Getting Started in Clinical Research

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 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. 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 an FDA form 1572 (statement of investigator). 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 present a completed form, 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. The Office of Grants and Contracts signs these agreements and can 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.

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 support investigator-initiated protocols. Many clinical research studies can be funded by routine K- or R-series awards. There are special considerations, however, for studies that are defined as clinical trials (see NIH definition). Some NIH Institutes and Centers fund Clinical Trial Planning Grants(R34) to prepare for Phase III trials. Full trials are funded via a different mechanism, such as a clinical U01. Institutes have varying policies on the investigator-initiated research they will accept. See, for example, NHLBI and NIAID web sites on clinical awards. 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 (IND) or Investigational Device Exemption Application (IDE) with the FDA. The Clinical Research Office can assist with assessing the need for an IND/IDE. The faculty sponsor of an IND/IDE is responsible for meeting all monitoring and reporting to the FDA on all studies initiated under that approval. For faculty who sponsor studies at sites other than UVa, the Clinical Research 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. The University requires that corporate sponsors of research contracts publish their clinical trials on a public site such as ClinicalTrials.gov (as does NIH, for trials under its support).  Furthermore, U.S. Public Law 110-85 requires that the sponsor of an IND/IDE or PI register all trials of drugs and biologics subject to FDA regulation (other than Phase 1) and trials of devices (except for small feasibility and pediatric postmarket surveillance) and post information on results of those trials.  The Clinical Research Office can assist with posting a study on ClinicalTrials.gov.  Finally, 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.
• Source of study 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 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, case report forms), 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, clinical research coordinators, and IRBs are involved.

The Principal Investigator is responsible for:

• assuring that the study budget is adequate for the planned studies, including required payments to the Medical Center and providers of the various clinical services;
• obtaining IRB approval of the study protocol prior to initiating research, and any subsequent modifications to the study protocol or forms before initiating any changes in study procedures;
• submitting required progress and adverse event reports to the IRB;
• 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 IRB and UVA Conflicts of Interest (COI) Committee of existing financial COIs and newly-occurring COIs through the end of the study.

Clinical research coordinators are responsible for:

• managing the conduct of clinical trials, under the direction of the PI;
• maintaining in-depth knowledge of protocol requirements and Good Clinical Practice as set forth by federal regulations;
• providing the following:
  • sound conduct of the clinical trial per protocol, from recruitment through follow-up;
  • 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.

The investigator must recover all study costs.  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 Research Office can assist in the development of 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 guidance on budgeting for a clinical trial.

The PI 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 Research Office provides assistance with development of a billing plan delineating which study procedures and interventions 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.

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 in the various clinical departments of the School of Medicine.

The Clinical Research Office conducts continuing education programs for both clinical investigators and CRCs, including an annual series, “brown bag” sessions, mentoring of CRCs, and link to the NIH Clinical Center’s video series, “Introduction to Principles and Practices of Clinical Research.”

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.

The Medical Center’s Investigational Drug Service supports clinical research research (including randomization, blinding, preparation of placebos, storage and inventory of medications, etc.).  These services are provided at cost to the investigator.

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. Jae Lee (982-1033, jkl7n@virginia.edu) for additional information.  The Division also has posted on its Web site a request for biostatistical services form.

SOM core facilities provide subsidized services at reasonable cost to University users; for clinical investigators, these might include flow cytometry, DNA sequencing, or the biorepository and tissue research facility.  Certain research centers and complex NIH research awards provide additional cores to support patient-oriented research.

UVA IRBs conform to federal restrictions on what can be included in advertisements.

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 ClinicalResearch Office to ensure quality of study results, protect subject safety, and to maintain statutory and regulatory compliance.

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.

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.  See a broader discussion of this topic on this 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. 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. Refer to the SOM policy on authorship and to the UVA Research Misconduct Policy, which covers data integrity.
• Conflict of interest (COI). Clinical investigators 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. Refer to this 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 Policy, ” Payments for Referring or Enrolling Patients in Clinical Trials“): 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).

Several committees and offices are charged with compliance oversight of clinical research.  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 Research Office can provide on-site mentoring of 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, which may take several hours to complete.  This training must be completed before the IRB will approve a study.  Incoming faculty may complete this training before arriving at UVA, to expedite subsequent protocol submission.
• Institutional Biosafety Committee 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 IBC training for bloodborne pathogens.  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 on shipping infectious substances.

2.  Once the protocol has been developed:

• Budgeting.  The investigator is responsible for assuring that the 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. Physician providers cannot negotiate charges for Medical Center procedures.  Charges for Medical Center services will be billed to the study, based on a fixed formula for the cost of the service.  The Clinical Research Office can help generate an appropriate budget for these services.  The PI must also assure 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 sponsor.  The Clinical Research 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, via your department administration, to Grants and Contracts. Although not all the information requested on the 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 Conflict of Interest Disclosure 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 (see https://ehs.virginia.edu/Biosafety-IBC.html).  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/IDE 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 Research Office can help assess the need for an IND/IDE.

3.  Navigating the review committees:

• Cancer trials.  If the study involves cancer patients, 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 at least three weeks before the next scheduled meeting.  See Protocol Review Committee guidance.
• IRB review.  Studies involving human subjects must be approved by the IRB.  Protocols must be submitted on forms generated by the IRB Protocol Builder.  See IRB guidance.  The protocol must be submitted for pre-review at least 5 days before the full submission deadline.  IRB meetings are scheduled every two weeks; submission deadlines are approximately 8 days prior to each meeting.

4.  Once you have IRB approval:

• Submit the signed IRB approval (Form 310) to Grants and Contracts to allow the study agreement to be signed.