Editor’s Note: Welcome to “Eye Catching: Let's Chat,” a blog series featuring contributions from members of the ophthalmic community. These blogs are an opportunity for ophthalmic bloggers to engage with readers with about a topic that is top of mind, whether it is practice management, experiences with patients, the industry, medicine in general, or healthcare reform. The series continues with this blog by Mark Packer, MD, FACS, CPI. The views expressed in these blogs are those of their respective contributors and do not represent the views of Ophthalmology Times or UBM Medica.
Ophthalmologists often approach me about getting involved in clinical research, mostly because they know that I’ve been a principal investigator, medical monitor, or clinical consultant in over 60 trials related to FDA clearances and approvals. Here’s what I tell them.
Being a principal investigator demands a very different set of values from being a practicing ophthalmologist. 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 surgeons adopt a fresh perspective on their daily work.
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The purpose of clinical research for regulatory review is to collect data that will allow a determination regarding the safety and effectiveness of novel drugs and devices. While there are excellent resources available from many sources—including guidance documents from the FDA, which describe the principles and processes involved in conducting research—intellectual understanding does not generally lead in and of itself to sustained success. Practical experience is often necessary to build the transition from theory to practice. My observations here should not be taken as a textbook chapter on clinical research; rather, they are my personal perspective based on 20 years of experience in the field.
Clinical trial protocols and agreements specify a list of responsibilities, which represent a good starting point for understanding the commitment involved in conducting research. Per the FDA, the general responsibilities of investigators include 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; and Ensuring that informed consent is obtained from each subject in accordance with 21 CFR Part 50 and that the study is not commenced until FDA and IRB approvals have been obtained.
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This list of responsibilities might be considered the bricks in the structure of good clinical practice, while the mortar consists of each site’s standard operating procedures, delegation process, and documentation. However, the investigator must always maintain personal responsibility for the construction.
I’m reminded of a dialogue that occurred during an FDA audit. The Investigator opened the conversation, saying that he intended to fully cooperate with the investigation of the site. “Thank you,” said the auditor, “but we are not investigating the site. We are investigating you
In this light, it is you – the investigator – who is always accountable for your actions. It is wise to consider this reality in every decision you make. As one of my mentors 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 beyond that of ophthalmologists in routine clinical practice. A routine after-hours phone call from a day one post-op patient might be handled with advice to “use your eye drops and come see me in the morning,” but a phone call from a research subject in whom an investigational device has been implanted carries much greater freight. Your response may be second-guessed by the Medical Monitor, the Vice President of Clinical Affairs, the CEO, and the FDA. I’d recommend giving some consideration to the implications of everyday decisions before agreeing to participate in a study.
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Participation in clinical research trials can open opportunities for professional advancement. However, empathy and intellectual challenge are likely to be better motivation than desire for enhanced status and financial rewards. I’d rather have an investigator who really cares about outcomes and is someone I can trust, or is at the very least honestly committed to problem-solving for its own sake, rather than someone who simply wants fame and fortune. My own motivation comes from creating solutions that improve clinical outcomes. The stronger your motivation, the greater chance you will resist destructive forces that challenge your integrity. It all comes down to you – and whether you actually enjoy what you are doing, or are doing it mostly for secondary gain.
The integrity of the data is one of the key questions asked in 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 these deviations mount up during an investigation, one begins to sense that perhaps the investigators are not following the rules and that, perhaps, the integrity of the data is 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 have impact on the results. Lost data mean wasted time and effort on everyone’s part.
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The law defines valid scientific evidence as “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." The “qualified experts” often include members of FDA Advisory Committees, who hear the evidence from clinical trials and vote on the safety, effectiveness, and the 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, which is, after all, 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, depending, 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, read the protocol with care. Make sure you 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 you do believe there’s a good chance of success, based on your best medical judgment, then make sure that the endpoints in the protocol, if satisfied, would in fact prove to you that the drug or device does
represent an improvement over the standard of care.
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Next, make certain that you can comply with the requirements of the protocol, given the particular clinical environment in which you work. The sponsor will ask you to quantify the number of subjects you can enroll, and you will be held to your answer. Enrollment often depends on investigator enthusiasm and specific methods put in place to identify potential subjects, as well as the number of patients who meet inclusion and exclusion criteria. It is worth taking the time to search your database and make sure the study is a good fit for your practice. It is much easier to say “no thank you” before you start, than fail at meeting enrollment objectives. In addition, pressure to meet unrealistic enrollment targets has the potential to erode subject safety, with extremely negative consequences. Therefore, a realistic appraisal of your own ability is crucial to success.
Financial considerations are, of course, very important to any business, including the business of clinical research. The clinical trial agreement will specify the compensation provided for a given study. In order to determine whether or not the compensation is acceptable, you have to know the cost of performing the study at your site. Only by knowing your costs can you determine if the compensation proposed for the study means making a profit or accepting a loss. Ignorance of the financial realities will certainly lead to dissatisfaction. Of course, there is always the potential of negotiating in order to meet your 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 will help keep these discussions rooted in reality.
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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. It’s always good to keep that in mind.
Perseverance means steadfastness in doing something despite difficulty or delay. Ultimately, perseverance is the only way to success. Therefore, if clinical research sounds attractive today, challenge your own motivation, increase your understanding, and develop your ability to persevere.