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Benefit-Risk Assessment of Patient-Centered Clinical Trials
technical guidelines
(Draft for comments)
August 2022
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Guidance on benefit-risk assessment techniques for patientcentered clinical trials
1. Introduction
As subjects in drug clinical trials and objects of medical practice, patients
Personal experience with disease states and treatments can provide a closer look at drug development
Patient expectations, more valuable information. "Patient-centered" drug development,
It refers to starting from the patient's needs, regarding the patient as an active participant, and taking the clinical
Value is the ultimate goal, this concept has become the core guidance of current drug research and development
Thought. Review agencies are exploring how to design and implement "patient-centred"
Drug clinical trials and incorporating patient needs into drug benefit-risk assessments
in the system.
Patient experience data (PED) refers to all
Information provided by the patient (but not limited to the patient himself) about the patient's knowledge of the disease and
Treatment experience, needs, opinions, preferences and other information. meaningful patient body
Experimental data can be used as one of the scientific basis for drug benefit and risk assessment.
This guidance aims to clarify the definition, classification, and
Applicability, scientific considerations of benefit-risk assessment based on patient experience data
Quantities, communication with review agencies, etc., provide sponsors with information on how to use patient experience data
According to support the marketing registration application and the benefit-risk assessment of the whole life cycle to provide reference
Test.
This guideline only represents the current views and understandings of drug review agencies.
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Not mandatory legally binding. With the progress of scientific research, this refers to
The relevant content in the guiding principles will be continuously improved and updated. apply this guideline
Please also refer to the Technical Harmonization Conference for International Registration of Drugs for Human Use (ICH)
and other relevant guidelines that have been published.
2. General principles
The benefit-risk assessment of a drug should generally be based on a range of efficacy and safety
sexual evidence. Reliable patient experience data as evidence for benefit-risk assessment
One, used to discover unmet clinical needs, identify target patient populations,
Identify key elements of clinical trial design, determine the clinical significance of endpoint assessments
meaning, assessing the patient's benefit preference and risk acceptance, etc.
The applicability and scope of the PED in the benefit-risk assessment depends on
Types of PEDs, purpose of collection, study design, collection scenarios, data quality,
Interpretability of the results, etc. In general, using methodologically sound
(methodologically-sound) and fit-for-purpose
The PED obtained by the collection tool can provide direct evidence for the benefit-risk assessment.
according to. The so-called methodological soundness, that is, to ensure the methods used to collect and analyze PED
and processes are rigorous, robust, and adhere to scientifically established principles and best
good practice; fit for purpose means study design, patient population and study
between the choice of research method and the intended use of the data. When PED as
When the critical evidence (or one) supports the benefit-risk assessment, it needs to be communicated with the
Communicate with review agencies to ensure data are collected through pre-designed studies that
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The study has a pre-defined research protocol and analysis plan, and ensures that the included samples
Representativeness, standardization of data collection, and data reliability and integrity
and scientific.
The collection process of PED is dynamic and progressive. in drug programs and
In the early clinical stage, PED data are mostly qualitative, and the collected content is mostly for patients
Perspectives on disease and available treatments. With the deepening of research and development, the income of PED
Quantitative methods can be added to the set, gradually focusing on the patient's expectations for specific drugs
A benefit perspective, including trade-offs of benefits and risks. When the drug is on the market, it can
Continuously collect PEDs of real-world drug use as needed to achieve future
The ultimate goal of maximizing patient benefit and minimizing risk.
3. Classification of patient experience data
Patient experience data can be categorized in a variety of ways. According to the source of the PED, it can be divided into
Collected for the sponsor, or not collected by the sponsor. Depending on the collection method of the PED, it can be
Divided into pre-designed clinical trials, patient preference studies, natural history studies
Research, interviews, questionnaires, expert consultation, summary of patient exchange meetings, etc. PED's
The nature of the data includes qualitative, semi-quantitative or quantitative. PED in benefit-risk assessment
The main uses in , including clinical outcome assessment (clinical outcome
assessment, COA), patient preference information on benefits and/or risks
(patient preference information, PPI), and other
and treatment insights, needs or priorities. The COA and
PPI-related content.
