Interpretation of CDE's newly released document-"Technical Guidelines for Long-term Follow-up Clinical Research of Gene Therapy Products"

In order to guide and standardize the clinical trials of gene therapy products, on December 3, 2021, the official website of the Center for Drug Evaluation of the National Medical Products Administration issued the "Technical Guidelines for Long-term Follow-up Clinical Research of Gene Therapy Products" (written on December 1, 2021.
), implemented since the date of issuance, this guideline discusses the observation methods and research design of long-term follow-up clinical research of gene therapy, and focuses on the observation purpose, consideration elements, design and implementation of long-term follow-up clinical research of gene therapy, as well as different gene therapies Special considerations for products and other related requirements are provided to provide technical guidance for long-term follow-up clinical studies of such products, to ensure timely collection of signals of delayed adverse reactions, to identify and reduce such risks, and to obtain the long-term safety and effectiveness of such products.
Sexual information
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This article sorts out the long-term follow-up clinical research content of gene therapy products and shares with you with your own interpretation
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PART 01.
Introduction to the long-term follow-up policy of gene therapy products at home and abroad Although gene therapy has great potential in curing diseases, it will also have long-term or permanent effects on the human body.
Patients receiving gene therapy have delayed adverse reactions.
Risks may increase.
For example, changes in the biological characteristics of living cells of gene therapy products persist in the body for a long time, which may increase unpredictable risks
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In order to assess and reduce such risks, and to understand the changes in treatment effects over time, it is necessary to carry out long-term follow-up of subjects participating in gene therapy clinical trials
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At present, both the US FDA and the EU EMA have issued relevant technical guidelines.
Upon inquiry, the EU EMA issued "Guideline On Safety And Efficacy Follow-Up-Risk Management Of Advanced Therapy Medicinal Products" in 2008 and "Guideline On Follow" in 2009.
-Up Of Patients Administered With Gene Therapy Medicinal Products" guide provides sponsors with a risk profile based on gene therapy and guidance recommendations for long-term follow-up considerations
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The "Long Term Follow-Up After Administration Of Human Gene Therapy Products" issued by the US FDA in January 2020 provides recommendations on how to design a long-term follow-up study, as well as long-term follow-up observation elements, duration, data collection and reporting requirements, etc.
Questions provide guidance
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Considering that there are no relevant guidelines in China for standardizing and guiding the design of long-term follow-up clinical trials of gene therapy products, in April 2019, the State Food and Drug Administration launched the China Drug Regulatory Scientific Action Plan, and the Center for Drug Evaluation is responsible for implementing the "Cell and Gene Therapy" "Product Technology Evaluation and Supervision System Research" is included in the first batch of research projects.
Among them, the "Technical Guidelines for Long-term Follow-up Clinical Research of Gene Therapy Products" is an important content of the gene therapy drug technology evaluation system, which helps guide clinical trials of gene therapy drugs CDE started in January 2021 on the basis of fully investigating the research and development of the same species at home and abroad and related clinical trial technical requirements, and issued a draft for comments in June 2021 (the deadline for the meeting is July 4, 2021) , On December 3, 2021, CDE officially released the "Technical Guidelines for Long-term Follow-up Clinical Research of Gene Therapy Products", which will be implemented from the date of release
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PART 02.
How to consider formulating long-term follow-up strategies in line with gene therapy products? The main purpose of the long-term follow-up of gene therapy products is to collect the subjects’ delayed adverse reactions and understand the existence of gene therapy products in the body, so as to identify and reduce the long-term risks of patients receiving gene therapy products
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What is the appropriate duration of the long-term follow-up? As an emerging therapy, the long-term safety of gene therapy is still unknown.
The duration of long-term follow-up should be sufficient to observe the risks of the subject due to product characteristics, exposure (biodistribution and route of administration), etc.
It should be no shorter than the expected occurrence time of delayed adverse reactions
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Generally speaking, the long-term follow-up observation time for different types of gene therapy products is recommended in the following table: 2.
