CDE for comments: Public consultation on the Guidelines for the Design of Clinical Trials of Lysovirus-type Drugs (Draft for Comments)

Introduction: There are no relevant guidelines for the design of clinical trials of lysovirus-type drugs in China.
is a class of viruses that can selectively replicate within tumor cells through different regulatory mechanisms to lysate tumor cells, while minimizing the effects of normal cell growth.
the development of tumor immunotherapy, the therapeutic potential of lysovirus drugs in various diseases such as malignant tumors has received more and more attention.
with the development of lysovirus-type drugs, it is found that these drugs have more unique considerations in clinical trial design.
ICH and EMA, FDA do not have relevant technical guidelines.
Taking into account that there are no relevant guidelines for the design of clinical trials of lysovirus-type drugs in China, our center in full research and development of the same varieties at home and abroad and related clinical trial technical requirements on the basis of the draft "lysovirus-type drug clinical trial design guidelines", after expert discussion, has formed a draft for comments.
we sincerely welcome all sectors of the community to the draft for comments and suggestions, and timely feedback to us, in order to follow up the improvement.
for comments shall be one month from the date of publication.
your feedback please send to the following contacts: Contact: Huang Yunhong, Liu Xiao Contact: huangyh@cde.org.cn, liux@cde.org.cn.
thank you for your participation and support.
The National Drug Administration Drug Review Center, August 7, 2020 lysovirus-type drug clinical trial design guideline i, outlines that lysovirus refers to a class of viruses that may selectively replicate within tumor cells and then cleavage tumor cells, but do not affect normal cells, including different RNA and DNA viruses, and can target multiple types of tumors.
The mechanism of treating tumors is constantly being studied, and several of the main mechanisms that are now more recognized are: the virus cleavages cells directly through its own proliferation in tumor cells; The tumor-specific antigen released by the tumor cells of the solution activates the body-specific immune response and enhances the systemic anti-tumor effect, and stimulates the antiviral immune mechanism within the tumor cell by infecting the tumor cells, releasing a variety of antiviral and inflammatory factors, and promoting the death of the tumor cells or surrounding tumor cells.
as early as the middle of the last century, lysovirus began to be tried for tumor therapy, with the development of tumor immunotherapy, lysovirus drugs in a variety of malignant tumors in the treatment potential has received more and more attention.
To date, a number of lysovirus drugs have been approved by drug regulators in different countries for clinical treatment of tumors, such as the 2015 successful approval of the lysovirus drug T-VEC abroad for the treatment of non-removable skin, cortical and lymph node lesions that relapse after initial surgery, further promoting the development of lysovirus-type drugs.
has entered clinical trials of the lysoma virus its parent strains are mainly adenovirus, herpes virus, pox virus, etc.
in some cases, in order to improve the potential virus or safety of these viruses, the lysovirus is also genetically modified.
, depending on the type of virus, can be given locally or throughout the body, and currently the adaptive disease is dominated by solid tumors.
the multi-functional properties of the lysovirus in tumor therapy give it the potential to work with other drugs, and the treatment methods that have been used in combination with clinical trials include radiotherapy, chemotherapy, immuno-checkpoint inhibitors, etc.
, however, there are many regulatory challenges to the development of lysovirus-like drugs, including, but not limited to, clinical trial design and pharmacological challenges.
guidelines are mainly applicable to the single-use or co-use clinical trial design of lysovirus-type drugs for the treatment of malignant tumors, including exploratory clinical trials and corrogical clinical trials.
Addition, applicants should refer to the Code of Quality Management of Clinical Trials (GCP), the International Coordinating Committee on Technical Registration of Human Medicines (ICH) and relevant guidelines issued at home and abroad in connection with the common requirements and requirements for clinical trials.
principles to be followed in clinical trials of general drugs and duplicates of other guidelines are not repeated in these guidelines.
in these Guidelines represent only the current general understanding of clinical trials of lysovirus-like drugs and cannot cover all situations encountered in the development of new drugs.
the progress of scientific research, the recommendations and recommendations of several technical problems in clinical trials of lysovirus drugs will be constantly improved and updated.
in the research and development process, according to the principle of specific analysis of specific problems, based on preclinical data and past research results of related varieties, scientific design of clinical trials, timely improvement of trial design and risk control programs.
