Getting Started in Clinical Research
Summary and quick links
What is clinical research?
General issues concerning clinical research
What is Good Clinical Practice?
Industry-initiated clinical trials
Investigator-initiated clinical research
Responsibilities in clinical research
Funding and initial approvals
Funding sources for clinical research
Preparing budgets and billing for clinical trials
Development and submission of human use protocols to the IRB
Training for investigators and clinical research coordinators (CRCs)
Personnel, space, and other resources
Hiring clinical research staff
Coordinators and clinical space for investigator-initiated research
Pharmacy services
Biostatistical support
Finding UVA collaborators: the Research Faculty Directory
Accessing SOM/UVA research core facilities
Conducting your research
Recruiting research subjects
Quality assurance and monitoring activities
Conducting retrospective research using Medical Center patient data
Management and integrity of research data
Regulatory issues
Environmental health and safety
Responsible conduct of research
Navigating the regulatory compliance requirements at UVA
Industry-initiated clinical trials. The majority of clinical studies conduced at the SOM are industry-designed and -sponsored Phase 1 to Phase 3 clinical trials, with the ultimate goal of FDA product licensure. The investigator's role in these studies varies considerably. Most of these studies are multicenter studies that follow a protocol developed by the sponsor with little intellectual input by the investigators. At the other extreme are single site studies where the investigator plays a primary role in the design as well as the execution of the study. The process associated with industry-initiated studies follows this general schema:
- Individual faculty can contact a company directly; alternately, the sponsor or its contract research organization (CRO) will inquire if an investigator wishes to participate in a planned study.
- Because company product development plans are confidential, the PI must sign a confidentiality disclosure agreement (CDA) before being sent a full protocol for consideration. If you receive a CDA, review it and forward it to SOM Grants and Contracts, which negotiates and signs such documents.
- The company will provide a protocol synopsis and a feasibility questionnaire for the faculty to review and complete. The Clinical Data Repository may be useful for assessing the patient population available for potential participation.
- The company may conduct a preliminary site visit or hold an investigator's meeting to discuss the project in greater depth.
- The PI must submit the protocol for review and approval by the IRB. If the research is being performed under the auspices of the UVA Cancer Center, its review committee must approve, as well. If the project will be performed in the General Clinical Research Center, its scientific review will be required. Please note that a clinical trials agreement with the sponsor may not be signed and recruitment and clinical activities cannot take place prior to IRB approval.
- The sponsor will ask the PI to complete a statement of investigator form (1572, http://www.fda.gov/opacom/morechoices/fdaforms/CBER.html) required by the FDA. Note that by signing this form the investigator assumes responsibility for all aspects of the conduct of the study at the UVa site. In most cases the sponsor will complete this form and present it, along with a financial disclosure statement, to the investigator for signature.
- The clinical trials agreement is a binding contract defining the study to be undertaken, remuneration, reporting, intellectual property, confidentiality, publication rights, etc. SOM Grants and Contracts signs these agreements and provide a sample agreement. The F&A rate on clinical trials is 25% of total direct costs.
- Representatives of the sponsor hold a study initiation meeting with the PI and his/her team to walk through the study protocol prior to initiation of recruitment. This ensures that the latest, approved versions of protocols, consent forms, and case report forms are understood and used appropriately by all parties.
- Study initiation, conduct, and close-out.
Investigator-initiated clinical research. Initiating one's own clinical research project provides greater flexibility but comes with greater responsibilities. A brief outline of these, with resources for help on each, follows:
- Funding. NIH and the corporate sector both support investigator-initiated protocols. Many clinical research studies can be funded by routine K or R01 awards. There are special considerations, however, for studies that are defined as clinical trials (see NIH definition). NIH funds Clinical Trial Planning Grants to prepare for Phase III trials (R34s: certain Institutes and Centers only). A full trial would be funded via a different mechanism, such as a clinical U01. Institutes have varying policies on what types of investigator-initiated research they will accept. See, for example, NHLBI, NIDCD, and NIAID Web sites. Industry supports investigator-initiated projects that are in concert with the existing development pathway for one of their products or that test innovative uses of an existing drug.
