Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures Documents

DAIDS Requirements for U.S. Laboratories

Guidance to Investigators participating in Clinical Trials funded and/or sponsored by DAIDS

This document outlines the Division of Acquired Immunodeficiency Syndrome (DAIDS) laboratory-related requirements and deliverables for US laboratories.

US laboratories that perform any test, including waived tests on "…materials derived from the human body for the purpose of providing information for the diagnosis, prevention or treatment of any disease or impairment of, or the assessment of the health of, human beings" must meet certain federal requirements. Laboratories that perform tests for these purposes fall under Clinical Laboratory Improvement Amendments (CLIA) requirements. An overview of CLIA requirement can be found in the document CLIA Application for Certification (PDF). All laboratories performing waived tests must apply for a CLIA certificate of waiver. For more information see: An overview of the application for CLIA certification.

Laboratories should be conducting operations in accordance with Good Clinical Laboratory Practices (GCLP). These GCLP standards should be applied to all laboratories performing testing that supports a clinical trial funded and/or sponsored by the DAIDS. Institutions must also meet sponsor-specific requirements as outlined in the Sponsor Statement section of the GCLP standards document.

GCLP embraces both the research/pre-clinical and clinical aspects of Good Laboratory Practices (GLP). Complying with GCLP is an ongoing process that is central to optimal clinical research laboratory operations. DAIDS may monitor the progress toward GCLP compliance through ad-hoc and/or annual audits or site visits. GCLP compliance will ensure that consistent, reproducible, auditable, and reliable laboratory results that support clinical trials will be produced in an environment conducive to study reconstruction, and ensure the safety of the Research Subjects. See: NIH/NIAID/DAIDS guidelines for GCLP standards (PDF).

This guidance document is provided to clearly define the standards that encompass GCLP to include applicable portions of 21 Code of Federal Regulations (CFR) part 58, or GLP, and 42 CFR part 493, or Clinical Laboratory Improvement Amendment (CLIA) rules. Due to the ambiguity of some parts of these regulations, these GCLP standards also include guidance from accrediting bodies such as the College of American Pathologists, and other agencies with deemed status and ISO 15189 Certification, e.g. South African National Accreditation System.

1. Laboratory Safety, Diagnosis and Primary Endpoints Tests
   Tests that are used for diagnosis (e.g., HIV, CMV, HSV, Syphilis), determining eligibility (e.g., pregnancy test), monitoring the safety of the intervention (e.g., hematology, chemistry), making patient management decisions (e.g., CD4, viral load, drug levels), or as primary study endpoints, must be performed in laboratories that are Clinical Laboratory Improvement Amendments (CLIA) certified.

   All laboratories performing testing that supports a clinical trial funded and/or sponsored by the DAIDS must be enrolled in an EQA program for all DAIDS clinical trial analytes.

   These tests (including CLIA waived tests) must be quality assured by CLIA approved Proficiency Testing (PT) providers, such as the College of American Pathologists (CAP). See: A list of CLIA Approved PT providers (PDF).

   1.1. CD4 Testing

   CD4 determinations must be done using standard flow cytometric measurements, and consideration should be given to the Centers for Disease Control and Prevention (CDC) guidelines that describe dual-platform technology - Morbidity and Mortality Weekly Report (MMWR) 1997;46 (No. RR-2), or single-platform technology - MMWR 2003; 52(RR-02).

   If CD4 is a primary endpoint of a proposed trial, in addition to being CLIA-certified, the laboratory that performs CD4 testing must participate in the DAIDS Immunology Quality Assessment (IQA) CD4 proficiency testing (PT) program. Information about the IQA CD4 PT program.

   Enrollment in this program will have to be requested from DAIDS. There is no fee for participating in the IQA CD4 PT program or for receiving assistance from the IQA. However, laboratories are responsible for the cost of test kits/reagents used to test the proficiency panels. These costs should be taken into account when preparing the budget for conducting the trial.

   Please contact Daniella Livnat at 301-435-3775 or to discuss.

   1.2. HIV Virology

   Consensus virological methods

   If HIV viral load, HIV DNA PCR or HIV genotypic drug resistance testing is a primary endpoint of the proposed trial, laboratories that perform these tests must participate in the DAIDS Virology Quality Assessment (VQA). More information about this program.