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(1) Clinical outcome assessment (COA)
The clinical outcome assessment (COA) is
From patients and their caregivers, physicians, or other evaluators to evaluate patient
assessment tools or means of individual feeling, functioning or living status of the individual, usually requiring
Subjective assessment of process rather than direct presentation of facts. COA's Evaluation Dimension Package
including symptoms, daily functioning, general health status, quality of life and satisfaction
wait. Depending on reporter type or assessment method, COA-based clinical endpoints can be
Divided into four types, including patient-reported outcomes (patient-reported
outcome, PRO), clinician reported outcomes (clinician reported
outcome, ClinRO), observer-reported outcome (observer-reported
outcome, ObsRO) and functional outcome (performance outcome,
PerfO).
PRO is a measure of health reported directly by the patient
External Corrections and Interpretations by Physicians or Others. PRO tools often include questionnaires
Surveys, digital scoring forms or patient diaries etc. For example, using a 10-point visual
Analog pain scale (visual analog scale, VAS), health survey short form
(the 36-item short from health survey, SF-36). ClinRO is a
Professional health care personnel based on examination or observation of patients' disease and health status
Quantitative results, mostly related to the patient's signs, behavior or other phenomena related to the disease
Clinical judgment based on symptoms or clinical judgment based on laboratory indicators. For example, system
Lupus disease severity activity score (SLEDAI-2K), Hamilton
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Dayton depression scale (HAMD). ObsRO is developed by caregivers in their daily lives
Measures of reported patient health outcomes. For example, childhood Dravet syndrome
Diary of seizure frequency. PerfO is a standardized function for patients to complete
Measures assessed by an appropriately trained person or by the patient alone during the task
value. For example, measures of walking speed (eg, 6-minute walk test, 6MWT),
Memory retrieval tests (such as word recall tests) or other cognitive tests (such as
Numeric Symbol Substitution Test), etc.
COA-based clinical endpoints can be used as the primary endpoint for evaluating clinical benefit
(single or composite endpoint) or pre-defined secondary endpoints. Clinical Benefit Definition
Improvement in individual patient perception, function, or survival for a treatment or intervention.
For example, clinical trials of hereditary angioedema can use a combination of
Visual Symptom Assessment (VAS) score
Time to symptom relief was used as the primary endpoint. Key in Myelofibrosis Indications
In clinical trials, imaging findings (spleen volume reduction) were used as the primary end point.
Points, and the modified myelofibrosis symptom score form collected from the patient's diary
(MFSAF) as a key secondary PRO endpoint. also,
Safety and risk tolerability can also be assessed by COA. For example, visual
Symptom Assessment Questionnaire (Visual Symptom Assessment Questionnaire
[VSAQ-ALK]) is a PRO tool for assessing vision-related
Symptoms, also used to assess safety outcomes in NSCLC, were written
included in the manual.
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(2) Patient preference information
Patient preference information (PPI) is
Refers to patients' choice intentions for different clinical outcomes or other characteristics of specific treatments
Qualitative or quantitative assessment of willingness and acceptance. In the benefit-risk assessment,
PPIs can provide information on a patient's preference for benefit and tolerance for risk. example
For example, asking patients who received different treatments about their preference for a particular therapy (e.g.
Tendency to use topical, oral, and injectable medications), or ask patients
Willingness to accept risk in exchange for possible benefits (e.g. acceptable quality of life
How much is lost in exchange for a certain degree of survival time extension).
At different stages of drug development, PPIs may have important effects on the treatment background, end point
Both selection and dynamic benefit-risk evaluation are guiding. PPI helps
Clarify the importance of benefits (i.e., trial endpoints) to patients, and understand the importance of patients to
The benefit and risk trade-offs of specific drugs, and understanding the patient population's
Treatment preference and heterogeneity.
The application of PPIs in benefit-risk assessment needs to fully consider the background of indications
Scenarios, the value of PPI for indication assessment, PPI collection methods and collected patients
Viewpoints are representative. For the following situations, when performing a benefit-risk assessment
It is necessary to carefully consider whether the PPI is really valuable: (1) The drug has a clear curative effect
Under the premise, there are serious risks or risk uncertainties, and PPI prompts patients to
willing to bear higher risks to obtain possible benefits; (2) in the test population,
There are large differences in the views of the most important benefits and/or risks among different patients;
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(3) The patient's point of view is inconsistent with that of the medical professional. Generally speaking, yes
For drugs with poor efficacy or serious safety problems, PPI cannot be used alone
Conduct a benefit-risk assessment.