, clinical trial design points similar to other anti-tumor drugs, lysovirus clinical trial process is usually divided into: exploratory clinical trials and corroroidative clinical trials.
Exploratory clinical trials are preliminary studies on drug tolerance, safety, immunogenicity, pharmacogenetics, etc., and preliminary exploration of dosage, administration program, tumor effectiveness, etc. to provide data support for the design of late-stage test programs.
confirmable clinical trials are exploratory clinical trials that further confirm the subject's clinical benefits and safety/tolerance on the basis of one or more specific tumors, providing sufficient evidence to obtain a listing license.
the use of randomized control design in corrogical clinical trials, if randomized controlled studies are not possible, the reasons should be explained and the reasonableness of the proposed trial design should be explained.
In considering the design of clinical trials of lysovirus, it is important to focus on the following issues: (i) The subject population is ethically required, and clinical trials are usually conducted first in subjects who have failed or failed standard treatments, and then gradually advance to the earlier stages of treatment of the disease after obtaining precise safety and efficacy.
During the exploratory clinical trial phase, one or more tumors should be selected for clinical trials with reference to preclinical studies to obtain the initial results of the drug's sensitivity to different tumors, which should then be expanded in one/several of the most developed tumors.
Because the pre-existing immunity of the virus may affect the safety and effectiveness of the drug, and accordingly change the route of administration, administration program, etc., it is possible to focus on the impact of human-related pre-existing immunity in the epidemiological data of the population, such as pre-existing immunity on the application of this product, should be limited in the study of population entry criteria.
Because lysovirus drugs activate the mechanism of immunity to tumors, if immunosuppressants are possible in the treatment of adverse reactions, it is recommended to exclude subjects with immunodeficiency in order to protect the safety of subjects when they enter the group.
subjects with other underlying diseases, such as those infected with the virus in the past, should consider whether the combination of drugs will have an impact on the efficacy of the lysolyvon virus.
(ii) drug administration program 1. The specific route of administration should be selected according to the tumor species and drug characteristics.
scientific assessment should be carried out before selecting the route of dosing, including the rationality of the chosen route of dosing, and the possibility of replication of the virus in non-target areas.
from the point of view of safety risk in general, when the proposed treatment of adaptive diseases as solid tumors, it is recommended to first use local drug treatment to explore, accumulate relevant safety data, and then explore whole-body drugation.
2. Dose exploration Due to the complexity of lysovirus products and the limitations of animal models, if the non-clinical study data do not provide sufficient safety information, the initial dose and dosage range should be carefully selected in the subjects to provide sufficient basis for the design of post-confirmed clinical trials.
dosing in-tumor injections, the total dose should be scientifically set.
For lysovirus drugs that have been modified to express specific cytokines and antibodies, the effects of these expressions themselves and the synergetic effects after overlaying lysovirus should be taken into account, and the dose used in the first human trial should be reasonably set.
3. If the preclinical study data are not sufficient to indicate the efficacy and safety of multiple dosing, it is recommended to first explore the single treatment of a single drug, and then to carry out multiple dosing of a single drug.
It is not recommended to have subjects receive this dose multiple times during the single dose increment phase of a single dose, if all subjects in a dosage group do not complete the safety assessment and the safety of the dose group is not confirmed.
should set clear dosing standards and/or maximum number of dosings when multiple dosing is performed.
4. Combined administration of lysovirus drugs in the use of other drugs should be based on data from preclinical studies.
recommends that clinical trials of combined therapy be conducted after preliminary pharmacological data and safety tolerance for single-drug therapy have been confirmed.
the joint dosage exploration program refers to the single drug dosage exploration program.
