Boost Your Practice With Clinical Trials

Being an investigator enhances your reputation, differentiates your practice and improves patient care.

By Michael S. Korenfeld, MD

People enter the profession of medicine for a variety of reasons. Some are interested in the science of medicine, some enjoy the rigors of the hunt for the correct diagnosis, some seek the prestige and some are just people persons. Most choose medicine (at least in part) to have a “stable” and “secure” well-paying job.

I chose ophthalmology for all of those reasons, plus I enjoy microsurgery and the opportunity to innovate, which our profession has in abundance.

As it turns out, most of my reasons for practicing medicine are still available to me, but I must admit to becoming progressively less enamored with the incursion of insurance company policies and especially the government in my daily medical activities. Also, the history of being paid well for difficult and risky work may become history itself. It seems the government has taken physician reimbursement, tied it to a rock, and thrown it overboard. Naturally, the rest of the insurance industry feels compelled to follow suit, and so, down goes the reimbursement for doing the same work.

Adding That Extra Dimension

Assuming you wish to stay within your means, and you want to maintain your selected lifestyle, you are going to have to do something more each year just to tread water. Some doctors try to gain efficiency and see more patients. This idea clearly has limits on how far you can take it, and it always increases the chances that you will miss things as you have less time per patient. It is also more stressful and less fun.

Other doctors will seek to increase reimbursement by adding new, mostly insurance-independent procedures, like keratorefractive surgery or cosmetic surgery. Still others steer towards other disciplines and offer spa-like services or hearing services and hearing aids. The best new option is offering “lifestyle” implants to cataract surgery patients. This is a legitimate way of offering patients a better product, and getting paid more for the extra work and expertise that is necessary to get regularly good outcomes with these lenses. During my career, I have looked into all of these things, and only settled on the ones that I am most comfortable with.

Why I Chose Clinical Trials

The one practice offering that I am very happy I got involved with is clinical trials. By participating in clinical trials, I am able to greatly increase my knowledge of many types of medications and devices, thus remaining in the forefront of my profession while developing productive relationships with some very bright people. Participation in clinical trials has also enhanced the reputation of my practice, which is now known as a practice that is in the vanguard of progress in the ophthalmic arena. And finally, being involved in clinical trials has allowed us to help many of our patients to better deal with their eye problems. So I see participation in clinical trials as one of the most socially productive uses of my skills to both advance our profession and be compensated for my knowledge and my organizational abilities.

How did I get involved in conducting clinical trials? Simple. At the beginning of my private practice, I was asked by the ophthalmologist who I shared an office with if I would like to become a sub-investigator for some ophthalmic allergy eye drop clinical trials. Up to that point, I had been heavily involved with non-clinical research, but I had no easy access to laboratory space and I no longer had any research funding. The clinical trial world addressed my interest in research and the remuneration addressed my need to do more than tread water.

In this article, I will explain the essential requirements that a physician must meet to participate in clinical trials as a Principal Investigator. Some of you may find these requirements too daunting to pursue further. Others may be intrigued by the rewarding possibilities of this work.

What's Involved in Clinical Trials?

Being a Principal Investigator for FDA-approved clinical trials is interesting, rewarding professionally, and more remunerative than anything else I do for the same amount of time. In order to conduct a clinical trial correctly, you need dedicated space for study monitors to review study materials, space for your clinical coordinators to administrate the study and an exam room with equipment that is calibrated each month. In our facility, we have a separate exam lane for study patients, so the assessments are always made on the same equipment. You will need a room that can be locked to store the study documents and a lockable cabinet that will contain the study medication or device. You may need to own a specular microscope, which normally has limited value in clinical practice, but is often required for many drug and device studies for endothelial cell counts. You may also need a -30 degree freezer and a centrifuge for the processing and storage of drawn blood.