4. Patient experience data support benefit-risk assessment
(1) Overview of important factors in benefit-risk assessment
Benefit-risk assessment is the trade-off between the benefits and risks of a drug. Benefits include Pro
Clinical benefits and other benefits (such as medication convenience, compliance, etc.);
Risks refer to adverse events and other adverse effects associated with a drug.
The benefit-risk assessment was carried out from the following aspects (see Table 1): "Treatment
Background analysis" (incidence, severity and prognosis of the disease, available treatments
characteristics of the law, unmet clinical needs, etc.), specific drug "benefits" and "risks"
and risk management”. For each of the above areas, relevant evidence needs to be assessed (including
including data quality and credibility), as well as uncertainties and their potential impact. most
Finally, the evidence and uncertainties about the benefits and risks of the drug are synthesized, combined with
The severity of the disease and the current unmet clinical need to derive benefit-risk
specific conclusions of the assessment.
Table 1. Patient-Centered Benefit-Risk Assessment Framework
Evaluation Dimensions
Application Scenarios of PED
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Identify and measure the most important symptoms of the patient, the burden of the disease on
the patient, understand the
natural history of the disease, including the occurrence and development of the disease, the
severity of the disease treatment background, prognosis, etc.
analysis
Determine the important risks and benefits of the existing treatment for the patient, Assess
unmet clinical needs Understand the
characteristics of treatment that patients are most concerned about, and clarify the degree of
demand for new treatments
Combine COA assessment results, patient preference information, and other
PED information incorporated into assessment of benefits
• Evaluate the clinical benefits of drugs based on COA endpoints • Determine the clinical
relevance of research evaluation endpoints and measurement indicators
benefit from
sex
• Evaluate whether the change value (threshold value) of the measurement index is clinically
meaningful, including the smallest difference between groups, the change threshold value
at the individual level, etc.
• PPIs suggest patient propensity for other benefits
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Combine COA assessment results, patient preference information, and other
Incorporation of PED information into risk assessment
• Evaluation of drug safety and
tolerance
Risks and Risks •
Evaluation of the severity and frequency of security incidents
manage
clinical significance
• Understand the patient's knowledge of risk, the impact of risk on the patient's
life, and the burden of risk management measures on the patient
• PPI provides patient acceptance of risk
Benefit-Risk Conclusion
(2) Patient experience data support benefit-risk assessment
In the benefit-risk assessment, the patient experience data can be the following series
Column considerations provide useful information such as the natural history of the disease, key symptoms
symptoms, impact on the patient’s life, patient’s experience with treatment or concern for unmet needs
perceptions of needs, prioritization of disease management, patient or relevant caregiver reports
outcomes, patients’ preferences for treatment options or outcome indicators, etc. (see Table
1). According to the purpose of data collection, data type and data quality, the PED
The scope of application and role are not the same.
1. Therapeutic context of drug use
The PED can provide a patient's perspective on the impact of disease and experience with existing treatments.
point. For example, the PED helps to gain a clearer understanding of the impact of the disease on the patient, which
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These are the symptoms and signs that patients are most concerned about, the most disturbing, and the most affecting daily life.
quality of life; understanding patient burden of disease and impact of symptoms. PED also helps
To understand the extent to which currently available treatments are meeting the medical needs of the patient population
degree, and the degree of need for new treatments, including efficacy, safety,
Tolerability, convenience, accessibility, etc.
For evaluation indicators affecting pathogenesis, clinical symptoms and clinical benefits
For diseases that are not yet fully understood, PED data can also help to gain insight into the disease
natural history. For example, some rare diseases have low incidence, complex phenotypes, and
The cognition of the effectiveness of clinical diagnosis and treatment is limited, and the clinical trial of new drug research and development is limited.
The experimental design and effectiveness evaluation pose great challenges. As a disease has the most say
of patients and their families whose experiences and perspectives inform the development,
It provides a reference for the assessment of disease severity and prognosis.
2. Drug benefit-risk evidence
The PED can assess the clinical relevance, benefits and risks of endpoints for clinical studies
The clinical significance of the risk, the tolerance and acceptability of the risk, etc. provide the patient's perspective.
point.
