Administration announces guidelines for clinical trial of overactive bladder drug

Pharmaceutical Network January 4 hearing to guide and standardize overactive bladder drug clinical trials, the State Food and Drug Administration has developed a "clinical trial of overactive bladder drug guiding principles", is now released.

announce.

Annex: Overactive bladder drug clinical trials guidelines

food drug Regulatory Authority

December 25, 2017

This guideline follows the general requirements for clinical trials of drugs and sets out the prerequisites and basic technical requirements for OABD drugs, but does not completely cover the various situations that may occur in OAB clinical trials. The guiding principle is Drug registration Applicants and clinical trial researchers provide technical guidance in the planning, design, implementation and monitoring of clinical trials as well as the collection and analysis of experimental data to enable safe and effective OAB drugs to be used more and earlier for clinical treatment.

This guideline is intended primarily for clinical trials of new chemical drugs for OAB therapy, and clinical trials of OAB therapeutic biologicals and others may refer to these guidelines.

(A) definition

OAB is a syndrome characterized by urinary urgency, often accompanied by urinary frequency and nocturia, with or without urge incontinence, urinary tract infection or other definite pathological changes OAB in the urodynamics can be expressed as Detrusor Overactivity may also be other forms of urethral-bladder dysfunction OAB has no definite cause and does not include symptoms caused by urinary tract infections or other bladder-urethral lesions.

(B) the pathogenesis

OAB may include and is not limited to the following pathogenesis: ① neurogenic doctrine: central nervous system, peripheral nerve, especially the bladder afferent nerve abnormalities can lead to OAB symptoms; ② myogenic theory: spontaneous contraction of detrusor smooth muscle cells And enhanced intramuscular impulse transmission can induce involuntary detrusor contraction, resulting in OAB symptoms.

(C) clinical evaluation of drug efficacy

The efficacy evaluation method includes the evaluation of symptoms, quality of life and urodynamic examination.

1. Symptoms and related evaluation indicators

Symptom evaluation is important because the OAB is defined as a symptom, Symptoms and related measures must be highly relevant to OAB and their changes are important to the patient, and the rationale for observing changes in symptoms and symptoms should be confirmed.

(1) evaluation index

Symptoms and evaluation indicators highly correlated with OAB include urinary urgency, frequency of urination, single urination, urinary incontinence and urinary incontinence (diaper usage), etc. According to the above symptoms, urination diaries can be combined Other validated symptom-related scoring scales were used as comprehensive observational indicators, and urinary-related indicators could also be observed separately.

(2) evaluation method

The main method of evaluation is diarrhea diarrhea diarrhea refers to the patient for at least 24 hours period for their own urination records.The records include the number of urination, urination time, a single urination, urinary incontinence, urinary incontinence, urine The number of urinary urgency and water intake etc. The number of days of urination diary should be set according to the symptom and the characteristics of the patient group.If only the frequency of urination should be observed for at least 3 days, Need to observe the number of urinary incontinence, it should be observed for about 1 week in the clinical trial evaluation, urination diarrhea records based on the recommended urination frequency, urinary urgency, urinary incontinence frequency or both as an observation.

2. Quality of life evaluation

OAB efficacy reviews include a validated Quality of Life (QoL) rating, and when evaluating QoL, participants are required to fill in the questionnaire for a period of time.

Since QoL reflects the overall condition of a subject, including the state of micturition, the QoL assessment can be used as a complement and re-confirmation of symptom assessment.

3. Urodynamic evaluation

Urodynamics is a lower urinary physiological function test.Hydrodynamic examination with the evaluation of OAB drugs are highly related to the content of urine flow measurement, determination of residual urine, bladder pressure, etc. The advantages of the above urodynamic examination Is that its placebo effect is small in comparison with symptoms and QoL and changes are observed in a short period of time.The disadvantage is that the correlation with symptoms and QoL is uncertain and partly due to invasive examination.Therefore, Kinetic tests can be used in clinical pharmacology.

(1) residual urine volume and urine flow rate determination

Some of the pharmacological effects of OAB therapies are the inhibition of detrusor contraction, and the residual urine volume and the change in urinary flow rate can be calculated from the residual urine volume measurement and the urinary flow rate measurement, and thus it is estimated that such drugs Adverse reactions (Urinary retention, etc.) The recommended use of transabdominal ultrasonography residual urine test.

