It Is Time for Patient-Reported Outcome Measures to Be Included in the Approval Process for Solid Organ Transplant Medications

The drive to develop more therapeutic options for kidney transplant recipients continues. In this issue of JASN, Budde et al.¹ report the findings of a large multinational trial randomizing kidney transplant recipients to either remain on calcineurin inhibitors (CNIs) or be converted to belatacept. This study is an important addition to the kidney transplant literature because it reproduces the clinical use of belatacept and demonstrates noninferiority to remaining on CNIs. The traditional outcomes measures (patient and graft survival, rejection, and development of de novo donor-specific antibodies) used to assess the efficacy of immunosuppressive medications were studied. Although of clinical significance, this study does not measure outcomes that are important to patients because traditional end points do not capture outcomes from the patient's perspective.

As the practice of kidney transplantation evolves, it is becoming essential to tailor therapy to the needs of patients. These requirements can be varied and may include once daily medication dosing regimens to accommodate a work schedule or reduce side effects that limit life participation. Although belatacept is an excellent immunosuppressive medication and provides better long-term eGFR outcomes,² in clinical practice, it is also frequently used to reduce the many side effects of CNIs.³ The elimination of these side effects allows patients to more fully participate in life and work in addition to experiencing an improved sense of well-being. In the case of belatacept, the increased risk of early rejection does not impair long-term graft function. However, in general, do the benefits of eliminating side effects offset an increased risk of rejection and potential graft loss? The answer depends on your perspective. For clinicians, graft loss resulting in the need for dialysis may not be a risk worth taking to reduce side effects. On the other hand, for a patient, a rejection detected and treated early resulting in a long-term eGFR comparable with or higher than with CNIs may be worth the risk, particularly if there is a better side effect profile. Which choice is correct is unknown. This uncertainty highlights the importance of including patient perspectives when deciding on outcomes to be measured when designing clinical trials for new immunosuppressive medications.

The development of new therapeutic agents in transplantation is impeded by excellent expected outcomes, resulting in little room to demonstrate a superior effect.⁴ Acknowledging this, the authors designed a noninferiority trial. They concluded that belatacept is noninferior to CNIs for patient and graft survival, rate of rejection, and formation of de novo donor-specific antibodies. There is little debate that these outcomes are significant and should be included in new drug approval. However, is belatacept really a noninferior choice for treating kidney transplant recipients? There are neurocognitive, metabolic, cosmetic, and compliance benefits of belatacept over CNIs. These outcomes were not included when evaluating belatacept for de novo immunosuppression or conversion immunotherapy. Additionally, although not a traditional patient-focused end point, kidney function, as assessed by eGFR, factors heavily into a patient's sense of well-being.⁵ There is a growing consensus that outcomes important to patients, patient-reported outcome measures (PROMS), should be incorporated into clinical trials in kidney transplantation.⁶

In the disciplines of rheumatology⁷ and inflammatory bowel disease,⁸ PROMS are now being used to assess the efficacy of medications. There is a growing realization that the way a patient feels and “improved quality of life” are significant measures of drug efficacy, and they are leading to investment in the development of new medications. Nevertheless, drug development for novel immunosuppressive medications has primarily stalled because of the difficulty of surpassing the already lofty outcomes achieved in traditional measures of success. This makes the proposition of investing hundreds of millions of dollars into drug development less appealing and perhaps not worth the risk. In addition, because the transplant recipient population is relatively small compared with other indications and is medically complex, the repurposing of already approved medications for other indications in transplant presents a substantial risk. Adverse outcomes attributable to the transplant population may result in warnings that impair the use and marketing of the agents for the primary indication.

Including PROMS in clinical trials for transplantation will result in additional and meaningful criteria for evaluating outcomes important to clinicians and patients. Although the field of transplantation is slow to modify clinical practice partly due to the regulatory environment and the need to maintain good clinical outcomes, migration to better therapies for patients eventually occurs. The slow uptake of belatacept is an example, and was it not for the logistic challenges of drug administration, utilization of belatacept would be much greater due to its superior side effect profile. The ability to market a drug not only for traditional end points but also, for a better side effect profile or better life engagement would incentivize pharmaceutical companies to invest in new therapeutics for transplantation. In addition to providing more therapeutic options for patients, this renewed investment and research could lead to new therapeutics that provide superior long-term outcomes, such as better kidney function and delayed or eliminated return to dialysis. As demonstrated by the long-term results of the belatacept trials, the potential to achieve durable, long-term function of a kidney transplant is possible.²

Innovation in transplantation is stalled, and both clinicians and patients are settling for “good enough.” Solid organ transplantation is a medical miracle. The early pioneers in the field persevered through barriers and made what was thought to be impossible possible. We, their descendants, have worked to be good stewards of their achievements and have held to the old tenants of protecting the allograft and keeping the recipient alive, with an imposed stoicism on our patients that the side effects are to be tolerated. After all, the side effects are better than the alternative. Graft survival and patient survival are foundational principles of which the field of transplantation cannot lose sight. However, in our quest to put more years into life, we cannot ignore that our patients may want more quality of life in their years. The Federal Drug Administration is beginning to consider patient perspectives on the efficacy of transplant medications to gain a more holistic view of how to approve new therapies.⁹ It is time for the transplant community to shift its frame of reference from exclusively the traditional outcome measures and advocate for the inclusion of patient-focused outcomes in the approval process for new therapeutic agents in transplantation. This will better serve our patients and will lead to generational advances in solid organ transplantation.

Disclosures

R.N. Formica reports consultancy agreements with Gennentech Pharmaceuticals, Mallinckrodt Pharmaceuticals, Novartis, Sanofi, and Veloxis Pharmaceuticals; honoraria from Gennentech Pharmaceuticals, Mallinckrodt Pharmaceuticals, Novartis, Sanofi, and Veloxis Pharmaceuticals; scientific advisor or membership with Gennentech Pharmaceuticals, Novartis, and Veloxis Pharmaceuticals; speakers bureau via nonbranded educational lectures for Sanofi; and other interests/relationships as President of the American Society of Transplantation and a member of the United Network of Organ Sharing/Organ Procurement and Transplantation Network Membership and Professional Standards Committee. N. Turgeon reports consultancy agreements with Natera as Chair of the Medical Advisory Board and Vertex as a member of Data Safety and Monitoring Board; honoraria from Natera and Vertex; and scientific advisor or membership with American Journal of Transplantation as an associate editor, Clinical Transplantation as an associate editor, JASN, Natera as Chair of the Medical Advisory Board, and UNOS as the Policy Oversight Committee Chair.

Funding

None.