The Importance of Drug Safety and Tolerability in the Development of New Immunosuppressive Therapy for Transplant Recipients

The Transplant Therapeutics Consortium's Position Statement

Mark D. Stegall; Kenneth Troy Somerville; Matthew J. Everly; Roslyn B. Mannon; A. Osama Gaber; M. Roy First; Neetu Agashivala; Vanessa Perez; Kenneth A. Newell; Randall E. Morris; Debra Sudan; Klaus Romero; Sonya Eremenco; Maria Mattera; Nicole Spear; Amy C. Porter; Inish O'Doherty


American Journal of Transplantation. 2019;19(3):625-632. 

In This Article

Abstract and Introduction


The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.


Over the past 50 years, solid organ transplantation has improved remarkably. Kidney transplantation has developed to the point where it clearly results in higher patient survival, higher quality of life, and lower health care costs compared to dialysis[1,2] and the 1-year graft survival after a deceased donor kidney transplantation is 95%.[3]

Yet transplantation could be better. For example, approximately 20% of patients die in the first 10 years after a successful kidney transplantation.[3] The need for lifelong immunosuppression means that patients are at risk for malignancy and opportunistic infection.[4] Many patients experience significant side effects from immunosuppressive medicines including diarrhea, diabetes, and tremors, thereby diminishing quality of life.[5] Finally, almost all kidney allografts eventually fail and most young recipients will need a second or even a third transplant in their lifetime. The combined impact of alloimmunity; comorbid diseases such as diabetes, obesity, and hypertension; and potentially nephrotoxic calcineurin inhibitors contributes to chronic renal allograft injury and late graft loss.[6]

Unfortunately, new therapeutic options that might improve patient outcomes have not emerged and standard-of-care (SOC) immunosuppression has remained relatively unchanged for almost 20 years. Recognizing the need to improve the process of developing new therapies in order to make the space more accessible to the pharmaceutical industry, the American Society of Transplant Surgeons (ASTS), the American Society of Transplantation (AST), and Critical Path Institute (C-Path) established the Transplant Therapeutics Consortium (TTC) in March 2017 as a public-private partnership between the transplantation community, the biopharmaceutical industry, and the US Food and Drug Administration (FDA) (Figure 1).

Figure 1.

The Transplant Therapeutics Consortium (TTC) founded as a public-private partnership between the transplantation community, the biopharmaceutical industry, and the US Food and Drug Administration (FDA)

From its inception, the TTC members have striven to understand potential challenges to the development of new therapies from all perspectives including industry and regulatory agencies. The decision was made to focus on kidney transplantation initially and to extend our efforts to other types of organ transplantation later.

The TTC identified long-term graft survival as one of the major unmet needs in kidney transplantation and plans study issues related to new endpoints and biomarkers needed to streamline the evaluation of new therapies. However, in early discussions within the TTC, developing new tools to assess drug safety and tolerability also emerged as an important issue for the development of new therapies.

The use of "Drug-Development Tools" (DDTs) (methods, materials, or measures that aid drug development[7]) has emerged as a key component of developing new agents in all therapeutic areas. An appreciation of the role of DDTs in the evaluation of new therapies is important in order to understand the rationale for the TTC's proposed activities. A core concept of the TTC is that the historical patient-level data from numerous multicenter trials and in large, single-center databases is a valuable resource to the community, and that these data have the potential to drive innovation in drug development. An entire section of this article is devoted to Drug-Development Tools (or DDTs).[7]

This article has 3 goals. First, to examine why issues related to drug safety and tolerability are important for the development of new therapies for transplant patients in order to bring the industry and the FDA perspective to clinicians. Second, to examine the current status of patient-reported outcome (PRO) measures and to describe how these important measures of drug tolerability might someday be incorporated into the evaluation of treatment benefit for new drugs in transplant recipients. And the third goal is to introduce the concept of DDTs and to educate the transplant community about the critical role that DDTs (developed in collaboration with the FDA) play in improving the process of developing new therapies for transplant patients.

Drug Safety and Tolerability

Issues related to a drug's safety can be a major barrier to regulatory approval and clinical acceptance as a new therapy. Kidney transplantation is clearly safer than dialysis when viewed as overall patient survival over time.[1,2] However, there are clear safety issues associated with receiving lifelong immunosuppressive therapies. With the current SOC (tacrolimus, mycophenolate mofetil, and sometimes prednisone), it is accepted that kidney transplant recipients incur numerous adverse events (AEs) and serious adverse events (SAEs)[8] (see Table 1). For example, infections and malignancies are relatively common and can be life-threatening. Similarly, new-onset diabetes requiring insulin injections is common, and readmissions for nephrotoxicity and rejection are accepted AEs associated with kidney transplantation.