- Intellectual property. Inventions generated in the course of an investigator-initiated trial are the property of the University and subject to its Patent Policy.
- Regulatory requirements. In addition to the mandatory approvals for all clinical research, investigator-initiated trials must satisfy the following:
- IND Application and reports to FDA. If the trial involves the administration or implantation of a drug, biologic, or device in a manner or for an indication that is not FDA approved, the PI may have to file and maintain an Investigational New Drug or Investigational Device Exemption Application with the FDA. The Clinical Trials Office can assist with assessing the need for an IND/IDE. As sponsor of an investigator initiated IND, the faculty member is responsible for meeting all monitoring and reporting to the FDA on all studies initiated under his or her IND/IDE. For faculty who sponsor studies at sites other than UVa, the Clinical Trials Office can assist with monitoring services at remote sites. The cost of this monitoring must be included in your study budget.
- Publication of the protocol on a public Web site such as ClinicalTrials.gov. The University requires that corporate sponsors of research contracts publish their clinical trials on a public site. NIH encourages that all trials be listed. Furthermore, U.S. Public Law 110-85 (eff. 10/27/07) recently expanded the requirements for clinical trials registration. Specifically, the sponsor of the IND/IDE or PI must register all trials of drugs and biologics subject to FDA regulation (other than Phase 1) and trials of device (except for small feasibility and pediatric postmarket surveillance). The information that must be posted also has been expanded, now including results information. Click here for the full text of PL 110-85. The Clinical Trials Office can assist with posting a study on ClinicalTrials.gov. UPDATE: The International Committee of Medical Journal Editors has mandated that all Phase 1 clinical trials published in their journals must be registered at a public site, effective July 1, 2008.
- Obtaining drug, if an unlicensed product. The mode of manufacture, testing for purity/adherence to specifications, and packaging of drugs, biologics, or devices must be described in the IND/IDE Application. These activities generally are performed under Good Manufacturing Practice (GMP), often by an outside contractor.
- Project management. The PI must develop a Manual of Procedures, study documents (protocol, consent, CRFs), Data Safety Monitoring Committee, reporting procedures for adverse events, etc. These administrative requirements vary depending on whether the clinical research meets the definition of a clinical trial and are even more demanding for multi-center clinical research projects, where several PIs, CRCs, and IRBs are involved.
Responsibilities in clinical research.
The Principal Investigator is responsible for
- assuring that the study budget is adequate for the planned studies including payments to the Medical Center and providers of the various clinical services that may be required by the study;
- obtaining IRB approval of the study protocol prior to initiating research and approval of any subsequent modifications to the study protocol or forms, before initiating any changes in study procedures;
- submitting progress and adverse event reports to the IRB as required;
- ensuring that all members of the research team follow Good Clinical Practice (see below) and comply with IRB requirements;
- compliance with federal regulations such as HIPAA, use of hazardous materials, etc.;
- assuring that clinical charges are billed appropriately to third party payors as standard of care or to the study funds as research;
- notifying the UVA Conflicts of Interest (COI) Committee of financial COIs and newly-occurring COIs through the end of the trial.
Clinical research coordinators are responsible for (cf. Clinical Trials Office "Human Subjects Research Guide"):
- managing the conduct of clinical trials, under the direction of the PI;
- maintaining in-depth knowledge of protocol requirements and Good Clinical Practice (GCP) as set forth by federal regulations;
- providing the following:
- sound conduct of the clinical trial per protocol, from recruitment through follow-up of subjects;
- meticulous maintenance of accurate and complete documentation (e.g., regulatory documents, signed consent forms, IRB approvals, source documents, drug dispensing and subject logs, and study-related communication);
- organizational management of the trial (e.g., timeliness in completing case report forms, data entry, reporting adverse events [AEs], and managing caseload and study files);
- communication of protocol-related problems to all study staff and PI (e.g., questions regarding the conduct of the clinical trial, possible AEs, or subject compliance);
- professional conduct in the presence of subjects, research staff, sponsors, monitors, auditors, etc.
Funding sources for clinical research. The Clinical Trials Office (924-8530, uvaclintrials@virginia.edu) can match clinical faculty with industry sponsors seeking clinical trial sites.