   To request enrollment in VQA PT program(s), please contact Joe Fitzgibbon at 301-451-2738. For HIV viral load certification, the laboratory is required to successfully complete testing of an initial panel of 20 coded samples and two subsequent five-sample panels. The process of achieving certification takes at least five months.

   For laboratories performing testing for DAIDS-sponsored studies, there is no fee for participating in the VQA program. However, laboratories are responsible for the cost of shipping the panels from the VQA to the laboratory, and for test kits/reagents used to test the proficiency panels. These costs should be taken into account when preparing the budget for conducting the trial.

2. Non-FDA Approved End Point Tests

   This section covers all research tests not yet approved by the US FDA and validated by International Conference on Harmonisation (ICH) or US Pharmacopeia. The endpoint tests must be performed in laboratories that conduct operations in accordance with GCLP.

   2.1. Investigational Use Only

   Endpoint tests, such as new non-FDA approved pharmacological and virological assays do not require an investigational devise exemption (IDE) submission to the FDA. These are classified as investigational use only (IUO) tests while clinical studies are being done to evaluate their performance. There is no existing DAIDS-supported Proficiency Testing Program for these tests, therefore, a suitable form of alternative proficiency assessments should be devised and proposed to DAIDS for approval. IRB review (21 CFR part 56) and human subjects regulations (21 CFR parts 50) apply.

   2.2. Research Use Only (RUO)

   RUO assays, such as Enzyme-linked Immunosorbent Spot (ELISPOT) and Intracellular Cytokine Staining (ICS), are intended to be used for performing basic scientific research, are not considered to be effective diagnostic tools and must be appropriately labeled “for Research Use Only, Not for use in diagnostic procedures”. External quality assurance should be applied to such tests. Information on EQA programs.

3. Study specific-Specimen Management Plan

   Each study must have a specimen management plan that describes sample acquisition, recording, testing, storing and shipping; including specimen flow chart, quality assurance (QA) oversight and corrective action (the latter two may be included in the Laboratory Quality Management plan). Details may be included in study/Network Manual of Operations and/or in study protocol appendices.

   If shipments of specimens are to occur, they must be done according to the most current International Air Transport Association (IATA) shipping regulations.

4. Study Specific-Laboratory Data Management Plan

   Each study must include a laboratory data management plan that describes the systems and processes for acquisition, data entry, recording, exporting, reporting, modification, security and archiving of laboratory test results. The plan should describe the QA oversight and corrective actions, and how all laboratory test results will be integrated into the general study database.

   If the laboratory plans to use a Laboratory Information Management System (LIMS) or a Laboratory Data Management System (LDMS), the elements of 21 CFR Part 11 compliance should be taken into consideration.

5. Laboratory Quality Management Plan

   Quality Management is a systematic approach to achieving quality objectives. The Laboratory Quality Management Plan (QMP) is comprised of Quality Assurance (QA) and Quality Control (QC) processes.

   The lab QMP describes the laboratory’s approach to management of quality and study-participant safety by providing guidance for the operation of a laboratory. It must monitor, assess, and correct problems identified in pre-analytical, analytical and post analytical aspects of all lab operations.

   All laboratories performing testing that supports a clinical trial funded and/or sponsored by the DAIDS must have a documented QMP that describes the overall quality management program of the laboratory. Please refer to additional guidance in preparing and implementing a QMP (PDF).

   The QMP should describe the following; the laboratory’s plan to ensure overall quality and patient safety, corrective action and preventive action (CAPA) activities, risk assessment activities, QC and EQA activities, monitoring of key indicators and continuous improvement plans.

6. GCLP Training

   This interactive three day workshop, sponsored by the Division of AIDS (DAIDS) and delivered by PPD, is intended to give participants an introduction to Good Clinical Laboratory Practices (GCLP) and their relation to clinical research. The course will provide participants with an understanding of the differences between FDA and CLIA regulations. In addition, other guidance and accreditation information is presented to augment and clarify GCLP. The topics that will be presented would be most appropriate for the Laboratory Managers/Supervisors, QA/QC Coordinators, training supervisors or other laboratory staff working in or planning to work in a GCLP environment. Participants attending the training will get an understanding of key components of Good Clinical Laboratory Practices (GCLP), and the role they play in assuring the validity of studies. The importance of documentation will be stressed throughout the training.