You will need special people to be your study coordinators. These individuals must be organized, detail-oriented, personable, intelligent, have great phone skills and be knowledgeable about the entire clinical trial experience from start to finish. These fine people make the clinical trial experience possible. Without them, you are dead in the water. Finding a person who can do this kind of work correctly is very difficult. Occasionally you can recruit such a person. More often than not, you will need to have a tremendous ophthalmic technician or nurse train in real time.

How Do You Get to Be a PI?

In my case, I was asked to be a sub-investigator (sub-I) for several clinical trials. I was hired by the manager of the site that was selected by the sponsor of the clinical trial. I performed activities that only a doctor was authorized to do. They took care of all of the paperwork and all other matters required for the proper conduct of the clinical trial. A sub-I at your site is very useful if you need to see more study patients per time than the PI can see alone, or if the PI is unavailable because they are in the operating room or out of town. The sub-I needs the same training on the protocol as the PI, since their responsibilities are the same as far as data collection from the study patients. There are some sponsors that will not allow an optometrist sub-I to collect certain study data, and sometimes an optometrist sub-I is not allowed to collect any data.

After I had a couple clinical trials under my belt, and added these experiences to my CV, I began to ask different drug companies if I could become a PI for their upcoming clinical trials. Eventually, some of the companies began to say yes. Sometimes the sponsor (the drug company paying for the conduct of the clinical trial) will do all of the varied activities required in a clinical trial. Often, they will outsource this responsibility to a Clinical Resource Organization (CRO), that receives payment directly from the sponsor, and then conducts all or most of the clinical trial activities on behalf of the sponsor. In order for the sponsor or CRO to say yes, they typically will ask you to complete a Confidential Disclosure Agreement, so they can talk with you about the details of their proposed study. All of the clinical trial work is performed with the strictest of confidence so you need to remember not to divulge confidential matters from one clinical trial to the sponsor of another.

Dr. Korenfeld spends a good deal of time explaining the details of specific clinical trials to patients who seek to be included.

The Protocol Summary

It is common that you will receive a Protocol Summary that tells you what is being studied, what the inclusion and exclusion criteria are for the subjects, and how many patients they expect you to enroll during the enrollment period. After this, the sponsor usually will ask you to complete a Site Feasibility Survey, where you tell them how many patients you have in your database that meet the required study patient profile. You will need a computer program capable of performing queries, so you can accurately answer this kind of question. They will often ask how many patients you think you can enroll per month. If the sponsor or CRO likes your answers, then they will set up a site visit, where they send a monitor out to your site to see if you have what it takes as far as physical plant and equipment. They also come to assess your knowledge of performing clinical trials and your interpersonal skills. After all, they will be relying upon you for very important work, and if the fit or feel isn't right for them, they can politely say, “no, thank you.”

By this time, the sponsor/CRO has sent the final protocol and a document known as the Investigator Brochure. The Investigator Brochure is a document that teaches the chemical structure of the study medication, its pharmacology, previous research, toxicology, and known safety and efficacy data.

The Principal Investigator must sign and return the signature page of the final protocol to document their complete understanding of it and their willingness to follow it closely. The PI must also complete a Delegation of Authority log that designates exactly which staff members will be assigned to specific duties under the protocol. If someone other than a designated person is discovered to have participated in the conduct of the study, or someone performs tasks not designated to them, there are severe repercussions. All study staff needs to be familiar with the final protocol since it is mandatory that it be followed exactly, and there are some very subtle requirements. For example, the interval between drop instillation must be carefully timed, assessments of ocular vital staining must be made at a certain time after the instillation, and the sequence of the exam elements is specified.

Regulatory Documents

The next required collection of paperwork is called the Regulatory Documents. These include your CV, your financial conflict of interest declaration and a copy of your medical license. Finally, there is the infamous Form 1572 — your contract with the FDA that says that you will perform all study activities yourself, or delegate some of the activities to your staff whom you directly supervise. Ultimately, you agree to be completely responsible for everything that has to do with this particular study, both the conduct of the study and the data integrity. This is a daunting form and confers tremendous responsibility on the shoulders of the PI.

