Clinical Trials Guidelines For Companion Diagnostic Reagents For Approved Anti-tumor Drugs (draft)

1Ⅰ. Preface
By testing samples from tumor patients with companion diagnostic
reagents, the results can provide significant information on safety and efficacy
of anti-tumor drugs for relevant patients, including: to identify patients who
are most likely to benefit from the drugs; to identify patients who have a
relatively large risk of suffering from relevant serious adverse reactions of the
drugs; to identify the population subgroup to whom the safety and efficacy are
guaranteed via sufficient studies and etc. Products used for the monitoring of
therapeutic drug, and detection of genetic polymorphisms of drug
metabolizing enzymes will not be regulated as companion diagnostic reagents. In recent years, with the development of precision medicine, anti-tumor
precision treatment drugs and companion in vitro diagnostic reagents have
been extensively used in clinical operations, and related industries have been
flourishing. At present, the number of registration application of companion
diagnostic reagents is creasing year by year, and the situation is pretty
complicated. In terms of product development, some products are co- developed with related anti-tumor drugs, and some products are developed
after related anti-tumor drugs are approved. In our country, the situation of
developing multiple companion diagnostic reagents for the same anti-tumor
drug is particularly notable. This guideline aims to provide applicants with
clinical evaluation methods for companion diagnostic reagents under the
premise of fully considering the reality of our country. This guideline are general requirements of clinical evaluation of
companion diagnostic reagents for approved anti-tumor drugs. Applicants
should determine whether the contents in this guideline are applicable based
Clinical Trials Guidelines for Companion Diagnostic Reagents for
Approved Anti-tumor Drugs
(Draft)
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on the specific characteristics of products. This document is a guidance
document for applicants and reviewers. It does not involve administrative
matters such as registration approval and will not be enforced as laws and
regulations. If there are other methods which can meet the requirements of
regulations, they can be adopted, but detailed research materials should be
provided. Key points mentioned in this guideline are made based on the
current regulations, standard systems and current knowledge level. With the
constant improvement of regulations as well as standards and the continuous
development of science and technology, relevant contents in this guideline
will also be adjusted in due course. Ⅱ. Scope of Application
Based on the characteristics of companion diagnostic reagents and antitumor drugs, for drug clinical trial, companion diagnostic reagents or clinical
trial analytical methods(CTA) are needed to screen the candidates or to
conduct bio-marker stratification analysis for enrolled groups. In the following
document, the companion diagnostic reagents or clinical trial analytical
methods(CTA) used in the clinical trials of anti-tumor drugs are named as “originally developed companion diagnostic reagents” The originally
developed companion diagnostic reagents also include reagents, for the
clinical testing analytical methods(CTA) adopted in the clinical trial, are
proved to be equal to clinical testing analytical methods(CTA) through
bridging studies after the drug clinical trial is completed, in the co- development process of anti-tumor drugs and companion diagnostic reagents. The companion diagnostic reagents for approved anti-tumor drugs
mentioned in this guideline are refer to companion diagnostic reagents
declared by relevant IVD manufacturers to complement the approved antitumor drugs after the relevant anti-tumor drugs are approved. For the products
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newly developed by the IVD manufacturers (the products those are not
originally developed companion diagnostic reagents, hereinafter referred to as “Newly Developed companion Diagnostic Reagents”), the following
requirements should be met for the application of this guideline ： 1. The
companion anti-tumor drugs have been determined at the IVD reagent product
design and development stage, the anti-tumor drugs should be one or several
specific approved drugs, not a certain type of drugs, and the names of drugs
should be indicated in the IFU after clinical verification is completed；2. Bio- markers to be tested by in vitro diagnostic reagents (e.g. genes and mutation
sites tested by gene detection products) and the status classification of
applicable population based on the bio-markers are consistent with originally
developed companion diagnostic reagents；3. The applicable population and
applicable sample types of in vitro diagnostic reagents should be consistent
with those of originally developed companion diagnostic reagents； 4. The
analytical performance, especially analytical sensitivity, should be comparable
to the originally developed companion diagnostic reagents. There are discrepancies between newly developed companion diagnostic
reagents and originally developed companion diagnostic reagents, for instance:
the abilities of testing more bio-markers, more applicable sample types, with
higher analytical sensitivity etc. The verification of comparability between
newly and originally developed companion diagnostic reagents can refer to
this guideline; as to the discrepancies between newly and originally developed
companion diagnostic reagents, sufficient clinical evidence should be provided
to prove the impact of those discrepancies on guiding clinical application of
related drugs, if necessary, clinical trials for co-development of anti-tumor
drugs should be provided to prove clinical significance of its companion
diagnosis.
