Considerations for Clinical Review of Cellular Therapy Products: Perspectives of the China Food and Drug Administration Center for Drug Evaluation

Abstract

With increasing numbers of technical developments and clinical studies, pioneering cellular/gene therapies are now available that could cure life-threatening disease. Cellular/gene therapy products are broad-ranging and complicated, and thereby bring challenges for clinical review by regulatory agencies. This review discusses principles for the clinical review of cellular therapy products, including protection of clinical trial populations, pharmacodynamics, pharmacokinetics, dose evaluation, clinical efficacy, clinical safety, and risk-management plans. Based on these principles, key points in the clinical review of chimeric antigen receptor T-cell therapy are also discussed.

Introduction

Technical advances and clinical studies of stem-cell therapy, immune-cell therapy, and gene editing technology led to the development of cellular/gene therapy products that can provide new therapeutic strategies and methods to treat several severe and intractable diseases. In particular, chimeric antigen receptor (CAR) T-cell therapy has been approved by the U.S. Food and Drug Administration (FDA) as a new treatment for hematologic malignancy. This approval marks the progression of cellular/gene therapy from a potential concept to a practical treatment. Therapies such as CAR T-cell therapy can induce rapid and durable clinical responses, but can also be accompanied by unique acute toxicities due to specific therapeutic mechanisms and immunogenicity, which can be severe or even fatal. Some early experiences indicated that cytokine-release syndrome (CRS) and neurotoxicity are the most common toxicities associated with CAR T-cell therapy. These cases demonstrate that risks for cellular/gene therapy products differ from those for other common pharmaceuticals. Therefore, clinical studies of cellular/gene therapy products require specialized monitoring and management.

The History of Cellular Therapy Product Regulation in China

The first guideline to define and classify biological products in China was promulgated by the China Food and Drug Administration (CFDA) as Approval Method of New Biological Products in 1999. In 2003, the CFDA published Guidelines for Human Cell Therapy Research and Quality Control of Products, and Provisions for Drug Registration (Order No.28) in 2007. In the 2007 version, biological products were divided into therapeutic products and prevention products. From 2009 to 2011, clinical application of autologous stem cells and immune cells was managed as a medical technology under the authority of the National Health and Family Planning Commission (NHFPC). The NHFPC subsequently published a list for review agencies and allowed clinical applications of stem and immune cell therapies as medical technology. However, in 2015, allowance of clinical applications of stem- and immune-cell therapies as medical technology was rescinded, and medical institutions were allowed to self-manage application of these treatments. After the Zexi Wei Event (Box 1) in 2016, the NHFPC immediately suspended all clinical applications without approval as a third type of medical technology. At end of this year, the CFDA/Center for Drug Evaluation (CDE) formally drafted and consulted the public to compile their Guidance for Research and Evaluation of Cellular Therapy Products.

Box 1.

Zexi Wei was diagnosed with synovial sarcoma and had been undergoing immunotherapy using autologous cytokine-induced killer cells. His family found the treatment through a Baidu search. The treatment was controversial and cost approximately U.S.$31,150. Before his death, Zexi Wei wrote about his experience, which, when reprinted in a news article, aroused public concern about cell-based immunotherapies.

The Scope of Cellular Therapy Products in China

According to CFDA guidelines, the scope of cellular therapy products encompasses treatment of human diseases with viable human cells, for which the origin, operation, and clinical trials are in compliance with ethical requirements. Moreover, development and registration of these products should follow the laws and provisions of the relevant drug administration. These guidelines do not apply to blood components for blood transfusion, established hematopoietic stem cell transplantation, reproductive-related cells, or tissue and organ products derived from cells.

Risk Management

Research and development for cellular therapy products is advancing rapidly. The existence of multiple cellular products as well as their distinct properties and complex nature require risk-management strategies tailored to each product.

The risk to patients depends on the type of cellular therapy product and the processes used for manufacturing. Thus, the risk of cellular therapy products should be fully analyzed based on current knowledge and expected clinical outcomes in the early stages of research and development. Safety data should be collected and updated throughout the product life cycle to prevent potential risks. General factors associated with overall risks for products include, but are not limited to: cell origin; extent of cell manipulation; the capacity of cells to proliferate, differentiate, and migrate; length of cell culture or exposure of cells to specific substances; cell life-span and generation; toxicities of noncellular components; cellular changes following physical, chemical, and/or gene modifications; combination products (e.g., cells and bioactive molecules or structural materials); the ability to activate immune responses; cross-reactivity; modes of administration and pretreatment; and the availability of clinical data or experience with analogous products.