The Clinical Trial Agreement

The Clinical Trial Agreement is the contract between you and the sponsor. It contains standard contract language, as well as requirements for your amount of malpractice insurance, matters of confidentiality, it stipulates who owns the data, and details how publishing the data will be handled. Each Clinical Trial Agreement also typically has a summary spreadsheet in it that stipulates exactly what measures the sponsor expects you to perform, in what order, for each study visit. This is useful for the budget person, since typically each line item has a fee that is paid upon completion.

The sponsor/CRO will send you a proposed budget for the conduct of the study. Usually, but not always, the budget looks like the summary spreadsheet with dollar amounts assigned to each step. Most commonly, the proposed budgets are reasonable. Sometimes there may be one or more line items that look like they are under-reimbursed, and you are allowed to make a counter-proposal to the sponsor or CRO. In addition to the line-item fees, there are often “cells” for a coordinator's fee, an advertising budget, a startup allowance and an overhead percentage that gets added to the total line-item fees.

There is also a dollar amount that is specifically stipulated for patients that “Screen Fail.” This can be an amount equal to the cumulative work you were required to do to determine the patient was a Screen Fail, or it can be a lump sum that is not related to how much work you needed to do in order to determine that the patient was a Screen Fail.

The budget typically includes a patient stipend amount, which is the payment that the site can tell the patients they will receive for being in the study. The patient stipend is also negotiable, as all elements of the budget are. At our site, patients often come from far distances, so if the patient stipend isn't sufficient, we often ask for that to be increased. Remember, patients participate in clinical trials for many reasons. They might want to further the cause of medicine, they might have had a family member who had the disease that is being tested, or they might be looking for something social to do. All of the patients want to be paid fairly for their travel and participation, and if the patient stipend is too small, that alone could reduce the number of patients that you enroll for a particular protocol.

IRB Authorization

Once your site and the sponsor or CRO have come to a mutually agreeable budget, you must now apply to the Institutional Review Board (IRB) for the right to conduct a specific protocol, with your specific credentials. The IRB is commonly centralized, so that they know the protocol well, and have come to terms with it for all of the investigators who choose to use the Central IRB. Some investigators work out of academic institutions, and typically each academic center will have its own IRB. Occasionally, you can appeal to the Local IRB to relinquish the IRB responsibilities to the Central IRB, and sometimes they will. Sometimes the investigator at an academic institution must work with the Local IRB. The IRB is an intermediary watchdog set up to interact only with the investigator. The IRB has no meaningful interaction or jurisdiction over the sponsor/CRO. For example, if there is a severe adverse event, it is the investigator's responsibility to notify the IRB, not the sponsor's. If your submission to the IRB is proper and complete, it typically takes no longer than a week or two for IRB approval.

At this point, the sponsor/CRO has accepted your site as a result of the site visit, you have signed the confidentiality agreement, you have signed off on the final protocol, all of your regulatory documents have been submitted, you have finalized the study budget, and you have applied to the IRB. Now, there is the formal training phase for the protocol.

As a Principal Investigator for a clinical trial, Dr. Korenfeld is responsible for filing numerous reports. Here, he catches up.

Investigator Meetings, Then and Now

In the old days, before the newest PhRMA regulations and the downturn in the economy, all studies were presented at Investigator Meetings. They were always held at very nice locations, in upscale hotels, and there were entertainment events woven into the educational elements, not to mention delicious food. The Investigator Meetings were a pleasant break from routine that gave you a chance to get away for a long weekend and be a bit pampered.

There are still plenty of sponsors that put on Investigator Meetings, but they are a little more reserved, as sponsors now concern themselves with such drivel as whether the hotel is too nice. Jeepers. Besides the fact that you get to go to very nice places and relax for a couple days, Investigator Meetings are really so much better than the alternative — the Webinar.