Transplant patients at baseline have single or multiple end-stage organ diseases that might either be directly related with SAEs or markedly increase their likelihood (ie, urinary tract infection in a patient with diabetes and an atonic bladder). Such high-risk comorbidities would generally exclude patients from clinical trials in other therapeutic areas. Determining that an AE or SAE is truly caused by the use of a novel, additional, immunologically active investigational drug that has been added to the SOC medications, which are already associated with a wide array of AEs, can be difficult. In fact, it is estimated that SAEs defined by the need for hospital readmission will be recorded in more than 25%-30% of transplant patients taking current SOC treatments.[9] Furthermore, as transplant immunosuppressive efficacy gradually improved, the assessment and level of acceptance of AEs by the transplant community have also changed with time. This is best exemplified by Orthoclone OKT3 (muromonab-CD3), the first monoclonal antibody approved by the FDA (1986), which opened the door to the use of monoclonal antibodies in diseases ranging from autoimmunity to cancer treatment. This agent was an important breakthrough in transplantation, but the associated AEs are significant when compared to today's immunosuppressive regimens.

Belatacept, one of the few drugs approved for kidney transplantation in the past decade, has a "boxed warning" stating: "Increased risk for developing posttransplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only."[10] This example illustrates not only the importance of safety in labeling, but also how the FDA may approve a drug for one group of patients and exclude others based on available safety data.

Other questions also exist regarding drug-safety profiles in kidney transplant recipients. Should acceptable safety profiles be the same for low-risk patients receiving de novo therapy for their first kidney transplantation as it is for patients with antibody-mediated rejection receiving rescue therapy to prevent imminent graft loss? What should the safety profile of a treatment be for immune tolerance protocols or for xenografts?

Yet another issue related to AEs and tolerability is that immunosuppressive drugs (ISDs) generally are dosed using a "one size fits all" approach. The tools available to measure the adequacy of immunosuppression in the individual patient are lacking. The development of a tool that provides evidence of adequate immunosuppression in a particular patient might allow tailoring of immunosuppression, which could improve both safety and tolerability.

What data do we have to evaluate the safety of a new agent in transplant recipients?Unfortunately, despite a large number of trials with an SOC arm, the risk for AEs and SAEs in kidney transplant patients specifically has been inadequately characterized. This is because the number of patients enrolled in each individual trial lacks the sample size and power to comprehensively characterize the safety profile for the general transplant population (with greater detail and longitudinally), let alone different patient subgroups. Therefore, even the seemingly logical assumption that there may be different frequencies of certain AEs in different subgroups of kidney transplant patients has had no granular, patient-level data to support it.

The TTC believes that decisions regarding safety could be enhanced by the development of quantitative DDTs that model the benchmark AE safety profile of the ISDs used as the SOC. This tool is intended to describe the varying probability of AEs occurring in specific subpopulations and will be developed from a large database of aggregated studies including the type and incidence of SAEs and AEs in kidney transplant recipients (low-risk patients and more complex recipients).

Drug Safety and Tolerability: A Biopharmaceutical Industry Perspective

Biopharmaceutical companies have additional reasons to be concerned about drug safety. A major issue is that SAEs might lead to the termination of a drug-development program or removal of a drug from the market.

Clinical trials in transplant recipients can be difficult. The requirements to use standard definitions of AEs make transplant studies expensive and onerous. For example, a significant amount of time is spent recording every abnormal blood value in a study, when over 90% of these values are considered clinically acceptable in transplant and organ failure patients. This can make it difficult to determine if an AE or SAE is specific to the new drug or just a common event that could happen in either the treatment or control group.

Discussions with biopharmaceutical industry members of the TTC have revealed that the perception that kidney transplant recipients have a higher likelihood of AEs may make some companies wary of seeking indications in transplantation. A steady stream of SAEs and AEs from a clinical trial can be alarming to companies, especially those that are new to the transplant field. Compared to psoriasis, lupus, or rheumatoid arthritis, the development of a novel immunosuppressant for kidney transplant may present a very different benefit/harm profile for some companies. Historical examples of drugs that appear to have failed in transplantation due to perceived safety issues and later received marketing approval in other disease states as single therapies are the JAK-3 inhibitor tofacitinib[11,12] and fingolimod (FTY720).[13,14] On the other hand, everolimus was studied and approved for advanced renal cell carcinoma as Afinitor in 2009 and as Afinitor Dispenz for tuberous sclerosis in 2012, as well as prevention of rejection in kidney transplant in 2010.

The TTC believes that a DDT that allows development teams to better understand and quantify SAEs and AEs might inform decision making both for pharmaceutical companies and for regulatory agencies. This tool also could inform decision-making by regulatory agencies.

A Quantitative Drug-development Tool: Understanding the Safety Benchmark Profile

DDTs designed to address unmet needs are defined as methods, materials, or measures that accelerate the pace and reduce the cost of medical product development.[7] Types of DDTs include, but are not limited to, biomarkers, clinical outcome assessments (COAs), clinical trial simulation tools, quantitative drug-development platforms, and animal models. DDTs are often developed as part of public-private partnerships with the FDA (ie, the TTC) and can best be developed with input from experts in many areas—including the FDA. The specific "context of use" (COU), is defined as the description of the DDT's intended applicability and describes the way the DDTs are to be used and the development-related purpose of the use.[7] There are specific, well-defined review mechanisms for DDTs by the FDA, and by the European Medicines Agency, which refers to DDTs as novel methodologies in drug development. These pathways are intended to achieve the appropriate level of regulatory acceptance for these tools, in light of their proposed COU. Regulatory acceptance means that the tool may be used with confidence as per its stated COU to optimize clinical trial designs and regulatory decision-making (Figure 2).