During the development of cellular therapy products, risk evaluation based on constantly changing risk factors should be performed frequently. In particular, risk evaluation should be considered when determining which risk factors are associated with product quality and safety, key data in nonclinical and clinical development, and risk-minimization measures.

In addition, the origin, acquisition process, and operation of cell therapy products should be ethical. Manufacturers should be required to establish an “informed and confidential” management system to allow donors to understand the use of these cells fully and to ensure full protection of their personal information. Disposal of unused or remaining cellular therapy products or donor cells must be appropriate from a legal, ethical, and biosafety standpoint. Thus, manufacturers should be required to establish a management system to ensure the traceability of products from donor to patient, that is, the donor–product–recipient axis or autologous products–recipient axis, while standardizing and monitoring operations to prevent mixing of different donor samples or different batches of samples strictly.

Clinical Development Considerations for Cellular Therapy Products

When cellular therapy products enter clinical trials, Good Clinical Practice must be followed. Clinical trials generally include clinical safety assessments, pharmacokinetic (PK) studies, pharmacodynamic studies, dose exploration studies, and confirmatory clinical trials. Depending on the nature of the product, protocols may be adjusted as appropriate. In view of the special biological characteristics of cell therapy products, clinical trials must be developed and conducted using strategies that differ from those used for trials of other drugs. To achieve the desired therapeutic effect, cell therapy products may need to be administered via specific surgical procedures, methods, or combinations of the two. Moreover, cell therapy products have unique properties, including production characteristics and the results of preclinical studies, which may affect the design of corresponding clinical trials.

Clinical development considerations should address the following items: protection of the clinical trial population, pharmacodynamics, PK, dose exploration, clinical efficacy, clinical safety, and a risk-management plan.

Protection of the clinical trial population

Selection of the most appropriate study population involves several considerations. The objective is to select a trial population using deliberative assessment of anticipated risks and potential benefits, while also allowing the achievement of study goals.

Early-phase trials will have considerable uncertainties about expected benefits or risks. For high-risk cell therapy products that have extended or permanent expected effects or require invasive procedures, only those patients who would gain the most benefit from the therapy should be selected for the clinical trial. Disease stage and severity as well as available medical treatments should also be considered when selecting appropriate subjects for clinical trials. Those patients who have incurable, life-threatening diseases and/or severe disability for which no effective treatments are available are candidates for clinical trials involving cellular therapy products. The potential risks should be identified and minimized for each subject. Furthermore, if patients require future transplantation of cells, tissues, or organs for disease treatment, the potential influence of antibodies induced by allograft cell therapy products on the success rate of transplantation should be considered.

Subject selection may affect the risks and benefits of clinical trials. Therefore, patient selection should minimize risks, improve analysis of clinical results, and increase both individual and social benefits. Meanwhile, the risks and benefits for subjects should be clearly outlined in the informed consent.

Pharmacodynamics

For individual cell therapy products, the main effect should be clarified, even if the mechanism is not clear. In early-phase clinical trials, the primary objective should be safety evaluation, and preliminary efficacy assessment, using either short-term responses or long-term outcomes, is a common secondary objective. Such proof-of-concept data can provide support for subsequent clinical development. Assessments of the activity of cellular therapy products can include specialized measures such as gene expression, cell engraftment, and changes in morphology and biomarkers, as well as more general measures such as changes in immune function, tumor volume, or various types of physiologic responses.

When a cellular therapy product is designed to correct functional deficiencies in impaired cells/tissues, functional tests should be implemented. If the intended aim of a cellular therapy product is to restore/regulate/replace cells or tissues with an expected lifelong functionality, structural/histological assays can be potential pharmacodynamics markers measured by microscopy, histology, imaging, or enzymatic assays. When the cellular therapy product involves noncellular components, compatibility, degradation rate, and functionality should be evaluated.

PK

Traditional PK studies are generally not suitable for human cellular therapy products. For human therapy products, in vivo studies should be developed to the greatest possible extent, and study requirements, possible methodologies, and feasibilities for clinical trials should be discussed. Additional attention is needed to monitor cell viability, proliferation/differentiation, tissue distribution/migration, and related biological functions during the intended activity of the products. If multiple administrations of cell therapy products are being considered, the clinical protocols should address the expected in vivo life-span and related functions of products.