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Ⅲ. Requirements on Clinical Trials
Clinical trials of companion diagnostic reagents consist of 2 parts, one is
the clinical accuracy studies, the other one is clinical verification of
companion diagnostics application. Based on whether the companion
diagnostic reagents have been used in the clinical trials of anti-tumor drugs
and its own characteristics of companion diagnostic reagents, the verification
of companion diagnoses can be divided into the following situations：
Reagents to be registered are originally developed companion diagnostic
reagents. If it’s an originally developed companion diagnostic reagent, data of drug
clinical trial can be submitted as the clinical trial data of verification of
companion diagnostics application. This part of data should be consistent with
those submitted to the center of drug evaluation for anti-tumor drug approval. Please refer to “Technical Guideline of Clinical Trial for Co-development of
Companion Diagnostic Reagents and Anti-tumor Drugs” for more information. Reagents to be registered are newly developed companion diagnostic
reagents. The verification of companion diagnostic application can be carried out
in the form of consistency comparison with originally developed companion
diagnostic reagents, bridging studies and observational studies on the efficacy
of approved anti-tumor drugs etc. 2.1 For the companion diagnostic reagents with approved drugs, extensive clinical applications, clear significance and whose interpretation are
easy to be standardized, if the performance of the reagents to be registered is
comparable to those of originally developed companion diagnostic reagents, the verification of clinical significance of companion diagnostic can be carried
out in the form of clinical comparison with originally developed companion
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diagnostic reagents. See the Annex 1 for a list of such biomarkers. As to the
bio-markers not included in list, the verification method of the clinical
significance of companion diagnostic should be determined after sufficient
communication with regulatory authorities. 2.2 Bio-markers to be tested by companion diagnostic products contain
those for negative selection for anti-tumor drug treatment efficacy. For
instance, KRAS genes, the IFU of already approved Cetuximab indicated
clearly that the drug should not be used for colorectal cancer patients with
KRAS gene mutation. For such bio-markers, the verification of companion
diagnostic application of newly developed companion diagnostic reagents can
be carried out in the form of clinical comparison with originally developed
companion diagnostic reagents, and clinical trials should focus on the
consistency between the products to be registered and originally developed
companion diagnostic reagents. Ⅳ. Clinical Trial Design
Verification of Clinical testing accuracy
For companion diagnostic reagents, before starting the verification
process of clinical companion diagnostic application, the testing accuracy of
the product on clinical samples should be verified. It is recommended to
perform the clinical trial according to the requirements of “Technical guideline
on clinical trial for in vitro diagnostic reagents” to verify the testing accuracy
of the products on clinical samples. 1.1 Clinical trial institutions
It is suggested to select at least three qualified clinical institutions filed
by medical device clinical trial institutions to perform the clinical trial. The
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Clinical research institution should have the advantages of testing including
pathological diagnosis, molecular biological methods etc. The staff
performing the experiments should have enough time to get familiar with each
part of the testing system (instrument, reagents, quality control and operation
procedures etc.) as well as the evaluation schemes. During the whole process
of the experiment, the reagent to be evaluated and the reference method
should be under effective quality control to ensure the maximum accuracy and
repeatability of testing data
1.2 Enrolled Population
The enrolled population should represent various features of target
population of the product, instead of only enrolling partial typical cases. In
principle, prospective collection of samples can better represent target groups. If necessary, cases can be collected retrospectively under the premise of
reasonable control of biases. The preservation condition of samples collected
retrospectively should meet the requirements of the reagents to be registered
and the reference methods. The enrolled population of clinical trials should be
applicable population of companion diagnostic reagents in terms of tumor
types, stages and preliminary treatment plan. The sample types to be verified
should be the applicable sample types of companion diagnostic reagents. During the clinical trials, the proportion of cancer cells etc. in the samples
should also be assessed. Clinical trial patient enrollment for the subgroup of
mutation of each biomarker should be based on the characteristics of product
design. For instance, the gene mutation detection products based on PCR
technology should enroll a certain number of cases for each gene mutation and
locus. The Clinical trials should adequately justify the patient enrollment. 1.3 Selection of Comparison Methods
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For gene detection product, it is recommended to use reference methods
for comparison to evaluate the detection performance of the reagents to be
registered on clinical samples. The reference methods can be first-generation
sequencing, technically mature second-generation sequencing or genetic
testing technologies universally acknowledged in clinical applications. The
testing of reference methods can be completed by clinical trial institutions or
by qualified third-party institutions. If the third-party institution is
commissioned to conduct the testing of reference methods, the commissioning
agreements between clinical trial institutions and third-party institutions
should be provided. And in the meantime, detailed information of reference
methods should be provided, such as principle of methods, required reagents
and instruments, performance verification of reference methods, quality
control of reference method, typical experiment graph and data. The above
material should be confirmed, stamped and signed by the clinical trial
institutions. For the bio-markers which have no clinical reference method such as the
bio-markers testing of protein level, under the premise that the testing results
are comparable, clinical trials can also adopt laboratory testing methods
normally used by clinical trial institutions (e.g. immunohistochemical
methods), or use the same type of product already approved and marketed for
comparison. 1.4 Clinical Evaluation Indicators
Clinical evaluation indicators of this clinical trial design mainly include
positive coincidence rates, negative coincidence rates, total coincidence rates, Kappa values etc. of the product to be register in comparison with the
reference methods. The 95% confidence intervals of each coincidence rate
should be calculated too.