Being an ophthalmologist is an incredible privilege—the ability to grant sight to patients as well as improve their quality of life concurrently is nothing short of awesome. The fields of both ophthalmology and optometry have experienced exponential technological, surgical, and medical growth over time and we have had the great honor to share this with our patients.
In concert with innovation and learning of new techniques, medications, and devices available to our patients, it is imperative to recognize the importance of the years of clinical research and development behind each of these advances. As a tremendous personal passion, clinical research in ophthalmology is a large part of my practice and has brought new technologies to our patients even before FDA approval, in some cases.
This article focuses on the benefits of clinical research in training and practice, as well as how to best approach the idea of clinical trial participation in patient communication.
Deciding to be part of a clinical trial—from a physician perspective
Incorporating clinical research into practice is a personal decision. For those who do not like research, you should not force it. Organizing research trials and managing administrative tasks alone is a labor of love—and for those of us who do this (and continue to do this every day), we understand the necessity of the (many) extra hours involved in bringing a trial to completion.
It is important to develop a research team: an organized supportive network within your office or clinic will help bring success and make these novel therapies a reality for your patients. The team may consist of a physician (principal investigator), clinical research coordinator(s), research technicians, among others. The benefits of participating in clinical research are important to understand, and this can be shared with your colleagues and staff in many ways. Innovation in science and medicine is exciting—and for the most part, people involved are just as excited to be part of what is pushing science forward. This positive environment surrounding clinical research is a key aspect to what will allow for successful enrollment in clinical trials.
That being said, it is important to consider what patients’ perspectives of clinical research are, in order to help your patients understand if trial participation is the right thing to do for them.
Deciding to be part of a clinical trial—from a patient perspective
When introducing clinical research to your patients (and in order to create successful enrollment), there are some key points to consider. Each trial has benefits and risks; before participating in a trial, all questions should be answered.1-4 Patients should be encouraged to take notes, or bring a friend or relative with them to help remember answers and think of other questions.1-4 Patients should be informed about key trial elements, which include:
Research study protocol:
It is imperative to review the type of study you are doing. Patients in an observational trial (no active treatment intervention) may be more apt to enroll vs. prospective interventional studies. The overall protocol of the trial, including study design (e.g., randomized vs. not randomized) should be discussed in order for patients to understand how the study will work and the chance of them receiving an experimental treatment or placebo in some circumstances.4-6 In addition, it is sometimes helpful to briefly review the phases research trials go through so that potential subjects can better understand what “phase” they are in, and the associated risks.
Before clinical trials, basic science research is done to increase understanding of normal human biology and disease to ultimately discover and develop new therapies to improve health.4,7 Testing in this stage is generally done in a lab on cells/tissues and possibly animals. Once the new treatment appears safe, has therapeutic potential, as well as a low risk of side effects, it may move into the various phases of clinical trials.4,7
Phases of clinical trials:
It usually takes years for a new drug or device to pass through clinical trials and receive market approval!
- Phase 0 (Exploratory/Pilot): This phase includes a small number (~10-15) of participants to test response to a small (sub-therapeutic) dose of a drug/early use of a device and explore diagnostic test results.3-7
- Phase I (Safety): This phase includes a slightly larger number of subjects (~20-100) and serves as the first stage in testing the therapy in question in healthy patients to establish a safe, therapeutic dose range of a medication/best use of a new device and identify any side effects.3-7
- Phase II (Proof of concept): This phase typically includes a much larger number of subjects (hundreds) to assess efficacy of a treatment, as well as further identify any safety issues.3-7
- Phase III (Regulatory): Involving hundreds to thousands of participants, this phase of clinical trial is done to confirm clinical benefits and safety risks. During this time, investigators may also compare the experimental treatment to another treatment (e.g. something already on the market as standard of care or a non-interventional standard care).3-7
- Phase IV (Post-Market Surveillance): These studies use large populations for marketing and safety surveillance of the now-approved treatment to monitor efficacy, safety, and long-term effects, as well as compare the approved treatment to others and confirm where it is best used.3-7
- Trial completion (at any stage): At the end of a trial, researchers will carefully examine data collected during the study before making decisions about the meaning of the findings and need for further testing. After a phase I or II study, researchers will decide whether to move onto the next phase or to stop testing due to safety or efficacy issues. Following phase III studies, researchers carefully analyze the data and decide if the results have true medical importance. Results are often published in peer-reviewed scientific journals; if particularly important, results may be discussed at scientific meetings.1-4 Ultimately, once a new therapy has been proven safe and effective in a clinical trial, it may become a new standard of medical care!