Dose exploration

One aim of early-phase clinical trials is to identify the effective dose range of the cellular therapy products. If possible, the maximum safe dose should also be investigated. Dose selection should be consistent with product potency and be based on findings from quality and preclinical studies.

In contrast to small-molecule drugs, establishing an initial starting dose for first-in-human trials of cellular therapy products based on traditional preclinical PK and pharmacodynamics can be difficult. If available, previous clinical experience with certain cellular therapy products can help to justify the clinical starting dose. Many cellular therapy products can be retained or have an extended duration of activity, so first-in-human trials should, in principle, use a single administration regimen, with repeated dosing used after gaining a preliminary understanding of product toxicity and activity duration. Early-phase clinical trials for cellular therapy products often adopt dose escalation in half-log (10^0.5-fold) increments. However, development of any dose-escalation protocol should also consider preclinical and clinical (if available) data regarding the risks and activities associated with dosage changes. In terms of safety risks that are specific for a given cellular therapy protocol, administration intervals and follow-up should be of sufficient duration to allow monitoring of acute and subacute events.

Although the dose of cellular therapy products may also depend on characteristics of individual patients, evidence from dose exploration in the early phases of clinical trials will provide an important basis for confirmatory clinical trials.

Clinical efficacy

Efficacy studies performed in the target patient population should have adequate sample size, reasonable controls, and clinically meaningful endpoints to provide a foundation for confirmatory clinical trials. At the same time, a clinical trial should be able to provide an appropriate dose schedule that results in a prospective therapeutic effect, suitable duration of therapeutic effect, and acceptable benefits and risks in the target population.

Confirmatory studies of specific indications should be consistent with existing general guidance. During studies, reasonable explanations for deviations from the norm are required. Previously validated or generally accepted endpoints can be used as surrogate endpoints, which are clinically meaningful and related to efficacy. If the product efficacy is dependent on long-term cell infusions, the clinical trial should include an observation period consistent with the expected biological activity of the product, and a long-term follow-up plan should be provided.

Clinical safety

Safety monitoring of cellular therapy products should be conducted throughout the entire development process. All safety issues arising during preclinical development should be appropriately addressed, especially when appropriate animal models are lacking or the absence of physiologic differences limits the predictive value of a homologous animal model for safety assessment.

When defining clinical studies and the target patient population, risk assessment of cellular therapy products should be taken as a whole, including accompanying surgical methods and/or immunosuppressive therapies. Since the major objective of early-phase trials is to evaluate safety, other subjects should be enrolled on a case-by-case basis based on the risk considerations only after safety for the first subject has been adequately assessed. General safety monitoring items typically include recording of symptoms and routine clinical measurements. Specific monitoring programs will depend on multiple factors, such as the nature and mechanism of the product, the study population, animal study results, and any related clinical experience. Sponsors should capture all adverse events during clinical trials. To identify unanticipated safety issues, additional evaluations may include assessments of specific safety issues, such as acute or delayed infusion reactions, CRS, autoimmunity, graft failure or product inactivation, graft-versus-host disease, new malignancies, transmission of infectious agents from a donor, and viral reactivation. In addition to general symptom records and routine clinical examinations, significant changes in biological processes should be monitored, including immune response, immunogenicity, infections, and malignant transformations during both confirmatory clinical trials and post-marketing phases.

Pharmacologic activity of cell therapy products may develop slowly or even be delayed. Therefore, subjects should be monitored continuously for both safety and pharmacologic activity, regardless of whether they receive the complete treatment regimen. For products with expected long-term viability, patient follow-up is required to confirm long-term efficacy and document safety issues. During the follow-up period, the trial should provide preliminary evidence of efficacy and duration of activity, and consider whether the product induces delayed safety issues. For risk considerations, clinical safety studies of repeated administrations should be performed. The determination of the maximum safe dose should also consider the possibility of repeated administrations.

Because there is considerable uncertainty about the frequency or severity of adverse reactions in trials of cellular therapy products, most clinical trials should include both stopping rules and risk assessment plans in addition to establishing independent data and a safety monitoring committee.

