Infection
 
ACTG 115                   A Phase I Study of the Safety,
                           Tolerance and
                           Pharmacokinetics of Aerosolized
                           Pentamidine and
                           Parental Pentamidine in Children
                           with HIV Infection and Suspected
                           PCP
 
ACTG 138                   A Trial of Two Doses of 2',3'-
                           Dideoxycytidine (ddC) in the
                           Treatment of Children with
                           Symptomatic HIV Infection who are
                           Either Intolerant of Zidovudine
                           and/or Show Progressive Disease
                           while on Zidovudine
 
ACTG 139                   A Phase I Study of the Safety and
                           Pharmacokinetics of Recombinant
                           CD4 Immunoglobulin G (rCD4-IgG)
                           in Infants and Children with
                           Documented HIV Infection

ACTG 155                   A Randomized, Double Blind
                           Comparative Study of
                           Dideoxycytodine (ddC) Alone
                           Versus ZDV/ddC in Combination
                           Versus Zidovudine (ZDV) Alone in
                           Patients who have Received Prior
                           ZDV Therapy
 
                               APPENDIX V
 
                                          12-14-89
 
GUIDELINES FOR THE ESTABLISHMENT AND ADMINISTRATION OF SUBUNITS
 
The Division of AIDS (DAIDS) is responsible for the clinical development
of safe and effective therapies for HIV infection and associated
opportunistic diseases.  To accomplish this mission, a national network
of institutions that evaluate potential therapies for HIV and its
sequelae has been established and is known as the AIDS Clinical Trials
Group or ACTG.  New drugs are being developed from the initial human
trials through pivotal phase III trials directed toward a new drug
application (NDA) submission.
 
In order to conduct clinical trials using investigational products, the
NIAID, DAIDS, must sponsor Investigational New Drug (IND) Applications
for specific drugs.  Federal regulations require sponsors of these
applications to assure that:
 
  o  investigational products are dispensed properly.  (Particular
     restraints are required to assure there is no diversion
  to non-study patients, that the drugs are properly stored, and that
     only specified individuals dispense or receive the drug).
 
  o  clinical investigators maintain adequate and complete records
 
  o  an institutional review board (IRB) that meets federal requirements
     will be responsible for initial and continuing review of studies.
 
In order for DAIDS to meet its responsibilities, certain administrative
and regulatory standards must be met.  How the components of the ACTU
network (AIDS Clinical Trial Units and their subunits) should interact
is described below.  Note that ACTU refers to the main site; subunit
refers to any site that is under the administrative umbrella of the
ACTU.  Site is a general term used to describe both ACTUs and subunits.
 
I. Conditions under which an ACTU may consider including additional
subunits
 
A. There is a strong rationale for the addition of another site.
Examples of some of the reasons why an additional subunit could be
advantageous could be:  increasing access to under-served populations
(minorities, intravenous drug users, females), or logistical conditions
that would enhance patient participation by establishment of a more
convenient site for accruing additional patients.
 
B. The ACTU has shown it is managing its clinical trials and
administrative responsibilities well.  Current success with existing
quality assurance programs is essential before additional sites may be
added.
 
C. The ACTU has the appropriate staff and time to provide liaison and
monitoring of its subunits.  The additional resource requirements for
managing another subunit must not detract from the current activities of
the ACTU.
 
II.  ACTU responsibilities in establishment of a subunit
 
The individual ACTU is responsible for the proper functioning of
subunits under its jurisdiction.
 
A. Prior to determining if a particular subunit(s) could become part of
the ACTU, the ACTU must present to DAIDS a rationale and justification
for doing so.  The justification must show that particular goals and
expectations of the DAIDS that cannot be accomplished through the
current institutional network will be met.  If rebudgeting of the
cooperative agreement is involved, such information must be included in
the justification.
 
B. A plan for how the ACTU will carry out its responsibilities regarding
its subunits will be submitted to DAIDS.  The plan should include, but
not be limited to the following:
 
1.  A description and/or map describing the geographic location of the
subunit to the ACTU and the pharmacy.
 
2.  A plan that describes how the pharmacist's responsibilities will be
met and how the protocol drug requirements will be satisfied.
 
3.  The designation of a specific person(s) at the ACTU who will provide
monitoring of subunits for maintenance of adequate and complete records
and proper site management.  This person will keep simple but adequate
records to show that proper monitoring of the subunit has occurred.
 
