How to write a clinical risk management plan for CAR-T cell therapy products that meets the registration requirements

On September 18, 2021, the official website of the Center for Drug Evaluation of the National Medical Products Administration issued the "Chimeric Antigen Receptor T Cell (CAR-T) Product Application and Marketing Clinical Risk Management Plan Technical Guidelines (Draft for Solicitation of Comments)" for comments The time limit is 1 month from the date of issuance.
This guideline is applicable to CAR-T cell therapy products.
After implementation, it will help reduce and effectively control the safety risks of CAR-T products after they are marketed to maximize the protection of patients
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The good efficacy of cell therapy products will lead the third industrial revolution of biomedicine
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At present, European and American regulatory agencies have formulated relevant guidelines for risk control plans for cell therapy products, such as the "Guidelines for Safety and Effectiveness Follow-up and Risk Control of Advanced Therapeutic Products" issued by the European Union EMA in 2018, but there is currently no domestic target for this category.
The requirements for writing a product risk management plan, this article sorts out the clinical risk management plan in this guiding principle and shares it with you based on your own interpretation
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PART 01.
Why is there a special guideline for CAR-T cell therapy products? Chimeric Antigen Receptor T Cell (CAR-T) product: refers to the genetic material with specific antigen recognition domain, hinge region, transmembrane region, costimulatory signal activation region, etc.
, through genetic modification technology, using viruses and other vectors Transformed into autologous or allogeneic T cells
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It is a relatively new field, which has shown good clinical effects for a variety of hematological tumors, and has shown greater therapeutic potential for the treatment of solid tumors
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Due to the characteristics and mechanism of action of CAR-T cell therapy products, they are different from small molecule drugs and traditional biological drugs.
Such products have a higher risk and exposed cytokine release syndrome and immunity during clinical trials.
Effector cell-related neurotoxicity syndrome and other adverse reactions that may be fatal if proper first aid measures are not taken in time
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In addition to CAR-T cells from autologous sources, CAR-T cells from transplant donors and universal CAR-T cells have also entered clinical trials
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Due to their novelty, complexity and technical specificity, they may bring long-term and potential safety risks to patients
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Therefore, the regulatory agencies' post-marketing risk management requirements for these products are also different from those of traditional drugs.
Considering that there are no relevant guidelines in China, CDE has fully investigated the research and development of the same product at home and abroad and related clinical trial technical requirements.
Drafted the "Chimeric Antigen Receptor T Cell (CAR-T) Product Application and Marketing Clinical Risk Management Plan Technical Guidelines (Draft for Comment)"
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PART 02.
Risk management plan policy review The drug risk management plan (RMP), as the name suggests, is a plan for the implementation of post-marketing drug risk management
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At present, there are few publicly published documents on the guidance and experience introduction of the content of the drug risk management plan.
Most domestic drug R&D and manufacturing companies have very limited experience in writing the drug risk management plan after the launch of new drugs.
The new "Drug Management Law" and "Drugs Regulations for Registration and Administration, Measures for the Supervision and Administration of Drug Production and other laws and regulations stipulate the drug risk management plan.
The author sorted out the relevant policies: (1) The CDE Tumor Indication Team of the State Drug Administration in September 2018 On the 13th, the electronic publication "Format and Content Requirements for the Drafting of the Risk Management Plan for the Marketing Application of Anti-tumor Drugs" was published, which provided for the first time the risk management plan template submitted in the application for the marketing of anti-tumor drugs
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Backstage reply [format] can be received free of charge (2) The new Drug Administration Law will be implemented on December 1, 2019.
Approved by the drug regulatory department of the State Council, drug marketing license holders should develop a post-marketing risk management plan and take the initiative to carry out Post-market research to further confirm the safety, effectiveness and quality controllability of drugs, and strengthen the continuous management of marketed drugs (Article 77) (3) The new "Drug Production" implemented on July 1, 2020 The "Supervision and Administration Measures" drug marketing authorization holders shall continue to carry out drug risk benefit assessment and control, formulate post-marketing drug risk management plans, actively carry out post-marketing research, and further improve the safety, effectiveness and quality controllability of drugs Confirm and strengthen the continuous management of marketed drugs (Article 40)
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(4) On May 13, 2021, the official website of the National Medical Products Administration issued the "Pharmacological Vigilance Quality Management Regulations" (GVP), which will be formally implemented on December 1, 2021.