Figure 2.

Pathway for developing novel quantitative drug development tools (DDTs)

Data are the foundation of all DDTs. The data required to achieve regulatory acceptance of a DDT are beyond the meta-data available from a published journal article. Integrated, longitudinal, patient-level data are required for quantitative DDTs intended to optimize clinical trial design. Aggregating the deidentified patient-level data from multiple studies (clinical trials, registries, and observational studies) into a harmonized database requires data standardization, and the Clinical Data Interchange Standards Consortium (CDISC) format that is required by the FDA for all data submissions. The CDISC Kidney Transplant Therapeutic Area User Guide v1.0 (TAUG-KT), completed in 2016, was developed by members of the transplant community and is available for this purpose.

The TTC plans to integrate the longitudinal patient-level data from several recent multicenter, industry-sponsored, Phase 3 (or 4) clinical trials into an aggregated dataset to be used to develop quantitative DDTs. To allow inclusion of specific subsets of patients, large single-center datasets that are detailed and generally complete may also be considered. Quantitative models will be developed using this aggregated dataset to describe the time-varying probability of individuals developing specific SAEs and AEs in association with SOC immunosuppressive therapies used in the control arms of kidney transplant trials. It is notable that the aggregated dataset will also be used in the TTC's biomarker/endpoint efforts to develop a DDT related to graft survival.

Patient-reported Outcome Measures

The FDA defines a clinical endpoint as how a patient feels, functions, or survives.[15] Patient-reported outcome (or PRO) measures are defined as "any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else."[16,17] Because PRO measures are a means to determine how a patient feels and functions, PRO measures are possible endpoints for drug-approval studies.

In 2016, the FDA held a meeting on Patient-Focused Drug Development (PFDD),[18] which highlighted the patient perspective on transplantation. At this meeting, transplant recipients indicated that the management of complex treatment regimens and side effects posttransplant remain key concerns, posing challenges for medication adherence. Indeed, many recipients experience side effects with immunosuppressive drugs including diarrhea, restlessness, tremors, insomnia, headaches, and depression. For patients, these side effects are constant reminders of the disease they have and the fact they are not "normal." It is also likely that some patients avoid taking immunosuppressive medications or other medications because of these side effects and the overall pill burden associated with these treatments.[18] Thus, it may be possible to achieve the same or even better graft survival aided by the development of biomarkers of tolerance or immunologic status and PRO measures to assess tolerance, in order to determine the lowest effective dose of immunosuppressive medications.

Over the past several years, there has been increasing interest in the use of PRO measures in many areas of medicine including recent progress in patients with cancer.[19–21] In transplantation, several PRO measures have been suggested, but none has yet been approved by the FDA for any transplant indication. Table 2 lists some of the health-related quality-of-life (HRQoL) and ancillary PRO measures that have been used in prospective renal transplant studies.[22–38] Other PRO measures have also been used in nonrenal transplant, pediatric populations, and in other disease states.

A PRO Measure Drug-development Tool

The TTC is considering the development of a PRO measure in its future scope of work. Unfortunately, the multicenter data needed to create such a tool are much less robust than data for other proposed tools. An assessment of the current status of PRO measures in other areas of medicine is an important first step in developing PRO measures in transplantation.

The proposed PRO measure could be a modified version of an existing measure or a new measure. Many currently available measures focus on HRQoL in kidney transplantation. In addition, PRO measures capturing immunosuppressive side effects and nonadherence have been developed. Outside of transplantation, PROMIS (Patient-Reported Outcomes Measurement Information System) is a source of measures and questions that have been tested and could be adapted to transplantation. However, there is a need for a kidney transplant–specific PRO measure, which captures all the key concepts of interest to the patient while adhering to FDA guidance for the use of PRO measures to support labeling claims in drug development.[16]

An example of a PRO measure from oncology that may be of utility to transplantation is the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).[19–21] The PRO-CTCAE has been developed over the last 10 years to measure the symptomatic AEs from the patient's perspective and consists of a 124-item library covering 78 symptomatic AEs to complement clinician AE reporting using the CTCAE.

The process toward validated transplant-specific PRO measures for tolerability assessment may be years away and will require the investment of resources but, in order to have these available in the future, the development process needs to begin now. Two valuable next steps in this process would be to mine and evaluate (1) the item library developed as part of the PRO-CTCAE for oncology and examine which items overlap with the symptomatic AEs experienced by transplant patients and might be adapted for use in kidney transplant, and (2) the existing PRO measures already used in kidney transplantation (Table 2).