4.  A plan for the specific method of collecting and transferring data
must be detailed with responsibilities identified for specific
individuals.
 
5.  The plan must identify all areas that require liaison and the
individuals responsible for these activities.  For example, the plan for
how the virology samples will be analyzed, by whom, how they will be
transported, and how results will be relayed to the site must be
submitted.
 
6.  A specific clinical person at the subunit must be identified as
responsible for the internal operations of the subunit.
 
7.  The ACTU must ensure that only immunology/virology labs that have
enrolled in the QA program will be utilized, presumably at the main ACTU
site.
 
The ACTU will submit to the Clinical Research Management Branch a plan
defining the role of the specific ACTU staff who are to oversee the
subunit(s).  Arrangements for the ACTU to oversee and be responsible for
the subunit(s) maintaining quality records and protocol management will
be included in this plan.  Once it is approved, DAIDS will send a letter
of approval to the ACTU's Principal Investigator.
 
If the subunit does not perform adequately or if the ACTU is unable to
provide proper liaison and monitoring, the ACTU staff should request
advice and/or assistance from the DAIDS.
 
III.  Conditions under which a subunit's participation may be stopped
 
If an ACTU finds it is unable to provide the appropriate monitoring, or
if the site, for any reason, is unable to function according to DAIDS
standards as defined by the Clinical Research Management Branch,
permission for a subunit to participate in the ACTU system may be
withdrawn by the DAIDS.  The first six months of a subunit's
participation in the AIDS program will be considered probationary,
although permission to participate may be withdrawn at any time.
 
IV.  New subunit start-up checklist:
 
A. All requested information has been submitted and approved by the
Clinical Research Management Branch of DAIDS.
 
B. Written IRB approval is obtained for the subunit to conduct clinical
trials for the specific protocol(s).
 
C. The DAIDS pharmacy staff has determined that the proper pharmacy is
in place and the drug has been received by the pharmacist.
 
D. All immunology/virology labs have been enrolled in the DAIDS quality
control programs.
 
E. The subunit has been registered as outlined in item VI, Subunit
Registration.
 
F. The nurse coordinator (and other nurses when appropriate) has been
instructed about regulatory and audit responsibilities as well as how to
complete the case report forms (CRFs).
 
G. Pertinent CRFs and the adverse effects reporting and pharmacy manuals
have been received by the site.
 
H. If data entry is to be performed at the subunit, the data entry
person will have been adequately trained.  When appropriate, an
agreement between the Clinical Trials Coordinating Center (CTCC) or the
Statistical Data Analysis Center (SDAC) and the subunit may be necessary
for forms to be held until suitable arrangements can be made for data
entry.
 
I. Arrangements for the responsible transfer of data from the subunit to
the ACTU have been made.  This includes identifying an available area
with limited access for patient records.
 
J. When appropriate, the subunit start-up visit by the CTCC monitors has
been made.
 
V. Pharmacy
 
Each ACTU is required to submit to DAIDS a plan describing how the
pharmacist's responsibilities and protocol drug requirements will be
satisfied.  In some cases, the drug requirements may be such that the
ACTU will be required to designate a pharmacist at the subunit(s).  In
other cases, where geographical and administrative arrangements between
the ACTU and the subunit(s) permit, it may be preferable for the ACTU
pharmacist to be responsible for dispensing drug(s) to the subunit(s).
In such cases, the ACTU is required to develop and submit for the DAIDS
approval a plan detailing how the pharmacist's responsibilities will be
met.
 
All pharmacies will be monitored at least once per year by the CTCC
regional monitors for the following:
 
A. proper drug accountability records, including the amount of
investigational drug received from the sponsor and its disposition.
(All records should be maintained for two years or as required by
regulation.)
 
B. proper security of the investigational drug
 
C. proper storage and labeling
 
D. proper drug/dose preparation
 
E. proper dispensing of drug by assuring that only authorized
investigators prescribe the drug and that all patients have signed the
consent form.
 
VI.  Subunit registration
 
A. The ACTU bears the burden of responsibility of its subunits'
activities and, therefore, must be fully aware of the subunits'
activities.
 