(2) bladder pressure measurement

The main purpose of bladder pressure measurement for OAB is to observe the detrusor overactivity.Observation indicators include the frequency and amplitude of involuntary contraction of detrusor muscle, bladder compliance, initial urinary bladder capacity, maximum urinary bladder capacity, etc. Among them, The maximum urinary bladder capacity is sensitive to changes in the bladder.If the above indicators after treatment changes, it can be speculated that the pharmacological effects of drugs.

In order to assure the objectivity and unity of interpreting the results of the bladder pressure test, it is best to make a central judgment by the central laboratory or by an equivalent agency.

4. Matters needing attention

(1) The urination-related behaviors can not be evaluated by short-term (for example, several hours) observation due to factors such as the subject's diet, social activities, urination-related environment (for example, whether there is a restroom nearby), and therefore should be used for a period of time evaluation of.

(2) The value of the relevant indicators should be the average value within a certain period of time (such as the average of one day, one week, etc.) Before and after the ratio, the rate of change (before and after the difference / before the value) and other methods of calculation, analysis should be based on indicators of the characteristics of the corresponding statistical analysis.

(3) medication time should be based on the characteristics of the drug decision.

(4) Because of the gender differences in the lower urinary tract, it is recommended that gender be used as a stratification factor in design and analysis.

(5) The therapeutic effect of the drug on OAB is determined by the change of symptoms, and the evaluation of the symptoms is subjectively evaluated by the subjects and the placebo effect is more obvious. Therefore, in the confirmatory clinical trial, the drug effectiveness should be evaluated With placebo or standard Controlled double-blind trial. In addition, it is best to include placebo-controlled studies in exploratory studies.

(6) Comply with the Guiding Principles of Biostatistics in Clinical Trial of Drugs, select FAS and PPS, and compare the concordance between the two.

Prior to conducting clinical trials, a full understanding of the pharmacogeographic data (including structure, preparation techniques, stability and quality control, etc.) and non-clinical data (including mechanism of action, pharmacology and toxicology, animal medicine Pharmacokinetics, pharmacodynamics, etc.), familiar with the characteristics of its pharmacology, pharmacological characteristics, possible target organs of toxicity and other information, and in clinical trial design, implementation and analysis of the results to be fully taken into account.

Before carrying out clinical trials, applicants should work closely with each other to formulate detailed clinical trial plans and plans and make timely revisions based on the assessment of the results of the phased research.

In order to ensure scientific and reliable clinical trial results, standardize the procedure, protect the rights and interests of subjects and ensure their safety, the "Code of Practice for Quality Control of Pharmaceutical Clinical Trials" should be strictly implemented during the clinical trials.

During clinical trials should also refer to the relevant clinical guidelines.

(A) clinical pharmacology research

The early stages of clinical pharmacology research, including the first human trials, are usually based on a relatively limited number of adults health Volunteers or patients as the object, focusing on the subjects to confirm the safety and tolerability, and should carry out pharmacokinetic studies, diet studies, etc .; if conditions permit, should be carried out with the pharmacodynamic properties of the active ingredients Related to the initial study, it is best to add placebo medication group.

In addition to healthy adults, normal elders can also be studied as subjects, if necessary, or in patients with liver dysfunction, renal impairment, etc., based on the pharmacokinetic characteristics of the test medications. In addition, Predicting drug interactions may require the use of specified drugs in combination therapies, which may be referred to in the Guiding Principles of Pharmacokinetics in Patients with Hepatic Impairment, Technical Guidance for Pharmacokinetics in Patients with Renal Impairment Principles "and" Guiding Principles for the Study of Drug Interactions ".

Usage and dosage

Clinical studies involving single and multiple dosing are required and multiple dosing trials are usually performed after safety and tolerability have been confirmed by a single dosing study.

The first dose of a single-dose test is usually based on the maximum initial dose as estimated from the non-clinical trials of two or more species of animals.Then, the dose is gradually increased while confirming safety and tolerability until Meet or exceed the estimated maximum clinical dose.

The dose for multiple dosing trials should be based on the results of a single dosing trial and the predicted clinical dosing, and should in principle be administered multiple times until it is speculated that the plasma concentration of the subject will reach steady state.