At the Investigator Meeting, you get to meet real people. You meet the other investigators and the sponsor and CRO staff. This is very important to build relationships and address the myriad of special questions and interests that you have. The opportunity to personally interact with the sponsor staff is very much like an interview. If you handle yourself well, come off as engaged and intelligent, and are personable, this can only help you with future opportunities with the company, whether it is future studies, speaking engagements or opportunities to write papers regarding the study results. The sponsor staff is usually composed of quite interesting and intelligent people who have had tremendous experiences in the field of medicine. I learn an incredible amount about drug development, FDA regulatory affairs and the characters who populate these different arenas.

It is fascinating, stimulating and a lot of fun, and none of this is possible with a Webinar, where each required element of the presentation is delivered by voice on the phone and Power Point slides on the web. It satisfies the requirement of conveying the required elements of the study, but in my opinion, it is vastly inferior to the Investigator Meeting. The Investigator Meetings facilitate the development of positive relationships, which ultimately is what clinical trial research is all about.

After the sponsor has presented the study, it is time to ship out the study supplies and the study medication. There are specific rules for storing these supplies, including accounting for their receipt, storing them behind locked doors, monitoring their use and keeping temperature logs for the study medication. If the sponsor wants you to record the findings onto a specific form, they will have provided this; it is called a Clinical Report Form. Some sponsors want you to record the findings directly into the computer, so if that is the case, that system needs to be established. You are now ready to fly.

How Do I Find Eligible Subjects?

The patients who will be identified for possible inclusion into the study can come from your patient database, IRB-and sponsor-approved advertising, or referrals from other sources. You cannot pay other sources for referrals, and there is no mechanism for a “co-management” relationship, unless the referring doctor is a bona fide sub-I.

In our institution, we have “frequent fliers” who've been in previous studies. These are our first resource, because these patients' clinical status is well known to us and they are motivated to be in studies. We will also run a computer query to identify patients with the correct demographics and diagnoses. This will enable us to then access the medical records of these people, then contact them for possible involvement in the study. I listen to my coordinators call these potential patients on the phone, and realize how critically important they are. If patients don't find their primary contact person to be approachable, they will just not be interested in participation. Our site has been historically very good “enrollers” because of the superb efforts of our clinical coordinators.

Following the Trial Protocol

After seeing the first several patients, it is common that the sponsor/CRO will send out a monitor to visit your site and make sure that you are adhering to the protocol and documenting all of the data properly. The monitors are detail-oriented people, as are the FDA inspectors, and they will literally go through every word of every document you have on each subject, looking for accuracy, consistency and compliance with the letter of the protocol.

If they find that you did something wrong early on, they can steer you in the correct direction. If you enrolled someone who was ineligible, they will point this out to you, and you will need to terminate the subject from the clinical trial. Your budgetary contract will not likely pay you for work that you did on ineligible subjects, so it behooves you to only enroll eligible subjects. Plus, if you violate the protocol with any regularity at all, you are not likely to be asked to participate in subsequent clinical trials, and at worst, you can get into real trouble with the FDA if they find that you are not living up to the 1572 contract.

Our monitors, who often work for different sponsors on different projects, sometimes comment on how easy it is for them to do their work at our site. The clinical coordinators have all of the documents completed correctly and on time, all of the accountability logs are proper, there is ample and comfortable space for them to work, and there are very few mistakes that they identify. This makes their very detailed work more pleasant, and they then return this positive feedback to the sponsor, CRO and new sponsors for future clinical trials; they form a positive relationship with us, which is a fundamental part of the clinical trial experience.

Just What the Doctor Ordered

As you can see, there are numerous steps and details in performing clinical trials. It takes a special kind of office to run FDA-approved clinical trials correctly, and enjoy it. If you are interested in research and product development, and you like being paid fairly for your work and expertise, clinical trials may be just what the doctor ordered. OM

Michael S. Korenfeld, MD is the owner of Comprehensive Eye Care, Ltd., in Washington, Mo. In addition to being a comprehensive ophthalmologist, he is extensively involved with new product innovation and clinical trial research, having served as the Principal Investigator in over 40 FDA-approved clinical trials in both pharmaceutical and device development.