This is China’s first special drug The regulatory document for vigilance setting, a separate chapter of the pharmacovigilance plan has 4 clauses, clarifying that the pharmacovigilance plan is a part of the post-marketing risk management plan of a drug, and it is a written document describing the safety characteristics of post-marketing drugs and how to manage drug safety risks ( Article 96-99)
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(5) On July 29, 2021, the Shandong Provincial Drug Administration will guide the holders of the drug marketing license in Shandong Province to formulate and implement post-marketing risk management plans in accordance with the "Drug Administration Law", "Vaccine Management Law", and "Drug Production Supervision" Management Measures," and other laws, regulations, rules and related regulations, organized the drafting of the "Shandong Province Post-Marketing Risk Management Plan Drafting Guide (Draft for Comment)".
The public is now soliciting public opinions.
The deadline is August 12, 2021.
The first post-marketing drug risk management plan guidelines issued by the provincial bureau
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PART 03.
Analysis of the key points of the CAR-T cell therapy product risk management plan.
The purpose of formulating RMP is to identify and describe the important identified risks, important potential risks and important missing information of the drug, and then propose a pharmacovigilance that matches the risk Activity plan and risk minimization measures to ensure that the targeted products have a satisfactory balance of benefits and risks within the conditions described in the product specification after the product is on the market
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At present, the development momentum of CAR-T cell therapy products is strong.
According to reports, there are currently two CAR-T cell therapy products approved for marketing in China; the remaining nearly forty CAR-T cell therapy products are in the clinical trial stage, and nearly ten have been approved.
It is in the key registration clinical trial stage
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The main content of the risk management plan for the application of CAR-T cell therapy products generally includes 4 parts, namely safety instructions, pharmacovigilance activities, post-market effectiveness research plans, and risk minimization measures
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The clinical risk management plan for the application of CAR-T cell therapy products for marketing should also refer to the ICH E2E Pharmacovigilance Plan, Pharmacovigilance Quality Management Standards and relevant technical guidelines issued by the drug regulatory agency in China
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01 Safety Description The safety description part mainly includes indication epidemiology, important confirmed risks, important potential risks, important missing information, etc.
, emphasizing the word "important", and important risks are divided into "identified" and There are two types of "potential"
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Theoretically, "identified" risks have at least the following two characteristics: (1) Risk-related adverse events are indeed observed during clinical treatment; (2) There is a clear causal relationship between risk and medication
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If the risk is only theoretically derived, or only occurs in non-clinical studies, or if there are risk signals but the causal relationship is not clear, it should be classified as "potential"
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According to the characteristics, targets and mechanism of CAR-T cell therapy products, the important confirmed risks are described separately.
Each risk is listed separately.
The safety risks may include but are not limited to: (1) and product quality characteristics , Storage and distribution related risks to patients 1) Risk of disease transmission: Consider the source of T cells (autologous or allogeneic), there may be risks related to infectious diseases (such as viruses)
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2) The risk of tumorigenicity: Considering the characteristics of the product, the use of integrated vectors (such as retrovirus or transposon) to insert foreign genes into the genome may be inserted near the proto-oncogene to activate the gene and cause tumors in the patient The risk increases
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3) Risks related to product storage, transportation and distribution (such as preservation, freezing and thawing processes), cold chain or other types of controlled temperature conditions being breached, and product stability related risks, which may affect CAR -The biological activity of T cells in turn leads to treatment failure
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(2) Risks related to product activity Risks related to product activity such as CRS, ICANS, etc.
caused by T cell activation
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(3) Risks related to the patient's underlying disease (or potential disease) or the interaction with other drugs in combination 1) Harmful immunogenic reactions and their consequences (including allergic reactions, neutralizing antibodies, etc.