Types of Clinical trials:
Studies may have different designs to ensure they achieve the best and most informative results. Potential subjects have a right to know the type of trial, as this may also impact decision to enroll.4-7
- Controlled trial: This type of study enrolls 2 or more groups of participants, one with investigative therapy (experimental group) and one with a comparison (or placebo) treatment (control group). This type of trial is important because it allows comparison between the two groups. The placebo used in the control group will usually appear identical to the study treatment (e.g., sugar pill, saline eye drops)—this helps to delineate if the effects of the study are related to the actual biochemical/physical properties of the treatment vs. psychological effects (i.e., “placebo effect”).3-7
- Blinded trial: In a blinded trial, patients are unaware of the treatment they receive until study completion.4-6 Blinding ensures that outcomes are not biased by subjects or investigators presumptions (i.e., what they think the outcome will be if they know which treatment each subject received). A study is double-blinded if investigators are also unaware of which treatment patients receive (this is typically recorded by another member of the research team).4-6
- Randomized trial: This means that each person in the study is assigned by chance to either the investigational treatment group or control group.4-6 Randomization helps to decrease the chance that patients in one group will be so different from the other that it could affect outcomes; it also helps to ensure that the groups have patients in similar states of health, so that the results are not skewed.4-6 Patients in randomized studies cannot choose which group they are in—this needs to be made very clear during the informed consent process.
- Crossover trial: In a cross-over design, all participants get to experience both the new treatment and the control/comparison treatment.2-7 The way this works is that after a certain period of time of being on the new treatment/use of the new device, or being in the control group, subjects will switch groups.3-7 There is usually a ‘washout’ period during which participants stop taking the treatment or control they were assigned for a certain period of time to ‘wash out’ any lasting effects before changing therapies. Crossover trials are usually longer in duration. However, the advantage of crossover studies is that patients become their “own controls”, which can make for a better comparison between treatment and control and stronger data analysis.4-7
- Observational trial: Observational trials involve no active investigational treatment or control group, but follows the outcomes of patients with certain conditions or on specific medications over time.1-4
Time dedicated to trial participation:
Trials generally last at least a few weeks to several years.1-4 Review of the timeline of trials and necessary visits may help a patient decide if enrollment is feasible—they need to think about transportation, their work schedule and whether or not the visits can be fit into their lives as well.
Risks of enrollment:
All clinical trials have risks (it can also be argued that there are risks associated with any medical test, procedure or treatment). The risk may be higher in a clinical trial, especially for a novel drug or investigative use of a novel device, because there are more unknowns.1-9 It is important to review this at length with patients, as well as ensure that all measures will be taken to ensure a safe clinical trial, with oversight from an institutional review board (IRB) and/or the FDA in some cases.
- Confidentiality: One of the fears patients may have when enrolling in a study is whether or not their protected health information (PHI) and/or identity will be kept confidential. In general, patients should be assured that information that is needed for the trial is only shared with the research team.8,9 In fact, most patients are assigned a research ID or ‘code’ which is then used as the study continues and for data analysis to further protect their PHI.8,9 In rare cases of adverse events or complications related to the trial, personal information may need to be exposed to the research team, IRB or FDA in order to best understand and treat the aforementioned event.8,9
- Costs: Oftentimes patients wonder if being part of a study will cost them money. In most cases, the study sponsor (e.g. a pharmaceutical company, university/institution, government agency) will provide treatment at no cost and may pay for any special tests related to the trial, including visits.1-4 Some sponsors may pay for more (e.g., travel time, mileage, etc). In the US, the Affordable Care Act (ACA) requires that health insurance covers routine costs of care for people who are in approved clinical trials.3,4 Of course, every trial course and sponsorship is different; this should be reviewed at length with potential subjects.
Informed consent must be clear and ongoing:
As a potential investigator, you must be aware that informed consent is a dynamic and ongoing process. Aside from the initial informed consent process which documents risks and benefits of study participation, any study changes must be communicated to actively enrolled participants. Research subjects must be notified regarding any changes in the study—this could involve anything from information regarding early study termination due to adverse events, newly discovered beneficial therapeutic effects of the item under study, as well as new forms of data collection that may influence number of study visits.8,9 Another important aspect of a clinical trial is that participation is entirely voluntary and that patients can leave the study at any time, with no impact on their current standard medical care.8,9
- Ensuring patients feel protected: Even after reviewing consent and successful enrollment, patients will still need to feel protected during the course of the trial and treatment.1-9 Another important aspect of clinical research to review with patients is that clinical trials are heavily regulated and must be conducted in accordance with standard ethical guidelines, codes of conduct and national laws to ensure patient safety, protection of human rights and privacy, good clinical practice, responsible research conduct and quality data collection.1-9 All trials, whether for a new or established treatment must be approved by an institutional review board (IRB). The IRB committee consists of doctors, researchers, lawyers and other members of the community who review the study protocol and all other study documents and forms to ensure the proposed study is ethical, that the rights of the participants will be protected and that the potential risks are minimized and reasonable when weighed against the potential benefits of the study.1-9 Once the study is approved, the IRB will continue to monitor the study.