2.1 Clinical relevance of study endpoints
Descriptions of clinical benefit usually include efficacy (e.g., survival, severe clinical
change in clinical outcome, reduction in symptoms, improvement in function), effect size
(effect size) and associated uncertainties (such as confidence intervals), treatment effect
The distribution of the effect in the population, the duration of the curative effect, etc. for effectiveness testing
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The selection of quantitative indicators is recommended based on the current knowledge of the disease and the acquired
To judge the clinical relevance of clinical endpoints and measurement indicators based on patient experience data
Sex, that is, whether it is the clinical indicator that patients are most concerned about or has the greatest impact on patients,
Or whether the measure predicts clinical benefit.
For direct (or relatively direct) measures of clinical benefit (such as
Relief, improvement of function, improvement of quality of life) as the clinical endpoint of the research
For trials, COA-based endpoints can be selected. This indicator is used as the main
Or key secondary endpoint indicators, should fully explain the selection basis, and provide COA
Data collection methods, measurement performance (such as reliability, validity), detailed data
Analysis and interpretation of results.
Benefits other than clinical benefit (e.g., ease of use of medication)
sex, adherence, etc.) may also become patient preference, and in the benefit-risk assessment
occupies a certain weight.
2.2 Clinical significance of benefits and risks
Clinical benefits and potential risks In addition to considering the degree of benefit and risk
In addition, whether this degree and size is clinically meaningful, patient
How to treat these clinical significance, etc., this is also a patient-centered benefit risk
One of the important considerations in risk assessment.
Minimum clinically important difference
difference, MCID) set a threshold of benefit with clinical value, representing
The minimal improvement that the patient deems valuable. When determining the MCID, it should be sufficient
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Consider relevant guidelines, expert consensus and other recognized standards; if there is no recognized standard
If there is no standard, it is necessary to set a clinically meaningful change through the collected PED and communicate with the reviewer
The evaluation agencies communicated in a timely manner to reach a consensus.
When meaningful differences are shown between groups, it does not mean that individuals acquire the desired
significant clinical benefit. It is also necessary to presuppose a clinically meaningful intra-patient
Indicator change threshold (clinically meaningful within-patient
change), to judge whether the patient has reached the treatment goal, this value can be used as
Supporting evidence of benefit. Alternative methods include anchoring, score-based
The method of cloth, etc.
2.3 Risk tolerance and acceptance
When judging the risk of a drug, the severity, occurrence, and
Frequency, reversibility, and tolerability characteristics, and the effect of adverse events on drug dependence
Sexual implications and potential consequences. PED can be a safety outcome itself
(COA as a safety endpoint), but also as other supporting evidence, such as
Risk awareness (whether the patient understands each type of risk and
likelihood), clinical importance (which risk does the patient perceive as
impact), the tolerability of adverse reactions, and the impact of risk management measures on patients
the burden caused by the
Patient preference data can also provide information on patient risk acceptance, i.e.
Whether patients are willing to accept possible risks based on the likelihood of clinical benefit.
For example, a patient with a serious life-threatening illness may be willing to
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risk in exchange for a specific benefit (such as prolonging life by only a few months); while some
Patients with chronic diseases, the existing treatment plan can stabilize the condition, the patient has adapted to the
disease and its impact on daily life, compared with existing treatments
The greater benefit may be expected from a treatment regimen, and the higher risk cannot be tolerated.
3. Drug benefit-risk assessment
When the drug has clear clinical benefit, and the safety profile is good, no
When serious security risks arise, the benefits can be judged to outweigh the risks.
When the drug has clear clinical benefits, but there are safety risks, it is necessary to
Weigh the benefit-risk ratio and consider whether there are effective risk management measures to control
risk.
When the drug has potentially serious safety risks (such as life-threatening, etc.) and/or
Benefit-risk assessment can be challenging when the potential benefit is limited or limited. In this kind of
Under certain circumstances, fit-for-purpose and reliable patient experience data are essential for evaluating drug
Monetary benefits-risks will help. The benefit-risk assessment of the overall population is important for clinical
The overall evaluation of clinical trial subjects; and subgroup evaluation is for some subgroups of patients
Group evaluation. When there is a discrepancy between the overall benefit-risk assessment and the subgroup assessment
Supporting data from both parts need to be carefully weighed when consistent, and can also be included
Patient's point of view. For example, the expected population of the evaluated drug for the overall indication
When the risks outweigh the benefits, if the PED can help identify risks with good benefits
If there is a specific subgroup of people, then this group can be used as the test object in subsequent research and development.
conduct research to demonstrate whether the drug has a beneficial benefit-risk
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than.