Preparing budgets and billing for clinical trials. The investigator must recover all of the costs of his or her study. Rarely, due to the scientific importance of a particular study and the existence of local funds to make up the shortfall, an investigator may choose to participate at a financial loss. The Clinical Trials Office can help investigators develop study budgets. Its personnel have access to current hospital laboratory charges and knowledge of a variety of costs that may not initially be apparent to new PIs. See their SOP on Preparation of a Clinical Trial Budget (SOP #20.04).
The Principal Investigator must ensure that all billing for costs incurred in the conduct of clinical studies is appropriate and in compliance with relevant laws and regulations. Clinical protocols may include both standard-of-care and experimental activities (i.e., not medically necessary or known to be effective). Standard-of-care procedures may be billed to government or private insurers or to the subject, except when the sponsor has agreed to cover those costs. In general, activities that are purely experimental may not be billed to Medicare, Medicaid, other third party insurers, or the research subject: these are the responsibility of the sponsor. (Rarely, per law or regulation, costs for experimental activities required for a clinical trial may be billed to a third party or to the subject, if they are not reimbursed by the sponsor.)
The Clinical Trials Office provides assistance with development of a billing plan delineating which procedures and interventions to be performed during the clinical study are standard-of-care vs. investigational, and who (sponsor, insurer, patient) will be financially responsible for each. In addition, the CTO can assist with properly budgeting for those interventions that will be billed to the study budget.
Development and submission of human use protocols to the IRB. Protocols are submitted to the IRBs via an on-line system. The IRB offers help in protocol development, either directly or through IRB support personnel who are located in the various clinical departments of the School of Medicine.
Training for investigators and clinical research coordinators (CRCs). The Clinical Trials Office "Training and Education" Web page describes initial and continuing education programs for both clinical investigators and CRCs. These include an annual continuing education series, "brown bag" continuing education sessions, mentoring of CRCs, and link to the NIH Clinical Center's video series, "Introduction to Principles and Practices of Clinical Research."
Hiring clinical research staff. CRCs and clinical research managers are hired through UVA Human Resources, in the "Health Care Compliance Specialist/Manager" or "Registered Nurse (Inpatient Research)" series, with the assistance of their department HR representative. These positions are described at the HR Web site.
Coordinators and clinical space for investigator-initiated research. Many units at the School of Medicine maintain their own clinical research units (e.g., Nephrology, Surgery). For investigators in other units, the Clinical Trials Office has a small number of clinical research coordinators and clinical research rooms that can be used on a fee-for-service basis.
The General Clinical Research Center provides the following resources for investigators: research nursing services, research subject advocate, biostatistics/biomathematics expertise, an exercise physiology laboratory, a core assay laboratory, a sleep research laboratory, a metabolic kitchen, and an informatics core. Investigators wishing to use the resources of the GCRC should submit their protocol to the IRB-HRS on-line system, which includes the GCRC Protocol Template. The protocol must be approved by the GCRC Advisory Committee prior to submission to the IRB. GCRC review is initiated by e-mailing the protocol template and consent forms to GCRCprotocols@virginia.edu. (On the horizon: the University has applied to NIH for a Clinical and Translational Research Award (CTSA) to support facilities and personnel for patient-oriented research. The CTSA will include "soup-to-nuts" support for new clinical investigators to help ease the transition to clinical or translational research.)
The UVA Cancer Center provides support to investigators in the design and writing of protocols, recruitment of patient subjects, and data safety monitoring. See their "Opening a Clinical Trial at U.Va. Cancer Center" for additional information, including review by the Center's Protocol Review Committee.
Pharmacy services. The Medical Center's Investigational Drug Service can provide several services in support of clinical research studies, including randomization, blinding, preparation of placebos, storage and inventory of medications, etc.
Biostatistical support. The Division of Biostatistics & Epidemiology (Dept. of Public Health Sciences) can help with study design, development of analytic plans, and analysis of pilot and clinical study data. Contact Dr. Mark Conaway (924-8510, mrc6j@Virginia.edu) for additional information. The Division also has posted on its Web site a request for biostatistical services form.