Risk-management plan

When establishing a risk-management plan, strategies for routine pharmacovigilance and traceability of the product should be described. Traceability in the donor–product–recipient axis, or of the product–recipient for autologous products, is required in all circumstances, including products based on cell lines. Considerations should also include possible efficacy and safety differences in adjuvant therapy, administration, individualized preparation, or special treatment (e.g., short duration of efficacy) of the product. Regulatory and feasible standard operating procedures should also be developed as a part of risk management.

Cellular therapy products may require special long-term studies to monitor specific safety issues, including efficacy loss. Long-term safety issues, such as infections, immunogenicity/immunosuppression and malignant transformations, as well as in vivo durability of associated medical devices/biomaterial components, should be addressed. Meanwhile, safety evaluation should include a sufficient follow-up period, which can even be lifelong in the case of high-risk cell therapies. As understanding of cell therapy products increases, the follow-up interval can be prolonged or shortened as needed. Special pharmaco-epidemiological studies may also be required based on the biologic characteristics of individual cellular therapy products.

Clinical Review Considerations for Car T-Cell Therapy

In August 2017, the U.S. FDA approved Kymriah as the first cell-based gene therapy for patients ≤25 years old with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Yescarta, approved by the U.S. FDA in October 2017, is the second approved gene therapy and the first for certain types of non-Hodgkin lymphoma (NHL). Both products are CAR T-cell therapies that target CD19 expressing cells in vivo. To prepare CAR T cells, the patient's own T cells are harvested and then genetically modified ex vivo by retroviral or lentiviral vectors encoding an anti-CD19 CAR. For Kymriah, the CAR is a murine anti-CD19 single-chain variable fragment linked by a CD8 hinge to a transmembrane region fused to 4-1BB (CD137) and CD3 zeta. For Yescarta, a CD28 hinge links to a CD3 zeta co-stimulatory domain.

To minimize the risk to patients, the CAR T-cell therapy should be primarily considered for the relapsed or refractory cancer. However, pre-existing immunity of patients will influence the fate and outcomes of response to immunotherapy and CAR T-cell therapy. A recent study evaluated 133 patients with ALL, chronic lymphocytic leukemia (CLL), or non-NHL treated with CD19 CAR. Patients having four or more prior antitumor treatment regimens and an absolute neutrophil count <500 cells/mm³ before CAR T-cell infusion had higher infection density.¹ In the multicenter ZUMA-1 Phase 1 study, a patient who experienced dose-limiting toxicity had a high-level inflammatory state baseline with underlying active herpes simplex virus type 1 on day 0 of CAR T-cell infusion. This case emphasized that the immune condition of patients should be cautiously evaluated before lympho-depleting chemotherapy,² and that patients with uncontrolled systemic infections should be excluded. Unlike immunotherapy involving monoclonal antibody, patients must have appropriate tumor burden in order to undergo CAR T-cell therapy. Patients having low tumor burden have lower CD19+ antigenic stimulation that drives CAR T-cell expansion and persistence. Yet, a higher burden has increased risks related to CRS or tumor lysis symptoms. Patients should also be excluded if they have recently received treatments that could influence CAR T-cell activity, such as corticosteroid therapy/low dose chemotherapy/cytotoxic chemotherapy.

Selection of the optimal dosing strategy and treatment duration of CAR T-cell therapy remains controversial.³ Kymriah and Yescarta are administered either as a single dose based on patient weight, or as a flat fixed dosing in JCAR017 (NCT03310619). Although those products had different dosing strategies, the total number of cells was approximately 10⁸ CAR-positive viable T cells. Previous experience might help to justify the clinical starting dosage. In a CAR T-cell therapy Phase 1 trial for ALL, the average cell number for responsive patients was 20 CAR⁺ T cells/μL in circulation,⁴ but the cell number increased to 30–40 CAR⁺ T cells/μL in patients with grade 3–4 CRS. Another clinical trial found that high-dose CAR T cells (2 × 10⁷ CAR⁺ T/kg) induced cardiac and neurologic toxicity, and even death.⁵ Early dose-escalation trials should not only avoid life-threatening toxicity at high-dose levels, but also reduce invalid security subjects at low-dose levels.

Despite the small number of subjects in previous clinical trials, the overall and complete response rates for CAR T-cell therapy were still higher than historical controls for hematological malignancies. Combined with risk–benefit assessment, the objective response rate should be higher than other end-line treatments for the given indication. The efficacy of CAR T-cell therapy is already generally accepted, but disease relapse occurred with CD19 negative hematologic malignancies or loss of CAR T cells in prior clinical trials. Therefore, progression-free survival or duration of response as secondary endpoints should be considered.

