An ophthalmologist considering clinical research activities should realize that they're significantly different from the treatment and care of patients during the normal course of practice. The benefits are real, such as bringing new products and procedures to patients, experiencing cutting-edge medicine, participating in a scientific inquiry and generating some additional income for the practice, but there are compromises, too. This article enumerates the considerations that should be made before deciding to conduct a clinical study.

Regulatory Responsibilities
The U.S. Food and Drug Administration Form 1572 outlines the legal and ethical responsibilities of any investigation regulated by that agency. The pharmaceutical or device manufacturer sponsoring the study will also re-quire an ethics contract signed by all parties involved in conducting the study. The overriding concern of everyone involved is the safety and welfare of the participant who's taking the risk of testing a drug or device. Serious legal ramifications exist for the physician/investigator who doesn't conduct the study properly or adequately protect the rights and welfare of the participants. While ethical investigators don't knowingly risk their practice and reputations to deliberately harm a participant, some do so unwittingly because of a lack of experience or expertise. Clinical research is complex and time-consuming. Acknowledgement of this and fam-iliarity with the basic principles of human subject protection will serve any physician well as he assumes the role of clinical investigator.

Clinical Issues
While ophthalmologists are accustomed to treating eyes as the organ of primary focus, in a clinical study, the physician must observe and evaluate the patient's whole system. If an ad-verse event occurs, the investigator must report on the status of the person's well-being in totality, paying at-tention to the possible causality of the incident. An eye drop, for example, may result in rash, hypertension or any number of side effects that have to be evaluated objectively. The investigator may have to obtain medical records from the participant's primary care physician as part of the reporting of the adverse event.

The protocol's specifications will indicate how to determine the start date of the adverse event—not the investigator's assumption or opinion. For example, if intraocular pressure increases, the start date may be the date extra drops were required, the date the event became sight-threatening or the surgery date. Reading and understanding the protocol is extremely important in a clinical study. Protocol amendments are important sources of additional safety and study management information.

Patient Appointment Times
Realize that screening visits to determine an individual's eligibility to participate in a study will take longer than the average appointment. Depending on the study, the investigator may be required to review or complete most if not all of the following: inclusion/exclusion screen, physical exam, ancillary testing, medical history, diaries and/or scales. He will also need to review the participants' commitment and understanding of the clinical study. These tasks can take from 30 minutes to an hour or more.

Some clinical studies require the investigator or subinvestigator to see the participant at every visit; others may permit the nurse/coordinator to conduct the visit. In any case, the principal investigator and/or subinvestigator will have to review the documentation. The average visit may fit into the typical 15-minute patient schedule. However, for more complex studies, the study visits can take up to three hours or more, depending on the testing involved.

Administrative Time
Another part of the principal investigator's obligation in conducting a clinical study is being available for meetings and consultations with the pharmaceutical company or its representatives (monitors) during the study. This may include an initial introduction visit, initiation visit and availability during the study for meetings with the monitor. Each of these meetings may take an hour or longer.
Almost every study has an investigators meeting associated with its start-up. This meeting will be at a hotel or resort, usually over a weekend and will take one to two days of the physician's time and up to three days for coordinators, raters or blinded pharmacists. Attendance at these meetings is extremely important. Scientific and study-specific details are reviewed. The pharmaceutical companies closely monitor the research team's interest and attention because they want to know that their multimillion-dollar study is in capable and committed hands.

Some studies will require a one- to three-day wet lab or training sessions for investigators. This may coincide with the investigators meeting but could be a separate session.

The investigator should also expect phone calls from the medical monitor of the study, project manager or other individuals who are concerned about the progress of the enrollment efforts or the participants in the study. The institutional review board for the study may also want to visit during the trial.
Another unanticipated aspect of a study is the time spent in reviewing documentation, data clarification queries, ancillary exams and laboratory results. The physician should also be prepared to review and sign-off on the correspondence that the study generates. Other areas that will need attention are:

• Contract and budget review and negotiations;
• Regulatory document preparation and submission;
• Regulatory document maintenance;
• Source documentation training and set-up; and
• Patient recruitment tools.
The principal investigator should carefully consider and plan who will be responsible for these activities prior to study start-up.

Certification of staff or training on equipment may have to be completed before a study can commence. Fundus photography, for example, may have to be done by a certified photographer. An investigator should look into the costs of hiring the necessary staff for a study before agreeing to a budget.