   The cost of the workshop is free, however all attendees are responsible for their own travel, hotel, and per diem expenses through their network or group affiliations. Training materials for each participant will be provided.

   A certificate of participation is provided to participants that attend the full three-day workshop. Information on upcoming DAIDS-sponsored GCLP training workshops.

7. Laboratory-Specific Auditing

   DAIDS and/or its contractor, PPD, may conduct laboratory-specific audit visits to determine laboratory readiness to participate in clinical trials, and, as indicated, during the conduct of a trial.

   GCLP compliance will ensure that consistent, reproducible, auditable, and reliable laboratory results that support clinical trials will be produced in an environment conducive to study reconstruction.

   In the U.S, annual audits are currently performed at Peripheral Blood Mononuclear Cells (PBMC) processing laboratories that participate in DAIDS Vaccine clinical trials. Additional laboratories are being added to this list on an on-going basis.

   DAIDS reserves the right to conduct for-cause or ad-hoc audits at any of the U.S. laboratories participating in DAIDS Clinical Trials.

   After an audit, performed by DAIDS or PPD, an audit report will be distributed to the laboratory. The laboratory is responsible for working with DAIDS to resolve the audit report findings. These audit report findings must be adequately addressed by the laboratory to maintain a satisfactory performance standard.

   For the types of audits performed and the report resolution process please refer to the GCLP Lab Audit Information Document (PDF).

   Please email DCLOTInfo@niaid.nih.gov for inquiries about the DAIDS-sponsored GCLP audit and report resolution processes.

8. Instrument and Method Validation

   DAIDS requires all laboratories to perform validation prior to implementing a new method or instrument for routine use, whenever the conditions change for which the method has been validated or if the change is outside the original scope of the method. If non-approved methods are considered, these must be validated in a study that compares a proposed method to a FDA-approved method. For For information on guidelines for conducting a validation study refer to the GCLP standards/guidelines (PDF).

9. Comprehensive Laboratory Plan. This is required for applications in response to the PAR-05-113 ‘NIAID Clinical Trial Implementation (U01) Cooperative Agreement’. The application must include a Comprehensive Laboratory Plan that contains the following:

9.1. For requirements described in Section 1.0 above (laboratories that are CLIA certified), please include the following in the Comprehensive Laboratory Plan:

9.1.1. Proof of laboratory accreditation/certification

9.1.2. A spreadsheet that lists all the tests that will be done for the trial, all the laboratories in which these tests will be done, and the external QA providers and PT surveys that will be used to monitor each test. The template is provided for your convenience as an example of how this information can be provided, see Protocol Analyte list template (Excel). You may modify this as appropriate

9.2. For requirements described in Section 2.0 above, please include the following in the Comprehensive Laboratory Plan:

9.2.1. A list of the RUO and or IUO tests

9.2.2. Test SOPs, for tests listed in 9.2.1 above, in a format that includes information about test principle, specimen requirements, reagents, supplies and equipment, procedure, calculations, quality control, procedural notes and references

9.2.3. Complete identifying information for the laboratories that will perform tests listed in 9.2.1 above (e.g. name of lab, geographical location, telephone number, email address)

9.2.4. A description of the proposed existing or alternative external PT measures undertaken for each test in each laboratory

9.2.5. A copy of the index of the laboratory’s QMP; not needed if the laboratory is CLIA-certified

9.3. For requirements described in Section 3.0 above, please include the following in the Comprehensive Laboratory Plan:

9.3.1. The study-specific Specimen Management Plan

9.3.2. Proof of training in IATA shipping regulations (certification) if specimen shipments are planned for the trial

9.4. For requirements described in Section 4.0 above, please include the following in the Comprehensive Laboratory Plan:

9.4.1. The study-specific laboratory data management plan

9.4.2. A description of the testing that was done to ensure that data flow smoothly and maintain integrity from the point of acquisition to the study database

9.4.3. Proof of 21 CFR Part 11 compliance if available

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