B. The site registration procedure for a subunit is the same as for
ACTUs.
 
All site registration correspondence and documentation (IRB approval,
FDA form 1572, curricula vitae, IRB approved consent forms) and
questions should be addressed to Ms. Jorgenson of the Operations Office
at the following address:
 
Division of AIDS, NIAID
Site Registration Desk
6005 Executive Boulevard
Rockville, MD  20852
Attention:   Ms. Kym Adams
Telephone:  (301) 230-3150
FAX:  (301) 480-5703
 
C. The site registration records are described below:
 
1.  1572's:  All physicians who order investigational drugs must have
completed a form 1572 or be under the direct supervision of a physician
who has signed the 1572.  A physician in a private office or an
institution other than the 1572 signer is not considered to be under
his/her direct supervision and must submit a signed 1572 and his/her
current curriculum vitae (CV).
 
2.  CVs:  The curriculum vitae of the Principal Investigator and all
co-investigators listed on the form 1572 must be submitted to the
Operations Office.
 
3.  Written IRB approval.  No research involving investigational drugs
can be conducted at a site, regardless of size or complexity, whose IRB
has not given written approval for this to occur.  This includes those
subunits that are private physicians or physician consortiums.  If a
site has its own IRB, that IRB must provide the approval.  If a site
does not have its own IRB, any IRB may be used.  However, we recommend
choosing an IRB that is familiar with the site and aware of the intended
patient population to be served.
 
4.  Consent form:  Documentation that the IRB has reviewed and approved
a consent form for each protocol is required.  The original IRB-approved
consent must be submitted.
 
These records will be obtained on an annual basis for all ACTUs.
 
VII.  Subunit responsibilities
 
In addition to its routine duties regarding its clinical trials:
 
A. Each subunit will conduct its own internal quality assurance audit.
 
B. Each subunit will assure that all patient records are kept in a
limited access area.
 
C. A designated clinician (nurse or clinical coordinator) will have the
ultimate responsibility for specific protocols and their proper accrual
and collection of data.
 
VIII.  Monitoring of ACTUs and subunits
 
In general, each site (ACTU or subunit) will perform an internal quality
assurance audit of its own records.  In addition, each site will be
monitored by someone outside the unit.  CTCC regional monitors will
visit ACTUs at least quarterly and more frequently when possible or
necessary.  The ACTU will be responsible for assuring the quality of the
data retrieved from its subunits and will monitor as needed to assure
this quality.  The amount of time spent devoted to monitoring may vary
according to number of patients enrolled and the experience of the
subunit staff.
 
The size of the subunit, the number of patients enrolled, the degree of
complexity of the protocols conducted, and the number and kinds of
problems encountered by the staff will determine the number of visits
that a regional monitor will make to a subunit.  However, at a minimum,
even small subunits will be monitored once, and preferably twice, a year
by the CTCC monitor.  All pharmacies will be inspected at least annually
and more often if problems are found.
 
Training will be provided as needed by the DAIDS and/or the regional
monitors for the ACTU monitor as well as the person designated by the
subunit to perform its own internal audit.
 
                        APPENDIX VI
 
                 REQUIRED COMPUTER EQUIPMENT
 
A. An IBM-compatible microcomputer with at least 640K RAM and 40 Mbyte
hard disk.
 
B. A 2400-band modem (preferably Multitech) and a dedicated phone line
for the modem.
 
C. A dot matrix, impact, or laser printer (a Hewlitt-Packard Laserjet
printer is highly recommended).
 
D. A copy of the latest version of BLAST with remote control
communications software.
 
E. A copy of the latest version of WordPerfect wordprocessing software.
 
                        APPENDIX VII
 
   COMMUNITY PROGRAMS FOR CLINICAL RESEARCH ON AIDS SITES
 
Addiction Research and Treatment Corporation
Brooklyn, NY
Telephone:  (718) 260-2917, 2961
 
AIDS Research Consortium of Atlanta, Inc.
Atlanta, GA
Telephone:  (404) 876-2317
 
Bronx-Lebanon Hospital Center
Bronx, NY
Telephone:  (212) 901-8646
 
Chicago Community Program for Clinical Research on AIDS
Chicago, IL
Telephone:  (312) 975-3261, 975-3000
 