Getting Involved with Research

Consider these facility needs you may need to satisfy:

• Case report forms, source documents and regulatory binders are required to be kept in a secured, locked location.
• Study medication has to be kept in a locked cabinet in a locked office or space that is climate-controlled. Temperature and humidity control is important to the stability of many compounds. Temperature logs must be kept to document the stability of the environment.
• There should be an office for coordinators to work on study documentation; this material cannot become mixed in with office charts.
• Provide a designated space for monitoring visits, which can take from one to four days.
• Have a dedicated fax machine available.
• Provide a computer for correspondence and study-related tracking and
metrics (enrollment, pending work, etc.).
• Install extra modem lines for remote data entry and monitor visits.
• Create a laboratory area or make arrangements to share a lab space and staff.
• Contract with an answering service or pager for 24-hour coverage.

The amount of time and energy that clinical studies require should not be underestimated. This is not an activity that can be done in a technician or nurse's "spare time." Case report forms and source documentation should be completed at the time of the participant's visit or shortly thereafter. Therefore, the coordinator of the study must devote adequate attention to this time-consuming and demanding task. Without careful documentation, the study results are worthless.

Some studies will require that the office or laboratory adopt standard op-erating procedures that will provide some consistency between testing sites or offices. Equipment or supplies that a physician normally uses may not be permitted by the study. Although the sponsor usually will supply this material, the office and clinical staff may have to be trained to use new techniques and materials. Calibration of equipment and standardization of practice among all sites in a study is very important to results. A central laboratory may be mandated. Staff will have to comply with the instructions the laboratory provides for testing, handling and shipping samples.

Staff will also have to be trained to ship hazardous material since sponsors and investigators are required to comply with federal shipping regulations.

Conducting clinical studies de-mands space. This activity will not fit into a corner of a physician's office. Since participant visits take more time, trying to juggle regularly scheduled visits with study participants may be difficult. A dedicated exam room is ideal. Laboratory space is necessary to draw and process blood. A room for monitors and auditors is needed where they can spread out bulky case report forms, medical records and source documentation. Many study monitors travel with laptops and need modem lines, faxes and a telephone. The notebooks where the participants' visits are recorded (case report forms, or CRFs) are large. There are numerous other files, notebooks and documents, supplies and equipment that need to be maintained during the study (See sidebar). All of these materials should be kept, ideally, in a locked office or cabinet to protect the sponsoring pharmaceutical company's confidential material.

Audits and Continuing Education
For studies that are particularly important to pharmaceutical sponsors, it is not unusual to have an audit during the course of the study. The investigator is expected to make time to meet with the auditor(s), be available for questions and participate in an exit interview at the end of the audit. An FDA audit may also occur during or after the study. FDA audits can take from two days to many weeks. The investigator should plan to be available during regularly scheduled office hours for the FDA auditor.

As the practice gains experience in conducting trials, it should probably institute an in-house auditing system to self-audit studies. An in-house system serves to catch errors before the monitor discovers them, providing better customer service to the pharmaceutical company. More importantly, such a system lets you quickly identify issues that could impact participant safety, such as dosing issues, concomitant medication errors and other concerns. This self-auditing function is one that physicians new to research should take on themselves in the first few studies they conduct, especially if the nurse/coordinator is new to research as well.

Many physician assistants, nurse practitioners, nurses, technicians and medical assistants are introduced to clinical research by the "learn by doing" method. This means that they are asked to be study coordinators without any training or preparation. While there is some merit to this method, it leaves a lot to be desired from the pharmaceutical company's viewpoint. A well-trained, experienced research team is preferred and will result in a better use of the monitor's time. More importantly, an experienced team serves participant safety better.
Gaining experience in clinical studies may be best accomplished by taking on a Phase-IV or post-marketing study. These studies tend to be less challenging and will give a novice investigator a chance to see if the fit is right before investing the time, energy and resources into a more complex study that may pose risks to both patient and physician.

Getting started in clinical trials requires much homework. But, for the physician who already puts great ef-fort into the clinical care of his patients, the transition to researcher will be an easy one. 

Patricia Seymour, MA, CCRC, CIP, and Maria Kerwin, BS, may be reached at Kerwin Seymour Research Services, Inc., (401) 349-0400. The authors extend their thanks to Lisa Scholz of Bausch & Lomb, Tampa, Fla., for her insights and expertise.