2. Observation and inspection indicators

(1) In order to evaluate the safety of medicines, the following observation and inspection indicators should be implemented.

● subjective symptoms

● objective observation (weight, blood pressure, pulse, body temperature, ECG, vision, fundus, etc.)

● General clinical laboratory tests (hematology, blood biochemistry, urine tests, etc.)

● Other evaluation and inspection items needed to evaluate the safety of various types of tests

(2) Pharmacokinetics

(3) If necessary, noninvasive urodynamic tests (urine flow rate determination, residual urine test, etc.) should be performed.

3. Clinical evaluation

(1) safety evaluation

Adverse events refer to all adverse medical events that occur after clinical trial subjects receive the test drug and may present with signs and symptoms or diseases or laboratory abnormalities but may not conclude that there is a clear causal relationship with the test drug. Should be its content, extent, occurrence time / mitigation time, the test drug medication situation, whether to take measures, after one record into the case report, and determine its causal relationship with the test drug will not be ruled out with the test drug The causal adverse event was considered as 'ADR'.

In the event of serious and unexpected adverse events, clinical trial responsible physicians should immediately take the most appropriate treatment, according to the requirements of the "Good Clinical Practice of Drugs" report the parties involved in clinical trials of drugs.If adverse events, At the discretion of the clinical trial responsible physician, discontinue / continue use of the test medication for that subject and record the details of the adverse event (symptoms, timing, extent, treatment, duration, course, outcome) Of the causal relationship.Observation of serious adverse events or adverse reactions, in principle, should continue until the symptoms or abnormal changes in clinical tests subsided.If there is safety problems, should study whether it can pass the test drug toxicity test or pharmacodynamic test prediction.

(2) Pharmacokinetics and other evaluation

Pharmacokinetic test data were obtained to evaluate the absorption, distribution, metabolism and excretion characteristics of the test drug.

According to the pharmacokinetics and pharmacodynamic properties of the test drug, calculate the appropriate usage and dosage, enter the exploratory clinical trial.

4. The use of urodynamic examination of clinical pharmacology

Clinical pharmacology studies are generally carried out in the early phase of clinical trials, but also in other phases according to the needs of drug development.

If necessary, a small number of patients with OAB can be targeted to explore the pharmacological effects of the test drug by urodynamic examination to calculate the safe and effective dosage.Only in separate experiments, some patients in other tests can also be combined test.

(1) test object

Patients with OAB (except for patients with major complications and those who are difficult to assess for efficacy).

(2) test method

Test drug Before and during treatment, after the end of the drug (or suspension) to implement the urodynamic examination. Urodynamic examination should be based on the characteristics of the test drug decisions.

(3) Clinical evaluation

During the entire trial, it is best to have the same examiner use the same instrumentation to examine the subject.

Through the determination of bladder pressure, the involuntary contraction of the disappearance or pressure reduction, the maximum bladder capacity increase as the goal, to confirm the efficacy of the test drug, calculate the effective clinical dosage.

At the same time carry out safety evaluation.In addition, urine flow rate determination or residual urine test can be found too strong pharmacological effects caused by urinary retention and other adverse reactions, and used to adjust the dosage.

(B) exploratory clinical trials

Exploratory clinical trial OAB patients for exploratory research, proof of concept and so on, to calculate safe and effective dosage, a clear clinical efficacy and adverse events dose response relationship, and then determine the best confirmatory clinical trial usage and adaptation Witness group.

Test object

OAB patients.

Given the limited availability of information on the availability and safety of medicines available at this stage, patients with major complications should be excluded, and patients who are difficult to assess for effectiveness should be excluded.

2 test methods

Randomly divided into groups of different doses for comparative trials between groups, it is advisable to carry out double-blind trials in at least 3 dose groups with placebo and, if necessary, increase the positive control.

Test drug use period, usage and dosage is determined by the nature of the evaluation method and test drug, should be scientifically and rationally set according to the characteristics of different test drugs.Generally recommended exploratory clinical trial duration should be long enough to cover the reach Maximum time to effect: For new compounds, the duration of the usual study is 12 weeks. Short duration of study may be used if adequate information is available on the time required for maximum effectiveness of the same class of drug.