Clinical Directors Network of Region II
Brooklyn, NY
Telephone:  (718) 492-3666
 
Community Consortium
San Francisco General Hospital
San Francisco, CA
Telephone:  (415) 821-5531
 
Comprehensive AIDS Alliance of Detroit
Harper Hospital Professional Building
Detroit, MI
Telephone:  (313) 745-9131
 
Delaware CPCRA
Medical Center of Delaware
Wilmington, DE
Telephone:  (302) 428-2744
 
Denver Community Program for Clinical Research on AIDS
Denver, CO
Telephone:  (303) 893-7051, 893-7691
 
Harlem AIDS Treatment Group
Harlem Hospital Center
New York, NY
Telephone:  (212) 694-4034, 694-4035
 
Henry Ford Hospital
Detroit, MI
Telephone:  (313) 876-7664
 
Hill Health Corporation
New Haven, CT
Telephone:  (203) 776-9594, ext. 296
 
Louisiana Community AIDS Research Program
Tulane University Medical Center
New Orleans, LA
Telephone:  (504) 584-1971
 
North Jersey Community Research Initiative
Newark, NJ
Telephone:  (201) 648-0350
 
Richmond AIDS Consortium
Richmond, VA
Telephone:  (804) 371-6471
 
The Research and Education Group
Portland, OR
Telephone:  (503) 781-3292
 
Washington Regional AIDS Program
VA Medical Center
Washington, DC
Telephone:  (202) 745-8301
 
                        APPENDIX VIII
 
            HEALTH RESOURCES AND SERVICES ADMINISTRATION
 
A.  AIDS Service Demonstration Projects
 
Maricopa County Department of Health Services
Phoenix, AZ
Telephone:  (602) 258-6381
 
AIDS Program Office
Los Angeles Department of Health Services
Los Angeles, CA
Telephone:  (213) 974-7803
 
Office of AIDS Coordination
San Diego County
Department of Health Services
San Diego, CA
Telephone:  (619) 496-5477
 
San Francisco Department of Public Health
San Francisco, CA
Telephone:  (415) 554-9000
 
County of Orange
Health Care Agency
Santa Ana, CA
Telephone:  (714) 834-2015
 
City Council of Denver
Denver, CO
Telephone:  (303) 893-7270
 
Jackson Memorial Hospital
Miami, FL
Telephone:  (305) 549-7744
 
Northwest Health Center
Fort Lauderdale, FL
Telephone:  (305) 467-4532
 
Comprehensive AIDS Program of West Palm Beach
West Palm Beach, FL
Telephone:  (407) 881-9040
 
The AIDS Service Delivery Consortium of New York City
New York, NY
Telephone:  (212) 268-4510, ext. 411
 
Philadelphia Health Management Corporation
Philadelphia, PA
Telephone:  (215) 985-2502
 
Puerto Rico Department of Health
San Juan, Puerto Rico
Telephone:  (809) 766-1616
 
AIDS ARMS Network
Community Council of Greater Dallas
Dallas, TX
Telephone:  (214) 521-5191
 
Harris County Hospital District
Houston, TX
Telephone:  (713) 652-1200
 
AIDS Health Service Program
Seattle, WA
Telephone:  (206) 296-4649
 
D.C. Department of Human Services
Commission of Public Health
Washington, DC
Telephone:  (202) 673-3679
 
AIDS Atlanta
Atlanta, GA
Telephone:  (404) 872-0600
 
AIDS Foundation of Chicago
Chicago, IL
Telephone:  (312) 642-5454
 
Associated Catholic Charities of New Orleans
New Orleans AIDS Project
New Orleans, LA
Telephone:  (504) 523-3755, ext. 324
 
Fenway Community Health Center
Boston, MA
Telephone:  (617) 267-0900
 
Maryland Department of Health and Mental Hygiene
Baltimore, MD
Telephone:  (301) 225-6804
 
United Community Services of Metropolitan Detroit
Detroit, MI
Telephone:  (313) 226-9400
 
County of Hudson
Jersey City, NJ
Telephone:  (201) 795-6933
 
New Jersey State Department of Health
Division of AIDS Prevention and Control, CN 363
Trenton, NJ
Telephone:  (609) 984-6000
 
