Clinical research in ophthalmology
Perspectives on how to catalyze the transition from theory to practice.
BY MARK PACKER, MD, FACS, CPI
Participation in clinical research demands a very different set of protocols from those that apply to routine ophthalmic practice. While the World Medical Association’s Declaration of Helsinki and the International Conference on Harmonisation’s Good Clinical Practice (GCP) documents underlie the ethical conduct of clinical research, the successful application of these concepts requires that ophthalmic professionals adopt a fresh perspective on their daily work.
The purpose of clinical research for regulatory review is to collect data that will allow the FDA to determine the safety and effectiveness of novel drugs and devices. Despite the availability of excellent resources, including those from the FDA, that describe the principles and processes involved in conducting research, intellectual understanding does not always lead to sustained success in clinical research. Practical experience is often necessary to build the transition from theory to practice.
In this article, I provide my personal perspective and factors to consider based on my 20 years of experience in the field, which should help to catalyze that transition from practice to clinical research.
Clinical trial protocols and agreements specify a list of responsibilities, which represent a good starting point for understanding the commitment involved in conducting research (See “Investigator responsibilities,” page 32). Consider these responsibilities the “bricks” of good clinical practice, while the “mortar” consists of each site’s standard operating procedures, delegation process, and documentation. The investigator maintains personal responsibility for the “construction.” During one FDA audit, an investigator said he intended to fully cooperate with the auditor’s investigation of the site. “Thank you,” said the auditor, “but we are not investigating the site. We are investigating you.”
In this light, whether you act as the investigator or the clinical research coordinator, you are held accountable. Consider this in every decision you make. As one of my mentor’s used to say, “Would you like to see that on the front page of the New York Times?”
Clinical research requires commitment. Completing Case Report Forms (CRFs) and answering telephone calls from subjects in the middle of the night means maintaining a level of dedication and trust that differs from routine clinical practice. During a routine after-hours phone call from a day-one post-op patient, for example, it might be sufficient to say, “Use your eyedrops and see me in the morning.” This instruction, based on an understanding of years of clinical experience and data on outcomes, does not need to be verified beyond normal practice protocols. But, a phone call from a research subject in whom an investigational device has been implanted carries much greater freight. Before agreeing to participate in an Investigational Device Exemption clinical investigation, consider that your response may be second-guessed by the medical monitor, the vice president of clinical affairs, the CEO, and the FDA.
Participation in clinical research trials can provide enhanced status and financial rewards. However, I’d rather have an investigator whose motivations include empathy and intellectual challenge and who really cares about outcomes.
My own motivation comes from creating solutions that improve clinical outcomes by guiding safe and effective innovation in ophthalmology. The stronger your motivation, the greater chance you will resist destructive forces that challenge your integrity. It all comes down to whether you actually enjoy what you are doing or are mostly interested in secondary gain. Through the investigators’ communications and actions, the motivation becomes clear to the staff.
Per the FDA, the general responsibilities of investigators includes the following:
» Ensuring that the investigation is conducted according to the signed agreement, the investigational plan, and applicable FDA regulations
» Protecting the rights, safety, and welfare of subjects under the investigator’s care;
» Controlling devices under investigation;
» Ensuring that informed consent is obtained from each subject in accordance with 21 CFR Part 50 and that the study does not commence until FDA and IRB approvals have been obtained.
The data’s integrity is one of the key factors regarding the evaluation of clinical research. Data flow from the clinical examination as recorded in a source document, to the case report forms transmitted to the sponsor, to the clinical data base and, ultimately, through biostatistical analysis, to the clinical study report. The protocol determines, in advance, the particular items of interest that are to be recorded, as well as the specific methods of measurement and the time periods for those measurements.
In this way, clinical research is very different from clinical practice, because any variations that fall outside of the strict instructions in the protocol are considered deviations. As deviations mount up during an investigation, it can give the impression that the investigators are not following the rules and that the data may be suspect. Sponsors must sometimes go to great lengths to explain why certain protocol deviations do not impact the integrity of the data — and must sometimes remove data from consideration due to significant protocol deviations, which may impact the results. Lost data mean wasted time and effort on everyone’s part.
According to the FDA, valid scientific evidence is “evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use.” In addition to investigators, the “qualified experts” often include members of FDA advisory committees, who hear the evidence from clinical trials and vote on safety, effectiveness, and relative risk/benefit of novel drugs and devices.
Biostatistics plays a major role in clinical research, as well as in the determination of safety and effectiveness. Sometimes, however, statistical significance, an abstract and somewhat arbitrary concept, does not imply clinical significance. Also, clinical significance, which is ultimately more important for real patients in the real world, may exist without statistical significance. This depends, for example, on the particular population under study. Nuances in the interpretation of “valid scientific evidence,” as well as the specific experiences that advisory committee members bring to the table, may ultimately make a difference in the outcome of FDA proceedings.
When presented with an opportunity to participate in a clinical research study, those involved must read the protocol with care.
The investigator must believe that the device or drug under investigation has a reasonable chance of representing an improvement over the standard of care — both in terms of safety and effectiveness. If the investigator concludes there’s a good chance of success based on medical judgment, then it must be clear that the endpoints in the protocol, if satisfied, would prove to you that the drug or device represents an improvement over the standard of care.
Next, the investigator and clinical research coordinator must make certain the practice can comply with the requirements of the protocol, given their particular clinical environment. The sponsor will ask for a quantification of the number of subjects the practice can enroll, and the investigator will be held to the answer. These enrollment figures often depend on investigator enthusiasm, as well as the number of patients who meet inclusion and exclusion criteria. It is worth taking the time to search the practice database and make sure the study is a good fit for your practice. It is much easier to say, “no thank you” before the trial starts, than to fail at meeting enrollment objectives.
In addition, pressure to meet unrealistic enrollment targets has the potential to erode subject safety, with extremely negative consequences. For example, incorrect IOL power calculations, which might occur due to a technician rushing to complete a lens order and entering the wrong “A” constant, will reflect poorly on an investigational device — even though the root cause of the adverse event is unrelated to the device. Therefore, a realistic appraisal of your own ability is crucial to success.
Financial considerations are very important to any business, including clinical research. The clinical trial agreement will specify the compensation provided for a given study. To determine whether the compensation is acceptable, the practice must understand the cost of performing the study to determine whether the compensation proposed means making a profit or accepting a loss.
Ignorance of the financial realities will certainly lead to dissatisfaction. The investigator can negotiate to meet the practice’s needs, with the understanding that the sponsor may simply choose another, less expensive site. Knowing the real value that you provide as an investigator, and potentially also as a key opinion leader or advisor to the sponsor, keeps these discussions rooted in reality.
The clinical research coordinator is a key member of the investigational team. Accurate, in-depth knowledge of the protocol, exceptional clinical ability, outstanding communication skills, extreme detail orientation, unremitting honesty and superhuman responsiveness complete my checklist for this job description. Trust is the hallmark of the successful relationship between the research coordinator and the investigator. After all, the delegation of responsibility in a clinical study is a matter of law.
If clinical research sounds attractive, question your motivation, understanding, and ability to persevere. Things can get tough — which way will you be going when they do? OP
Mark Packer, MD, FACS, CPI, is clinical associate professor of Ophthalmology at Oregon Health & Science University in Portland, OR.