(3) Patient experience data support the benefit-risk assessment of the drug's full life cycle
1. Pre-market research and development stage
The collection and application of patient experience data is a cumulative process. clinical
During the development process, the accumulation of patient experience data is used to guide the wider
benefit-risk assessment to support the decision to continue/discontinue drug development.
Most of the PEDs collected in the early stage are mainly qualitative data, which can be used for benefit-risk assessment.
Information provided for evaluation and drug development decisions includes identification of unmet clinical needs
Requirements, identification of target patient groups, identification of key elements of trial design, etc. example
For example, the PEDs collected in the early stage of clinical development can be opened-ended questions to understand
The natural history of the disease, preferences in clinical practice, differences in patient subgroups, etc.,
Thereby identifying unmet patient needs and identifying target patient populations.
With the continuous accumulation of PED, the scope of using patient experience data in the later stage
The scope is gradually focused, and the method is gradually quantified. For example, developing a quantitative COA tool
tools to more directly measure the clinical outcomes of greatest interest to patients and to validate the
The clinical relevance of the tool, identifying thresholds for clinically meaningful change;
Quantitative patient preference information to judge patients' willingness to use and risk acceptance
degree of acceptance. Quantitative PED information collected at these later stages can be used as an indicator of clinical validity and
Direct evidence or supplementary information from safety data to support dynamic assessment of benefit
risk. When faced with major development decisions that need to be discussed with review agencies, the PED
Collection and application can also be used as one of the important contents of communication with review agencies
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One.
2. Post-market use stage
During the post-marketing period of drug use, it should be based on continuously accumulated new information (including
Including PED), re-evaluate the benefit-risk status of the drug, so as to decide whether to adopt
Take corresponding regulatory measures, including revising the risk management plan, adding post-listing research
In order to maximize the benefit of patients,
Minimize risk. Encourage the collection of more PEDs after listing, such information can
Collected by the sponsor for the purpose of responding to specific postmarketing requests, or
Various types of research voluntarily initiated by sponsors, investigators, or patient organizations (e.g.
interviews, questionnaires, patient preference studies, etc.). these patients
The user experience data can not only truly inform the majority of patients, medical staff and related people
staff to communicate reflective patient experiences and feelings about drug use, and can also contribute to
Dynamic assessment of benefits and risks provides new evidence.
5. Communication
When a sponsor plans to collect and use patient experience data as a benefit-risk
As part of the evaluation, it is encouraged to engage with review agencies during the design phase of such studies.
Early communication to obtain information on study design, data collection and regulatory compliance
timely feedback as required. When the sponsor plans to use PRO or other COA as
When it is the main or key secondary end point of the confirmatory study, it should communicate with the review institution and
time to communicate. In addition, during the clinical trial, if due to changes in PRO or
Significant adjustments to the clinical trial protocol due to other COAs should be communicated with the review agency
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Communicate in time. For details, please refer to the "Communication and Exchange Office for Drug R&D and Technical Review"
"Guidelines for the Application of Patient Reported Outcomes in Drug Clinical Research"
(Trial)", "Guiding Principles for Patient-Centered Clinical Trial Design", etc.
related guidelines.
6. Conclusion
The "patient-centered" research and development concept should run through the whole life of drug research and development
cycle. During the drug development process, patient experience data should be continuously collected and incorporated
According to the data, in order to optimize the drug development plan and clinical trial design, the complete clinical
The clinical evidence chain is combined with the patient experience data to realize the benefits of the whole life cycle-
Risk dynamic assessment, and evaluate drug benefit-risk from the perspective of patients
than.
This guidance encourages sponsors or other parties to actively collect patient perspectives.
points and experiences to deepen understanding of disease and increase awareness of drug use
awareness, and patient needs regarding benefits and risks. PED supports drug development and
The evaluation is currently in the exploratory stage, lacking a unified classification method, clear
Research paths and applied principles. Measures already implemented abroad need to be combined with my country's
Factors such as cultural background, patient acceptance and the actual situation in China are further realized
Localization. For issues not covered by this guideline, applicants are encouraged to actively
Actively explore, develop and improve PED collection tools and analysis methods, and actively cooperate with review agencies
Organizations to communicate, in line with scientific and operable principles
In this context, increased focus on patient experience and application of this to patient-centered
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in drug development and evaluation.
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