General clinical laboratory tests (hematological examination, blood biochemical examination, urine test, etc.) should be carried out before, during and after the end of the test medication, and if necessary, according to the characteristics of the test medication ECG If the test drug during the implementation of electrocardiogram examination should be considered at the same time the characteristics of the test drug and the burden on the subject to set the optimal interval.In addition, depending on the characteristics of the test drug, and sometimes need some time after the end of medication Continue to observe within.

3. Clinical evaluation

(1) Validity evaluation

Determine the main evaluation indicators (urination frequency, urinary incontinence frequency, urinary urgency, etc.) and observe the secondary evaluation indicators.

(2) safety evaluation

Reference clinical pharmacology research results, and follow the relevant guidelines.

(3) other evaluation

If necessary, sparse point blood samples should be collected, drug concentrations measured, and population pharmacokinetics or population pharmacokinetic / pharmacodynamic studies conducted.

(C) confirmatory clinical trials

Confirmatory clinical trials using the recommended dose set in the completed clinical trial, compared with the control, to confirm the efficacy and safety of the test drug OAB.

Test object

OAB patients.

It is best to avoid the selection of patients with major complications, based on the characteristics of the test medication to be judged, the evaluation of the drug may have a significant impact on the evaluation of the symptoms caused by OAB patients should also be excluded.

It is recommended that you consider enrolling a certain number of elderly patients to assess the effectiveness and safety of that population. Pay attention to the effect of age on both validity and safety.

2 test methods

In addition, if the previous stage of the test for the recommended dose verification is not sufficient, you can also set multiple dose groups to test the recommended dose at the same time should be set according to the characteristics of the test drug best The duration of the study (for a reasonable evaluation of the effectiveness of the study medication, the expected duration of the study is at least 12 weeks.) The sample size should be determined to meet the statistical requirements.

3. Clinical evaluation

(1) Validity evaluation

Same as exploratory clinical trial.

(2) safety evaluation

Reference clinical pharmacology research results, and follow the relevant guidelines.

Because OAB is a chronic disease, it needs to cover at least 12 months of safety data and establish the long-term safety of new therapeutic interventions, which should generally include large sample sizes, representative patient population data as required by the ICH E1 guidelines , These data should meet the guidelines for population exposure requirements.According to specific pharmacokinetic characteristics, there should also be recorded clinically significant potential drug interactions.

Long-term medication test subjects and confirmatory clinical trials of the same OAB patients, but also can be directly to the confirmatory clinical trial subjects into long-term medication test.

For safety evaluation, a sufficient number of subjects over the age of 65 should be included in clinical trials.

It is advisable to communicate with the competent authorities at the time of submission of long-term medication safety data.

(3) other evaluation

Same as exploratory clinical trial.

(D) research after listing

Refer to Post-Market Research with reference to the Guiding Principles for General Considerations in Drug Clinical Trials.

(E) children with overactive bladder clinical trials

Pediatric OAB patients are often over-active in detrusor evaluation when measuring bladder pressure Therefore, pediatric OAB is different from adult OAB In the following sections of the exploratory and confirmatory clinical trials for the treatment of pediatric OAB drug are briefly described Content. Pharmacokinetic study of children's OAB drug reference "Pediatric population pharmacokinetic study of technical guidelines."

Etiology and diagnosis

The etiology of many children with OAB, known as idiopathic OAB, is partly associated with neuropathological changes, most commonly neural tube hypoplasia, and neurogenic Detrusor Overactivity (NDO). The potential consequences of NDO are more severe and affect the upper urinary tract: vesicoureteral reflux, hydronephrosis, recurrent pyelonephritis and underlying kidney damage. Lower urinary tract symptoms (urinary symptoms) are less common.

The normal developmental level of bladder control in children varies from person to person and can not be diagnosed as idiopathic OAB until the age of 5. First-line treatment of idiopathic OAB in children is behavioral therapy that includes providing information and behavioral advice When symptoms can not be controlled, medications may be considered.

The diagnosis of idiopathic OAB in children is based primarily on symptoms and is obtained through medical history collection, physical exams, and urinary bladder diary.

2. Subject's choice

Idiopathic OAB and NDO should be separately studied in separate trials.

