We are fortunate in our office to have the opportunity to take part in research of new biosimilar medications before they come to the market. Although the responsibilities involved with clinical trial research are sometimes burdensome, it is often interesting to get a window into the future.
As a brief primer, here is a summary of the various clinical trial phases.1
Following pre-clinical studies (i.e., animal studies that evaluate dosing safety, pharmacodynamics, and pharmacokinetics), phase 1 trials focus on the maximum tolerated doses of drugs, how the drug should be given, and pharmacologic effect. Phase 1 trials are typically small (around 20 people).1
Phase 2 trials enroll up to 100 people with the disease of interest and focus on therapeutic efficacy and toxicity via investigation of optimal doses, dose frequencies, administration, routes, and endpoints. In some instances, neither the investigator nor the patient knows who is on the experimental drug. Drugs that are identified as effective and safe in a phase 2 trial progress to a phase 3 trial.1 Approximately 1/3 of drugs tested in phase 2 trials will move onto phase 3 studies.2
Phase 3 trials compare the investigational drug with established therapies and/or placebo in a much larger and more diverse group of people (e.g., 300-3,000 subjects). The most common type of phase 3 trial focuses on comparative efficacy (i.e., placebo-controlled) and compares the intervention with a standard therapy or placebo. Phase 3 trials typically ensure balance in treatment allocation in order to compare treatment efficacy through randomization and stratification.1
Once phase 3 trials are complete and the data from them is compiled and analyzed, a drug company can apply to have the tested medication reviewed for possible approval by the U.S. Food and Drug Administration.
Centers that are involved in clinical research benefit in a variety of ways. Certainly, one of the major benefits is that it allows patients who would not otherwise be able to access certain medications to receive these drugs for free. There is, of course, a tradeoff. Participants in these trials must comply with rigorous standards at each regularly-scheduled visit that may involve extensive blood draws (i.e., 16 vials or more), electrocardiograms, time-consuming joint counts, and lengthy questionnaires. It’s not unusual for each visit to take 3 hours. So while patients receive a small stipend to compensate them for the time spent in the clinic for each visit, the wear and tear can be difficult for those dealing with chronic pain.
Patients involved in a clinical trial must also qualify via strict inclusion criteria. Some exclusionary criterion I have seen include no corticosteroid use for >3 months, no previous use of methotrexate, and no history of biologic therapy. Especially in the United States, finding patients who meet these criteria can be a major challenge.
So then what about the healthcare provider? What roles do we play?
First of all, if you are the assessor (i.e., the one performing the joint count or otherwise evaluating the patient), you are typically blinded to the investigational product that the patient is receiving. Your role is primarily to accurately document results from every patient visit. If you are unblinded, you will be aware of the drug the patient is receiving but you are not involved in the assessment of a patient’s progress. You are often responsible for distributing the specific, unmarked boxes containing medication to the blinded assessor. A third role can be the infusion nurse or medication administrator, who also must be blinded. In this role, the healthcare provider monitors the patient during administration of the investigational or comparator product for any untoward side effects. They must also scrupulously abide by set time limits for administration and monitor pharmacokinetic levels during the infusion.
In one recent study where I served as a blinded investigator, I met JY, a woman with severe rheumatoid arthritis (RA) in her late 20s who was significantly overweight. She had lost her job and her insurance, and was struggling to get through each day with terrible pain and restricted mobility. The majority of her RA symptoms involved her upper body—her toes were rarely involved. Exercise was a challenge due to JY’s weight, which excluded her from many study protocols. She was therefore thrilled to qualify for a clinical trial where she would be receiving either a biosimilar or its reference biologic.
At her baseline visit before any study drug was administered, I performed an assessment of JY’s joints. She had 28 tender and 30 swollen joints, which explained why many activities of daily living such as getting dressed were a significant burden. Nevertheless, JY was a great patient who was always prompt and conveyed a positive attitude. “I just want to get better for my sister’s wedding next year,” she told me. Having a concrete goal likely motivated JY, and she always had a smile for me when I entered the room with my electronic tablet to record any study-related findings.
Only 2 months after administration of the first Investigational product in this biosimilar trial— remember, I had no idea whether JY was receiving the study biosimilar or its reference biologic—JY’s swollen and tender joint count had markedly decreased. She was elated with how she was feeling, and I even joined JY in looking at dresses she might be able to wear at her sister’s wedding.
Unfortunately, the good vibes didn’t last long. Because the study protocol required extensive lab tests at every visit, I had more information available than I would with a normal patient. After 3 months in the trial, JY’s liver enzyme levels began slowly creeping up. At the following visit, they were high enough to preclude JY from receiving the investigational product. Not surprisingly, her tender and swollen joint count started to climb quickly, settling back in near baseline levels. As per the study protocol, JY’s participation was put on hold until it was determined whether it was safe to resume treatment.
As a nurse, this put me in a tough spot. It was heartbreaking to see JY’s deteriorating condition, but all I could do was assess her joints at each visit and report the findings. One of our rheumatologists also saw JY at every visit and did everything possible within the boundaries of the trial to mitigate her pain, but we were limited in what we could offer without JY dropping out of the trial altogether.
A month before JY was to attend her sister’s wedding, we started adjusting our expectations and looked for a dress she could wear comfortably that would cover her hands and arms. Thankfully, a week later, we received confirmation that the investigational product JY was receiving had indeed caused the liver enzyme abnormalities. She therefore discontinued participation in the trial and was started on a biologic agent outside of the trial. Our authorization department, the miracle workers that they are, found a program that qualified her for etanercept only because she had failed so many other therapies. Within 2 weeks, her joint count improved drastically. This helped her attend the wedding with far less pain and greater mobility. She said to me, “I may not be tiny or gorgeous, but I feel really so much better now. Thank you for being at my side!”
Being a part of clinical research requires an understanding of the roles of the healthcare team. There are limits to what we can do to help in some instances. Patients like JY are truly valued—not only did she bring a great attitude to every visit, but the data we collected regarding the ups and downs of her experience are extremely valuable when the final assessment of the results are calculated to determine overall efficacy and safety.
AUTHOR PROFILE: Jacqueline Fritz, RN, MSN, RN-BC, is Owner and Coordinator of Education at the Medical Advancement Center in Cypress, CA. Her primary responsibility is working as an advanced practice nurse for a large rheumatology practice where she is involved in patient visits, research programs, and infusion center coordination. In addition, she enjoys speaking, teaching, and learning about immunology.