- Meeting the research team: Another aspect of making sure patients feel secure during study enrollment is knowing who the research team is and identify the members that will be helping to care for them.
- Investigators: The lead doctor is the principal investigator (PI); any other involved investigator is called a “sub-investigator” (Sub-I). Investigators will supervise, administer and/or perform the treatment under investigation. The PI and Sub-I’s are responsible for ensuring good clinical practice, that the trial is run according to the protocol and safely and that participants receive appropriate care.1-4
- Clinical Research Coordinators (CRC): CRC’s are qualified clinical researchers that usually serve as the main point of contact for subjects and are present at the majority of study visits.1-3 They are involved in recruiting participants and providing them important information about the trial before enrollment and throughout the trial, organizing appointments and medical tests, monitoring participants, and data collection.1-4
- Sponsor: The sponsor of the trial may be a government agency, pharmaceutical or biotechnology company, charity, research organization, hospital, university or individual.1-3
- Monitors/Clinical Research Associates (CRA’s): These are individuals contracted or employed by the sponsor of the study.1-3 They are tasked with overseeing the trial to ensure that it is conducted and results are reported according to regulatory requirements. They perform site initiation visits, inspections, data and safety monitoring.1-4
Relationship to usual health care:
Typically, participants continue to see their usual providers while enrolled in a study. In fact, the patient’s provider may be an investigator in the study.3,4
Benefits of enrollment:
Only through clinical research can we gain insights and answers about the effectiveness and safety of new treatments, devices, and procedures. Groundbreaking scientific advances in the present and past were possible only due to participation of volunteers—both healthy and those with illness—in clinical trials.1-4 Research opens new doors to finding ways to diagnose, prevent and treat disease and disability. In addition, clinical trials provide the basis for development and marketing of new drugs, biologic products and medical devices. In this way, some trials may provide participants with the prospect of receiving direct medical benefits, while others may not.1-4
While the decision to enroll in a clinical trial may seem easy to an investigator, it is important to remember that you are first a physician and your goal is to provide the best possible care for your patients. If enrollment in a trial is something that you and your patients mutually agree upon, it can lead to amazing results—but should never be forced. Incorporation of research studies into clinical practice can open many doors in terms of therapeutics, devices, and surgical techniques to your patients. It can also increase the medical knowledge of your staff and may even lead to novel discoveries in your office!
REFERENCES
- Deciding Whether to be Part of a Clinical Trial. www.cancer.org. Accessed Oct 11 2020
- “NIH Clinical Research Trials and You” National Institutes of Health (NIH): https://www.nih.gov/health-information/nih-clinical-research-trials-you Accessed 11 October 2020
- Introduction to Clinical Trials—What are they? What happens? Who Is involved? Genesis Research Services. https://genesisresearchservices.com/introduction-to-clinical-trials-what-are-they-what-happens-who-is-involved/ Accessed 11 October 2020
- Learn About Clinical Studies. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/about-studies/learn Accessed 11 October 2020
- “What are Clinical Trials?” National Heart, Lung and Blood Institute: https://www.nhlbi.nih.gov/studies/clinicaltrials
- Sibbald B and Roland M. “Understanding controlled trials. Why are randomised controlled trials important?” BMJ 1998; 316:201. http://www.bmj.com/content/316/7126/201
- Corr P and Williams D. “E, The Pathway from Idea to Regulatory Approval: Examples for Drug Development.” In Conflict of Interest in Medical Research, Education, and Practice. Institute of Medicine (US) Committee on Conflict of Interest in Medical Research, Education, and Practice; Washington (DC): National Academies Press (US); 2009. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22930/
- Hills RK. “Informed Consent: How Much Awareness Is There?” PLoS One 2014; 9:e110139. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199663/
- Kadam RA. “Informed consent process: A step further towards making it meaningful!” Perspectives in Clinical Research 2017; 8:107-112. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543760/