Accessing SOM/UVA research core facilities. SOM core facilities provide services at a reasonable cost to University users; for clinical researchers, these might include flow cytometry, DNA sequencing, or the newly instituting tissue biorepository. Certain research centers and complex research awards (Cancer, Diabetes, and Digestive Health centers, etc) provide additional cores to support patient-oriented research.
Recruiting research subjects. The IRBs conform to federal restrictions on what can be included in advertisements. See the Clinical Trials Office Orientation Manual (pages 71ff. and 176ff.) for regulations, examples of recruitment ads, and strategies for maximizing recruitment in your study.
Quality assurance (QA) and monitoring activities. QA includes the development and maintenance of Standard Operating Procedures (SOPs) for clinical trials, training of clinical research personnel in study methods and regulatory compliance, and assistance in preparing for FDA, sponsor, or internal audits. Monitoring includes the following: tracking of patient accrual; assessment of patient eligibility and evaluability (e.g., completeness and accuracy of study records); reporting of adverse events to IRB and other investigators (PI/CRC responsibility); and interim evaluation of outcome measures and patient safety information (often conducted by an independent Data Safety Monitoring Committee). The majority of these functions are provided by the Clinical Trials Office to ensure quality of study results, protect subject safety, and to maintain compliance with regulations and laws.
Conducting retrospective research using Medical Center patient data. The Clinical Data Repository (CDR) represents a collaborative effort by the Medical Center and School of Medicine to provide clinical investigators with data for retrospective studies such as health economics, outcomes research, etc. The repository permits access to inpatient and outpatient data, physician encounter data, clinical labs and microbiology, and Virginia Death Certificate data. The CDR acts as an "honest broker" to protect of patient privacy and confidentiality. Patient identifiers are encrypted or omitted prior to their provision to investigators.
Environmental health and safety. Use of recombinant DNA or pathogens in clinical research or handling of patient/subject specimens outside of the Medical Center clinical laboratories requires approval of the Institutional Biosafety Committee. Use of biological, chemical, or radioactive hazards in clinical research is overseen by, and requires training administered by and approval of the Office of Environmental Health and Safety.
Responsible conduct of research. In order to ensure that the public can trust research performed by UVA investigators, the highest standards must be maintained by its faculty and staff. This topic is discussed more broadly in another section of this Web site.
- Good Clinical Practice (GCP). GCP is a broad set of practices required by regulatory agencies (e.g., the FDA and the International Conference on Harmonisation) to ensure the quality clinical trials data that serve as the basis for licensure of drugs, biologics, and devices (see http://www.fda.gov/cder/guidance/959fnl.pdf). These guidelines include such activities as IRB procedures, minimizing risks to research subjects, investigator and sponsor qualifications and responsibilities, recordkeeping, and so on.
- Authorship and data integrity policies. The SOM currently is developing a policy on authorship. Until it is published, use these guidelines. Data integrity at UVA is covered by its Research Misconduct Policy.
- Conflict of interest (COI). Clinical researchers should carefully avoid the appearance of conflict of interest (COI) because of the participation of research subjects and the potential impact of this research on patient care or health policy. Financial interests of study staff or their families must not influence, or appear to influence, the design, conduct or reporting of any clinical research. When submitting a protocol to the IRB or a clinical research proposal to the Office of Grants and Contracts, the PI should notify these offices of any potential financial conflict. See this Web site for a more detailed description of COI policy and procedures.
- Incentive payments. UVA SOM employees may not accept the following types of incentive payments in the conduct of clinical trials (see SOM Repository, Policy 2.200): time/enrollment incentives (bonus for enrollment by a certain date); milestone-based incentives (payment when all forms have been submitted); or enrollment-based incentives (payment for a specific number of patients, rather than flat per-patient remuneration).
