Article

A step-by-step guide to clinical trials

Participation is a marathon, not a sprint, say these veterans.

Implementing clinical trials in your ophthalmology practice can be very rewarding for both you and your patients. The main benefit is that you can offer your patients new and upcoming treatments for their diseases. There is also the advantage of being current on cutting-edge solutions in your specialty.

As a medical student, Dr. Khanani designed several prospective trials and, during his fellowship, he was involved in pivotal Phase 3 trials, an experience that provided insight into what is required to participate in clinical research. But, later, when he joined a multispecialty practice, there was no clinical research unit. We slowly started to invest in developing one, and our first trial was an industry-sponsored investigator initiated trial (IIT). Currently, on average, we participate in 10 concurrent trials.

While these experiences have been personally and professionally enriching, participating in clinical trials is also demanding. A good clinical research program needs a committed principal investigator (PI) who is willing to be very involved with the research staff and patients. Above all, a PI must make a significant time commitment. The PI is ultimately responsible for the oversight, conduct and integrity of the data collected at the site. If the clinician cannot commit the time necessary to perform clinical research, it is wise not to get involved.

The requirements don’t end with time. Read on as we walk you through what it takes to perform successful clinical trials.

WHAT TO KNOW BEFORE YOU APPLY

Patients and pathology

A busy clinic with daily new patient referrals showing a variety of pathology is essential for clinical research. Most clinical trials require a naïve patient population, which is why having two to three new referrals daily is important. When we started our clinical research unit, we saw approximately 40 patients a day, with two to three of them new patients. Naïve wet AMD, DME and RVO patients are needed for most retina trials. Some trials require dry AMD and uveitis patients. If the clinic is not busy, the number of patients eligible to participate in a trial will be low, so it may not be worth the effort to participate in research.

The linchpin

Once a practice clears those thresholds and decides it wants to participate in a trial, the most crucial thing is to have well-trained and experienced research coordinators. The success of the clinical trials unit depends heavily on good coordinators, as they deal with all the regulatory and protocol-specific paperwork.

Research coordinators perform the following duties:

  • Submit institutional review board (IRB) applications.
  • Fill out the FDA 1572 form.
  • Gather site CVs and medical licenses.
  • Ensure each team member has appropriate certification(s).
  • Keep track of investigational product (IP).
  • Schedule protocol training.
  • Monitor visits and site initiation visits with the trial sponsor.

Research coordinators also conduct study-related procedures, including consenting, blood draws, specimen shipment, EKGs, medical history collection, adverse event information collection, record patient blood pressures and future visit scheduling. In addition, a good coordinator can run multiple trials at the same time.

Finding a good research coordinator can be difficult — sometimes it even requires a national search. They can be found on health-care job websites, but Dr. Khanani has trained his own coordinators, since it’s hard to recruit a good one. For those sites that train an experienced technician to be a coordinator, be warned: This requires significant commitment for the technician’s education and training.

Have everything spelled out

The site needs to have standard operating procedures (SOPs) in place. SOPs should include:

  • How the site consents patients.
  • How safety documents are distributed.
  • How the site staff are trained.
  • How often the equipment is calibrated.
  • Where medication is stored.
  • Where/how the blood draws are conducted.
  • Where specimens are stored.
  • When specimens are shipped.

Trial sponsors will informs the site if they want a specific SOP. All studies require basic SOPs, which must be developed by the site. If the sponsor requires a new SOP, the site has to come up with the details.

Staff and certification

Every member of the study team needs to have Good Clinical Practices (GCP) and NIH Human Subjects Protection Training. A site also needs certified staff members who can perform vision testing using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, imaging, lab draws and specimen handling. Labs must be certified by the state, while specimen handling certification can be obtained by online IATA training. Each study requires a different entity of certification; there are several ETDRS companies and reading centers. The site has to bear the expenses of these initially if they don’t have any trials.

Additionally, staff training for the tasks listed above GCP and NIH training can be completed online. Protocol training for each study is performed by the study monitor or the PI.

Photographers are another necessity. They must be certified by a trial Central Reading Center and must be able to perform high-quality optical coherence tomography (OCT), fluorescein angiography, fundus photos and fundus autofluorescence (more on those, below).

Equipment

The expenses of participating in a clinical trial don’t end with personnel: An investment in equipment for clinical research is necessary, too. A site needs:

  • A locked refrigerator with an alarmed thermometer.
  • A -20°F freezer.
  • An EKG machine.
  • A centrifuge.
  • A blood pressure cuff.
  • A weighed scale.
  • A certified procedure room for blood draws.
  • A certified ETDRS room and ETDRS testing equipment.
  • Locked cabinets.
  • Ample space to store study-related documents and IP.

