Will new treatments decrease potential participants for ongoing and future research?
In a world where more efficient and better targeted treatments are being approved at an unprecedented rate, patients are understandably eager to take advantage of the new discoveries, especially when it comes to rare diseases such as Immunoglobulin A nephropathy (IgAN) where safe and effective treatment options are very limited.
IgAN is a rare disease that damages the kidneys’ tiny filtering units and can lead to kidney failure, requiring a kidney transplant or dialysis. It may go unseen for years and can happen at any age, but symptoms most often start before the age of 40. The causes of IgAN aren’t well known other than that immune and genetic factors may be involved. Disease progression depends on many factors and varies from person to person — and from ethnicity to ethnicity.
There is no cure for IgAN, and for decades treatments have focused on managing symptoms and slowing the progression of kidney disease. However, for the first time, effective treatment options beyond supportive care are becoming available, signifying a new era. Recently the FDA granted accelerated approval for Spartensan and Budesonide in adults with primary IgAN at risk of rapid disease progression. These drugs act in different ways to reduce the amount of protein that leaks into the urine, which in turn helps to protect the kidney.
This is obviously great news for patients, many of whom are eager to start the new therapy immediately. But early research successes are creating a new challenge for drug development. As new treatments become available, patients may well be reluctant to join new clinical trials where there is only hope — not yet proof — that the therapy will be effective. Some patients already enrolled in trials may wish to leave studies where they are receiving an experimental drug or even a placebo.
As this plays out in real time, our current and future clinical trials may be in jeopardy. The cascading effect of patients’ reluctance to enter new trials or, worse still, choosing to leave an ongoing trial, could eventually have a paralyzing effect on the development of new, even more effective treatments. Will this new era mean we are approaching a time when the old saying, “There is nothing that fails like success” might apply to the drug discovery process that has for decades yielded new, more effective treatments for chronic disease?
We are currently faced with just such a dilemma where we have several ongoing trials that are targeting different ways of treating IgAN. Physicians face an ethical dilemma when trying to determine whether to keep patients in studies or enroll them for a multi-year trial when new treatments are already available — especially in blinded trials where even the physician does not know if the patient is receiving an experimental drug or a placebo. There is also an increasing problem of patients taking prohibited medications without the knowledge of the investigators, which results in censoring of their data and affecting the integrity of the trial. A key example is the use of Ambrisentan in China. Even though there is no data for its effectiveness in IgAN, the announcement of the accelerated approval of Sparsentan resulted in an increase in the use of Ambrisentan, a similar class of drug approved for pulmonary hypertension in China.
To make matters more complicated, IgAN progresses at different speeds in different populations. Where the disease is progressing slowly, it can be argued that holding off the new treatment for trial participation can have more longterm benefits. But in patients where the disease is much more aggressive, there may well be organ-saving benefits to opting out of research efforts.
Innovation in the treatment of disease has been based on clinical trials, and it has worked very well to advance medicine. But something works until it doesn’t work anymore, and we are fast approaching the time when relying on what worked in the past may lead instead to failure if we do not begin to discuss and address this challenge.
The current landscape of clinical trials for IgAN is exciting indeed with nearly 50 trials listed on clinicltrials.gov testing different ways of targeting the disease. The hope for the future of IgAN treatments is to have multiple therapies available in order to best match a therapy to each patient’s unique medical and personal situation. The only way that we can achieve this goal is in partnership with patients who understand the value of participating in randomized clinical trials — our best mechanism for translating scientific discoveries into therapies that advance the standard of care.
It is a daunting thought that future innovations could be stymied by incremental success. We must clearly define the issue and, after careful consideration of all consequences, determine how we can keep innovation moving ahead while patients continue to reap the benefits of new treatments as they become available.
New Perspectives — New Models are Needed
Some new perspectives may be needed as we move forward, and all stakeholders should consider their roles in addressing ways to keep scientific innovation moving forward while best serving our global patients.
Value of Scientific Leaders in Clinical Trials — Scientific Leaders who are involved from the very beginnings of a study can have influence over their design and protocol. When Scientific Leaders are both clinicians and researchers, their perspective includes not only the potential benefits of the research but also how a specific trial might affect patients. As we move forward, these Scientific Leaders will be key in maintaining strong communication channels that flow between trialists, patients and their physicians. They can help physicians understand which patients are best suited for studies and most likely to stay till completion. They can also begin to include provisions in trial designs and protocols that address the possibility of patients desiring to leave studies early. For example, potential trial designs could include rescue therapy, basket trials and those designed to complete faster and more efficiently. In addition there could be potential incentives created in trials that insures early access to new therapies for patients, especially those who have participated in parts of the world where access to newly approved drugs is frequently delayed.
Need for Joint Care Plans for Patients — The idea of opening better communication between all healthcare professionals treating a patient is not a new one, but it becomes more critical when deciding to enroll a patient in a clinical trial. Whereas a nephrologist may clearly understand the nuances of the disease and whether or not a new treatment is the patient’s best option, their GP may see the situation differently. With a Joint Care Plan in place, patients could be assured that everyone involved was making the most beneficial decisions. This would lead to trials where participants are the most likely to benefit from and to complete a study.
Role of influential IgAN-specific organizations — We can also consider how organizations that patients rely on can help patients better understand their options. If patients are educated fully about all potential benefits and risks of trial participation, it could help ensure that those who choose to participate will complete the study. If could be beneficial to studies if patients had already considered that a new treatment might become available during the study and had discussed this possibility in advance with their nephrologist.
Role of Industry — Industry determines what the protocols look like, so by taking all factors into consideration at the very early planning stages they can make provisions that consider all possibilities for participants. Collaboration with Scientific Leaders, IgAN organizations and patients in the planning stages can help ensure that their trial is designed with the big picture in mind. Acknowledgement of these new challenges and proactive planning can help avoid issues that might derail a trial.
Role of Patients — Patients come in all forms. Some are extremely engaged in their care and do everything they can to learn about their disease and the options available to them. Others trust their healthcare providers and expect that the best decisions for them are being made. Therefore, although it is advisable for patients to learn all they can about their disease and take ownership of their healthcare journey, it is quite unfair to assume that all patients are going to have the experience or take the opportunities to engage in that manner. Therefore, there is a greater burden of responsibility on the professionals to ensure that patients remain knowledgeable, monitored and protected.
Kidney disease has had a long wait for new treatments, and these forerunners of, hopefully, many more to come are very exciting to patients and physicians alike. But it is yet to be proven that these are the right solutions for all patients, and there is much more work to be done. Everyone in the clinical research ecosystem needs to acknowledge the possibility that as new treatments become available, we could witness an increased difficulty in clinical trial enrollment. Together we should openly discuss the potential affects of such a phenomenon and work as a team to address the issue and determine the best way forward. A higher quality of life and greater longevity for patients is everyone’s ultimate goal, and research is the essential element in making even more beneficial discoveries. Our creative thinking and careful planning can help to avoid our early successes leading to future failures.