Navigating the regulatory compliance requirements at UVA. The compliance oversight of clinical research involves a number of committees and offices at both the School of Medicine and the University level. In many cases the review process is sequential, with action by one office contingent on prior approval by another. The process can be most efficiently navigated as follows:
1. General requirements that are not protocol-specific:
- Hiring a study coordinator. A well-trained study coordinator is not required for the conduct of clinical research but is strongly recommended. The requirements for regulatory compliance for human subjects research are complex and evolving. A study coordinator can help assure that these requirements are met and appropriate documentation is maintained. The Clinical Trials Office can provide on-site mentoring of inexperienced study coordinators.
- IRB training. All study personnel who will have access to human subjects or to research data from identifiable human subjects must complete the on-line IRB training modules (http://www.virginia.edu/vprgs/irb/training_citi.html), which may take several hours to complete. This training must be completed before the IRB will approve a study.
- IBC training. For studies that will collect or handle specimens from human subjects outside the clinical areas of the Medical Center, faculty and staff must complete appropriate Institutional Biosafety Committee training for bloodborne pathogens (https://vprgsecure.web.virginia.edu/bio/training.cfm). Bloodborne pathogens training for health care personnel provided by the Medical Center is not a substitute for the IBC training module. If biohazardous substances will be shipped, the individual(s) responsible must complete a specific training program (see https://vprgsecure.web.virginia.edu/bio/training.cfm).
2. Once the protocol has been developed:
- Budgeting. The investigator is responsible for assuring that the proposed budget is sufficient to fund all study related expenses. Budgets involving patients who may also be receiving non-research related care in the Medical Center or that involve purchase of clinical services from the Medical Center can be particularly challenging. Note that physician providers cannot negotiate the prices for Medical Center procedures (i.e., don't ask the radiologist how much your study will be charged for a chest x-ray). Charges for Medical Center services will be billed to the study, based on a fixed formula for the cost of the service. The Clinical Trials Office can help generate an appropriate budget for these services. Another challenge for studies that involve patients is the differentiation of standard of care charges (that may be legally charged to third party payors) from study charges that must be funded by the study. The Clinical Trials Office can also assist with this aspect of budgeting.
- Initiation of the study agreement for industry sponsors. SOM Grants and Contracts will not sign a study agreement without IRB approval. Negotiating the agreement can be quite time consuming, so it is prudent to start this process early. Initiation of this process requires that you submit a Proposal Approval Sheet/Goldenrod to Grants and Contracts. Although not all the information required for this form will be known at this point, complete as much as possible. Your Chair's countersignature on this form indicates his or her commitment to the time and space required to perform the study. The PI also must submit a Conflicts of Interest form and a Drug Study Questionnaire, if required.
- IBC registration. Your specific protocol must be registered with the IBC if specimens from human subjects will be handled in areas other than designated clinical space (https://vprgsecure.web.virginia.edu/ibc/). The IRB will not approve a study until the PI has received an approved registration from the IBC.
- Assessment of the need for an IND/IDE. If the sponsor does not already have an IND/IDE or if the study is investigator-initiated, an investigator-initiated IND/IND may be required. This will be required if the study uses a drug or device that is not already approved by the FDA or an FDA-approved drug or device in a manner in any way different from its approved use. The Clinical Trials Office can help assess the need for an IND/IDE.
3. Navigating the committees:
- Cancer trials. If the study involves patients with cancer it must be reviewed by the Cancer Center Protocol Review Committee before submission to either the GCRC (if applicable) or the IRB. The committee meets monthly and the protocol must be submitted in a form specified by the committee at least three weeks before the next scheduled meeting. Guidance is found on the committee Web site.
- GCRC review. If the study will use any GCRC resources, it study must undergo a scientific review by the GCRC Advisory Committee. This committee meets twice monthly. The proposal is submitted on the same forms as the IRB proposal. Guidance is provided at the GCRC Web site.
- IRB review. All studies involving human subjects must be approved by the IRB. Protocols must be submitted on forms generated by the IRB Protocol Builder. Guidance is available on the IRB Web site. The protocol must be submitted for pre-review at least 5 days before the full submission deadline. IRB meetings are every two weeks; submission deadlines are approximately 8 days prior to each meeting. These schedules are available on the IRB Web site.
4. Once you have IRB approval:
- Submit the signed IRB approval (Form 310) to the Grants and Contracts Office to allow the study agreement to be signed.