In addition, imaging equipment, including OCT and fundus/fluorescein angiogram camera, must be certified and sometimes upgraded to meet the specifications required by a study-specific reading center.

HOW TO GET PICKED

Once you are prepared to participate in a clinical trial, the next challenge is to be selected. Major contracted research organizations and pharmaceutical companies usually don’t get a new site involved unless they are aware the site has good staff and an excellent track record. To get on their radar, the PI has to contact them and show interest.

An IIT is a good way to do so, enabling a site to demonstrate that its research operations are in good shape. Also, major pharmaceutical companies will sponsor interesting IIT/IST from enthusiastic investigators.

Another challenge to getting selected: The imaging equipment and photographer cannot be certified at a clinical research site unless they are participating in a trial.

BCVA technicians also need to be certified; however, that can be done by hiring a third party even without participating in a clinical trial.

YOU ARE SELECTED — WHAT NOW?

Congratulations — and more paperwork

If a clinical trial is offered to a site, it must fulfill multiple steps before the trial can start. The first step is a confidentiality agreement (CDA) between the sponsor and the clinical trial site. The investigators and the site personnel must keep everything related to the trial confidential.

Once a CDA is in place, a feasibility questionnaire needs to be filled out. This helps the sponsor gauge if the site has the right staff, equipment and patient population for its specific clinical trial. It is always good to be conservative in terms of predicting patient enrollment, as this helps the sponsor set recruitment goals. If a site overestimates the number of patients it can enroll, this can result in slow recruitment for the clinical trial, which in turn reflects poorly on the site.

After the feasibility is done, the sponsor will usually schedule a pre-study visit (PSV) to any new site. The sponsor’s goal is to look at the facility, equipment, staff and other resources required for successful participation in the trial.

Once the PSV is performed and the decision to select a site is made, the contracting process starts. The sponsor usually has an assigned person to negotiate the contract with the site. The sites are expected to estimate all the associated costs to run the trial at a fair market value.

How to get — and keep — enrollees

Once a site begins a clinical trial, recruitment and retention are crucial for the success of the research department. All the physicians and the research staff should actively look for potential patients to enroll. A weekly reminder about enrollment and a meeting to discuss steps to improve recruitment are helpful. Giving note cards with inclusion/exclusion criteria for each study to all the physicians in the practice can be effective. Sponsors often support referral dinners as well, which can be very useful to notify physicians in the community about the study.

To retain patients, positive, clear communication is critical. At our site, the physicians identify the patients for the studies and discuss the risks and benefits in detail with them. We usually hold these discussions with the patient during the clinic visit to avoid inconveniencing them with another visit. We spend a lot of time answering all questions, and we give them a summary of the study that’s provided by the sponsor. We assure them that they will be treated with great care and attention and that most sponsors will provide transportation and patient stipend for their time. We also inform patients that we do blood work and other protocol-related testing to keep a close eye on the health of the whole body and to carefully monitor adverse events.

The clinical trials staff at Sierra Eye Associates. Standing, left to right: Amir Aziz; Margo Lewis; Nazrul Mojumder; Valery Cervantes; Mirna Garcia; Arshad M. Khanani, MD, MA; Brooklin Hall; Heather Southwick; Tiodora Lopez; Joshua Stoycoff. Sitting Left to right: Sylvia Arrona and Deanna Dorman.

After this discussion, if the patient decides to participate, the research coordinator is introduced and the patient is sent home with a consent form to have ample time to review. The clinical trial screening is scheduled for a separate date.

Research coordinators are the face of the trial at any site — in addition to the other duties they perform. As they collect the majority of the information, they are the staff members with whom the trial patient will be in close contact throughout, so trust is essential. The coordinator must be someone with whom patients feel comfortable.

Despite the research coordinator’s close involvement with patients, the PI should take time to thank each one for participating in the study at each visit as well. The PI should also update patients on their respective disease status and answer all their questions. These practices help ensure excellent patient retention in the clinical trials.

TEAM EFFORT REQUIRED

Participating in clinical research is a very rewarding experience for a site as well as the patients.

An enthusiastic PI and organized research coordinators are crucial to have a successful clinical research program. In addition, a site needs to invest in staff training, certifications and equipment. The start-up costs of all this are admittedly significant. The whole team has to be committed to the research program for it to be productive. OM

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