OAB pediatric enrolled exploratory and confirmatory clinical trials do not require a urodynamic study. Patients with idiopathic OAB over the age of 5 years, beyond this age, may not be diagnosed. Although urinary urgency is usually an idiopathic OAB The most prominent symptom in young children (<11岁) 的临床试验中, 因为无法明确表述不同的膀胱感觉 (例如: 尿急, 充盈) , 尿失禁, 尿频可能是观察到的症状.

The distribution of subjects in the age and / or weight subgroups should be guaranteed.

3. Research purposes and clinical efficacy indicators

The primary goal of developing new drugs for idiopathic OAB in children is to be improved during treatment and / or to be cured after the treatment is completed.The subjects' reported outcomes should be the primary endpoint and should be recorded through diaries (pollakiuria and urinary incontinence events ), Should complete 3-7 days record.

In idiopathic OAB children exploratory clinical trials - confirmatory clinical trials, including the following indicators of efficacy:

● average single urine output (recommended main efficacy indicators)

● maximum single urine output

● Average number of incontinence days / 24 hours

● Average night urinary incontinence frequency / 24 hours

● Dry (incontinence) days / 7 days

● average number of urination during the day / 24 hours

● The average number of urinary urgency / 24 hours

● residual urine output

Evaluation of the above indicators relative to the baseline changes.

In addition, the study should include a validated quality of life questionnaire as a secondary efficacy indicator.

4. Research Design

In children with idiopathic OAB clinical trials, it is recommended to use placebo control.

5. Dose selection and effectiveness studies

A dose-exploratory study is often required in the child population.If a range of adult doses has been established, a similar starting point for exposure to exposure in adults may be taken as a reasonable starting point.The choice of dosage (range) can be based on an older child / Adult pharmacokinetic and pharmacodynamic data obtained, combined with the known physique and body maturity of the model based on the predictive value of the model can also be used to optimize other methods, such as the sampling time point or The number of subjects in different strata Because of the frequent sampling in child subjects, ethically unfeasible, and for practical reasons, population pharmacokinetic modeling is the preferred method of data analysis.In order to establish The final dose regimen in children, which requires dose-exploratory clinical studies, should last long enough to cover the time to maximum effect, with a duration of at least six weeks.

In order to rationally assess the efficacy of study medication in children, the duration of confirmatory clinical trials for idiopathic OAB is expected to be 3 months, and it is expected that when the full treatment effect is clear and at the end of the 3-month study period, The main endpoint evaluation.

6. Security

Because OAB therapy may last a long time, follow-up to children should be continued for 12 months to demonstrate long-term drug safety, and extended studies following the open-label study for reasonable reasons after the first 3 months of study The safety assessment of new OAB drugs for children depends on the safety profile in adults, with particular attention to the effects on urinary retention and growth and development.

1. urgency: refers to a sudden, intense, and difficult to delay the desire to urinate;

2. Urge incontinence: refers to urinary incontinence accompanied by urinary urgency or urinary incontinence;

3. Urinary frequency: the frequency of subjective feelings of patients urinating too often, the diagnostic criteria for urination during the 8 times and above;

4. Nocturia: night (after going to bed to wake up time) due to urinary awakening frequency 1 and above, the reason may be nocturnal polyuria, sleep disorders or OAB and so on.

1. Overactive bladder diagnosis and treatment guidelines (2014 Edition)

2.EMA.Guidance on the clinical investigation of medicinal products for the treatment of urinary incontinence.1 January 2014.

3.MHLW. Activity of the bladder treatment of clinical evaluation of the method of related to the relevant provisions of the article. Http: //www.mhlw.go.jp, 2006-06-28.

4. ICH1. The Extent of Population Exposure to Assess Clinical Safety for Drug Intended for Long-term Treatment of Non-Life-Threatening Conditions.

5.CFDA. Clinical Trial of Drugs Quality Management Specification (Revised). December 2016

6. CFDA. General guidelines for drug clinical trials. January 2017

7. CFDA. Biometrics guidelines for drug clinical trials. June 2016

8. CFDA. Technical Guidance for Pharmacokinetics in Patients with Hepatic Impairment. May 2012

9. CFDA. Technical Guidance for Pharmacokinetics in Patients with Renal Impairment May 2012

10. CFDA. Guidelines for the study of drug interactions. May 2012

11. CFDA. Guidelines for pharmacokinetic studies in pediatric populations. July 2014