Evaluation of potential risk factors related to late-onset adverse reactions When evaluating the risk factors of gene therapy products, applicants should consider the Characteristics, while referring to the non-clinical and clinical data of the product and the known data of similar products, the applicant should obtain data used to assess the risk of delayed adverse reactions in non-clinical studies as much as possible
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Including but not limited to the following elements: 3.
Evaluation of potential risk factors related to the clinical research population (1) When designing a long-term follow-up clinical research program, the target subject population and characteristics, overall health, and treatment should be considered.
The impact of the patient’s expected survival and other characteristics on the collection of late-onset adverse reactions
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(2) When certain characteristics of the clinical research population (such as short life expectancy, multiple comorbidities, and exposure to other drugs such as radiotherapy or chemotherapy) may interfere with the observation and analysis of delayed adverse reactions, it will affect the long-term follow-up observation and evaluation (3) In subjects with milder or more limited disease, comorbidities, and limited or stable concomitant treatment, the evaluation data collected through long-term follow-up observation may be easier to analyze
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4, long-term follow-up of the design and implementation of (1) Informed consent 1) Content: The purpose must include long-term follow-up study, study program, duration, visit interval and researchers, ethics committees or the sponsor's contact information
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2) Note 1: When the risk of gene therapy products has changed in non-clinical studies or clinical trials, the informed consent form should be updated in time and the subjects should be notified
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3) Note 2: The informed consent should also explain the collection and storage of human tissue samples and genetic testing during the long-term follow-up period
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(2) Long-term follow-up clinical research plan design 1) Content: The subject's monitoring plan should be specified in detail, including the visit schedule, sampling plan, monitoring and inspection methods, and the target clinical events in the long-term follow-up clinical research
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2) Note 1: It is recommended that the sponsor provide a concise and scientific follow-up record guide for the investigator and related medical personnel (including doctors and nurses other than the investigator) to record all observation results and all data related to the study
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If important information that changes the risk of gene therapy products is obtained during clinical trials or after marketing, the follow-up plan should be revised and implemented in a timely manner
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(3) Implementation of long-term follow-up 1) Within 5 years after the subject receives gene therapy (or during the long-term follow-up period determined according to the risk of the specific product), clinical follow-up should record the subject’s brief medical history, using carcinogenic or mutagenic The status of drugs and other drugs and related adverse event information, newly emerging, recurring or aggravating diseases (such as malignant tumors, neurological diseases, immunogenic or autoimmune diseases, infections, and even death, etc.
) and related physical and experimental laboratory examination, the subject and the like pregnancy and fertility spouse
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At the same time, collect relevant samples as far as possible at the appropriate follow-up time point, use validated and sufficiently sensitive methods to detect the continued presence of gene therapy products in the body and analyze the relevant effects until the data shows that there is no longer any risk
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If there is an adverse event suspected to be related to gene therapy products during the follow-up process, a causal analysis of the correlation should be carried out in time based on evidence obtained from clinical, laboratory, molecular biology, cytogenetics, histology or HLA analysis or in-depth sequencing data.
, If necessary, increase the frequency of follow-up or increase the content of follow-up
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2) For gene therapy products with a follow-up time of more than 5 years (or a long-term follow-up period determined according to the risk of a specific product), after completing the first 5 years of follow-up, you can call or write questionnaires, etc.
, and collect relevant data as much as possible Samples should be kept to follow up with subjects at least once a year until the end of the follow-up period
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If the previous follow-up indicates that the product continues to exist in the body, it is recommended to observe until the data shows that there is no longer any risk
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References [1] http:// Columnist: Dr.
Sinan Biopharmaceutical senior engineer, licensed pharmacist, a porter of pharmaceutical policies and regulations in the self-media era, firm the goal of lifelong learning, insist on the combination of learning and use, Strive to achieve the unity of knowledge and action
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