Nassau-Suffolk Health Systems Agency
Plainview, NY
Telephone:  (516) 293-5740
 
B.  Pediatric AIDS Service Demonstrations
 
Case Management Demonstration
  Program for Pediatric Patients and
  Families in Los Angeles County
California Children's Services
County of Los Angeles
Department of Health Services
Los Angeles, CA
Telephone:  (213) 226-4471
 
Pediatric AIDS Health Care Demonstration Project
Public Health Trust-Dade County
Miami, FL
Telephone:  (305) 549-7744
 
Pediatric AIDS Demonstration Project
Georgia Department of Public Resources
Division of Public Health
Atlanta, GA
Telephone:  (404) 894-6622
 
Pediatric AID Program in New Orleans
Children's Hospital of New Orleans
New Orleans, LA
Telephone:  (504) 899-9511
 
Boston Pediatric AIDS Project
Dimmock Community Health Center
Roxbury, MA
Telephone:  (617) 442-8802
 
A Model Program for Pediatric AIDS
Prevention and Control in Michigan
Michigan Department of Public Health
Lansing, MI
Telephone:  (517) 335-8900
 
Development of a Statewide Health
  Services Network for Children with
  HIV Infection and Their Families
New Jersey Department of Health
Special Child Health Services, CN364
Trenton, NJ
Telephone:  (609) 292-5676
 
Northern Manhattan Women's and Children's HIV Demonstration Project
New York, NY
Telephone:  (212) 928-5103
 
Family AIDS Case Management Program
Home Care Services Program
Human Resources Administration
New York, NY
Telephone:  (212) 420-7490
 
Model Comprehensive Health Care Program for Adolescents
Montefiore Medical Center
Bronx, NY
Telephone:  (212) 920-6612
 
Bronx Pediatric AIDS Consortium (B-PAC)
Albert Einstein College of Medicine
Bronx, NY
Telephone:  (212) 294-2497
 
Brooklyn Pediatric AIDS Demonstration Project
Health Science Center
Brooklyn, NY
Telephone:  (718) 270-1828
 
Puerto Rico Pediatric AIDS Demonstration Project
Puerto Rico Department of Health
San Juan, PR
Telephone:  (809) 754-9576
 
Family AIDS Center for Treatment and Support (FACTS)
Rhode Island Department of Health
Providence, RI
Telephone:  (401) 277-2312
 
Pediatric AIDS Health Care Demonstration Project
University of Texas Health Science Center
San Antonio, TX
Telephone:  (512) 567-5215
 
Dallas-Fort Worth Pediatric AIDS Health Care Program
University of Texas Southwestern Medical Center
Dallas, TX
Telephone:  (214) 590-3946
 
Seattle-King County Pediatric AIDS Demonstration Project
Seattle-King County Department of Public Health
Seattle, WA
Telephone:  (206) 296-4677
 
                        APPENDIX IX
 
                  NATIONAL INSTITUTE OF DRUG ABUSE
 
            DRUG ABUSE TREATMENT RESEARCH UNITS AND CENTERS
 
Treatment Research Unit: IV Drug Abuse
Mercy Catholic Medical Center
Philadelphia, PA
Telephone:  (215) 898-6603
 
Treatment Research Unit:  Reducing AIDS Risks by Pharmacology and
Psychotherapy
Yale University
New Haven, CT
Telephone:  (203) 795-0705
 
Treatment Research Unit: Behavioral Pharmacological AIDS
Prevention in IVDUs
Johns Hopkins University School of Medicine
Baltimore, MD
Telephone:  (301) 550-0035
 
AIDS Reduction in Pregnant and Non-Pregnant Addicted Women
Virginia Commonwealth University
Richmond, VA
Telephone:  (804) 786-9914
 
Treatment Efficacy for Drug Abuse and AIDS Prevention
McLean Hospital
Belmont, MA
Telephone:  (617) 855-2716
 
A Treatment Research Unit for Intravenous Drug Users
Friends Medical Science Research Center
Baltimore, MD
Telephone:  (818) 881-3551
 
New Therapeutic Initiatives in Methadone Maintenance
Addiction Research and Treatment Corporation
Brooklyn, NY
Telephone:  (718) 260-2917
 
Improved Outpatient Treatment to Slow the Spread of AIDS
University of California San Francisco
San Francisco, CA
Telephone:  (415) 821-8764
 
Treatment of Addictions: Biological Correlates
The Rockefeller University
New York, NY