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2) Risks related to the patient's own condition (such as graft-versus-host disease, malignant tumors)
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3) Risks related to expected and unexpected genetic modification of patient or donor cells (such as apoptosis, functional changes, malignant tumors)
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4) Consequences caused by cell distribution, migration and proliferation
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5) Risks associated with concomitant treatment (use of immunosuppressive agents when concomitant use or treatment of complications, etc.
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(4) Risks to patients related to administration procedures and methods of administration 1) Risks related to surgical operations or product injections
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2) Risks of medication errors or improper medications related to medical devices for injection
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3) Risks related to incorrect product dosage and/or improper medication
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(5) Risks related to the product's persistence in the patient's body 1) In the event of adverse events, the availability of rescue measures or medications and their risks
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2) Late complications, especially malignant tumors and autoimmune diseases
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3) The potential impact of various diseases before diagnosis or treatment, currently accompanying or that may appear in the future, on CAR-T cell therapy products
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(6) Risks related to patient reproduction As this part of the information has not yet been obtained in clinical trials, there may be specific parent-child risks in theory, and relevant information can be collected after the listing. .
(7) Examples of other risks: Cytokine release syndrome caused by T cell activation, immune effector cell-related neurotoxicity syndrome, etc.
; Tumor lysis syndrome caused by rapid killing of tumor cells; Integration of genetic material into the host genome, long-term patients induced immunosuppressed (malignant) tumor formation; inducing autoimmunity or immunogenic response; graft-versus-host disease occurs or the original graft versus host disease exacerbation; as medication errors / damage caused by improper medication and the like
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Before receiving CAR-T cell therapy products chemotherapeutic drugs, monoclonal antibodies and other therapeutic lymphocyte Clear (clear leaching) can cause adverse reactions should be of particular concern, such as infections of leukopenia, thrombocytopenia and the like
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02 Pharmacovigilance activities Pharmacovigilance activities include conventional pharmacovigilance activities and special pharmacovigilance activities
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(1) Conventional pharmacovigilance activities CAR-T cell therapy products should include the collection, treatment, follow-up, analysis and evaluation of adverse events; the submission of adverse events and regular safety update reports; Remarks: clinical trials of conditional approved products as required Submission of suspicious and unexpected serious adverse reactions (SUSAR) and safety update reports (DSUR) during research and development; continuous monitoring of product safety characteristics
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(2) Special pharmacovigilance activities In order to identify, qualitatively or quantitatively describe the safety risks of CAR-T cell therapy products and supplement missing information, special pharmacovigilance activities should be adopted
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Including but not limited to: the marketing authorization holder should conduct evaluation and certification and regular re-certification of the treatment center; continue to carry out long-term safety follow-ups for patients receiving product treatment, and collect and evaluate CAR-T cell therapy products through non-interventional research.
Safety and efficacy in a wider population
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If there is no need to carry out special pharmacovigilance activities, declare directly; if there are special pharmacovigilance activities, write the following content centered on the type of activity rather than risk, and the language should be as concise as possible
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Examples are as follows: (1) Planned/ongoing special pharmacovigilance activities (2) Completed/terminated special pharmacovigilance activities When a special pharmacovigilance activity has been completed or terminated early, it is written into this section
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Briefly introduce the content and results of the completed/terminated activities, and the impact of the conclusion of the activity on the risk analysis and management plan
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3.
Post-marketing effectiveness research plan The post-marketing effectiveness research plan includes mandatory effectiveness studies required by conditional approval, mandatory effectiveness studies required by regulatory agencies, and other effectiveness studies promised/planned by the sponsor
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Examples of writing content are as follows: 4.
Risk minimization measures Risk minimization measures include conventional risk minimization measures and additional risk minimization measures
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(1) Conventional risk minimization measures Conventional risk minimization measures are applicable to all drugs, including drug inserts and packaging
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Conventional risk minimization measures are based on the list of targeted risks as shown in the following table: (2) Additional risk minimization measures are directly declared if additional risk minimization measures are not required; if additional risk minimization measures are required, the type of activity is used instead of safety The following content is written with the focus on sexual issues, and the language should be as concise as possible.
Examples are as follows: References [1] http://