Data from clinical trials suggested that CRS and CAR-T cell–related encephalopathy syndrome (CRES) are the most common toxicities observed after CAR T-cell therapy. In these studies, the mechanism by which CAR T⁺ cells kill tumor cells is thought to be the main reason for a series of adverse reactions. When CAR T⁺ cells recognize and kill target tumor cells, they also release cytokines and chemokines that recruit more immune cells and amplify the immune response.⁶ The timing of cytokine and chemokine release and induction of other immune effectors is consistent with CRS and neurotoxicity outcomes. Moreover, elevated concentrations of serum interleukin (IL)-6, interferon-γ, CRP and ferritin are associated with CRS,^7,8 such that treatment with corticosteroid and tocilizumab (anti-IL-6R antibody) that can reverse CRS may be needed for patients treated with CAR T-cell therapy.⁹ The CAR T-cell therapy–associated TOXicity (CARTOX) Working Group published recommendations for assessment and management of toxicities.¹⁰ They suggest a three-step approach to managing toxicity, including CRS, CRES, and hemophagocytic lymphohistiocytosis that involves assessment, grading, and treatment. CRS usually occurs within 1–2 weeks of infusion, while CRES occurs somewhat later. Thus, close monitoring, including assessment of clinical symptoms and laboratory tests, should proceed for at least 7 days after infusion. CRS and CRES grading is performed according to symptoms manifested by patients. Depending on the grading results, patients should receive prompt symptomatic treatment and appropriate levels of supportive care, which may even entail transfer to the intensive-care unit. Since several patients have died due to CRS and sepsis, empiric broad-spectrum antibiotic therapy should also be included as a part of CAR T-cell therapy. In patients with hematologic cancers, tumor lysis syndrome also warrants consideration. This syndrome is a common disease-related toxicity wherein cytokines released from lysed tumor cells can interact with CAR T cells to induce hypotension and inflammation that increases the risk of adverse effects of CAR T-cell therapy.¹¹

Clinical outcomes of CAR T-cell therapy were better when patients received lympho-depleting chemotherapy that could enhance the activity of CAR T cells and increase levels of several homeostatic cytokines and chemokines. Although several CAR T-cell therapy clinical trials included varying doses of lympho-depleting chemotherapy, there is no consensus about the best pretreatment chemotherapy regimen. High doses of lympho-depleting chemotherapy can induce febrile neutropenia before infusion and aggravate adverse reactions after infusion. Lower doses of chemotherapy could afford clinical efficacy with limited toxicity. For example, a chemotherapy protocol using fludarabine (Flu; 300 mg/kg) induced neurologic toxicity but not severe cardiac toxicity. The protocol for Kymriah calls for intravenous administration of 30 mg/m² Flu daily for 4 days and 500 mg/m² cyclophosphamide (Cy) daily for 2 days, starting with the first dose of Flu prior to initiating the CAR T arm of treatment. The Yescarta protocol also involves the same dose of Flu/Cy as Kymriah, but intravenous administration is given on the fifth, fourth, and third day before CAR T infusion.

Future Directions

CAR T-cell therapy, as a cellular/gene therapy, marks the progression of cellular/gene therapy into a practical treatment. CAR T-cell therapy is a significant breakthrough and offers improved clinical outcomes for refractory cancers. However, this treatment approach also brings challenges for risk management by regulators and medical institutions. Indeed, approximately 24% of patients cannot receive autogenous CAR T-cell therapy due to failed expansion.¹² Thus, cellular/gene therapy requires continued improvements to manufacturing techniques and criteria for immunological evaluation to bring benefits of CAR T-cell therapy to more patients. With advances in technology, increased knowledge, and accumulated experience, the CDE can gradually improve and refine specific technical requirements for different types of cellular therapy products. Due to the variety of available cell therapy products and their potential applications, a case-by-case assessment is warranted for the design of each clinical trial. Therefore, the CDE of the CFDA encourages prospective sponsors to meet with review staff early in the development program for new therapies.

Footnotes

Acknowledgments

We thank Ruibo Wang and Fei Sun for their contributions to this work. We thank the editorial board of Human Gene Therapy for their trust and support.

Author Disclosure

The authors have no conflicts of interest.

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