(iii) The clinical research stage of other exploratory studies, such as pharmacodynamics and immunogenicity, recommends the study of pharmacodynamics, including biological distribution, virus discharge, etc., and suggests paying attention to the method of clinical sample collection, the frequency of sample collection and the duration of the monitoring cycle.
should be considered in terms of the biological characteristics of the virus, including replication capacity, immunogenicity, continuity and incubation period, targeting, stability of detoxifying products, and drug administration pathways.
because the virus replicates in some tissues after drugation, adequate monitoring frequency and duration should be designed.
if the lysovirus shows latent reactivation, its exploratory study may last longer.
it may be difficult to detect the presence and/or distribution of lysolytic viruses in tumors, but if tumor removal or biopsies are possible, oncology pathology can provide valuable information.
Due to the limitations of ethical and clinical feasibility, it may be difficult to set up distribution laws in multiple point-in-time monitoring organizations, and encourage the collection of specimens through biopsies, detection of indicators in tumor tissue, and accumulation of scientific data at appropriate points in time, with the knowledge of the subjects.
routine testing, monitoring distribution should be encouraged, and the effect of biopsy on efficacy evaluation should be paid attention to.
encourage the exploration of biomarkers associated with efficacy.
effects of antiviral antibodies on efficacy of antimicroviral viruses are not yet known and may interfere with the distribution of the virus in the body.
pre-existing immunity to the virus (body fluid immunity and/or cellular immunity) may affect the route, dose and number of doses given.
, monitoring the immune response to lysovirus and expression products is important.
(iv) The total survival of efficacy evaluation is by far the most reliable clinical trial endpoint for evaluating the efficacy of anti-tumor drugs, and is usually the preferred endpoint.
for longer-lived tumors or for longer-term treatment interventions, a reasonable alternative endpoint can be chosen.
this section can be found in the Technical Guidelines for the End of Clinical Trials of Anti-Tumor Drugs issued by the Center for Drug Review in 2012.
In addition to systemic dosing such as chemotherapy or biotherapy, most lysovirus currently treated with solid tumors are localized, and the main endpoint of these trials is usually tumor response rates or progression-free lifetime (PFS) based on recent efficacy assessments.
Because the main mechanism of action of the lysovirus includes the direct lysolytic effect on the target lesions and the bystander effect on the distant lesions that are not given, even if the lysovirus is given in-tumor, its efficacy evaluation, including target lesions selection, measurement, etc., should fully reflect the anti-tumor effect, and the systemic efficacy assessment is still one of the main evidences of the effectiveness of the lysovirus.
scientific monitoring and evaluation of suitable non-drug-treated lesions can provide the necessary evidence for the bystander effects of lysovirus.
assessment of solid tumors is usually based on the WHO standard or the latest version of the international industry standard, for example, the remission evaluation standard for solid tumors can be referred to the widely accepted RECIST.
Although the main endpoints based on immunotherapy-related efficacy evaluation criteria have not yet been generally accepted to support drug regulatory approval, the immunotherapy mechanism of lysovirus may also cause false progression of tumors, so the simultaneous evaluation of immunotherapy-related efficacy may be considered during the exploratory clinical study phase in order to better respond to this situation.
(v) Safety evaluation and follow-up safety evaluation refer to the definition and standard of common adverse reaction event evaluation standard (NCI-CTCAE, latest edition).
should also consider the specific security risks of lysovirus, such as latent reactivation, wild strains reply to mutations, etc., set sufficient follow-up time.
duration of follow-up should provide preliminary evidence of effectiveness and the duration of the virus, and the possibility of latent reactivation of the virus should be considered.
recommends that viruses with long-term latent risks be safely followed up for longer periods of time and that viruses are no longer detected continuously, depending on the risk and characteristics of the virus.
It has been reported in some clinical trials that the toxic side effects increase when the lysovirus is used in combination with radiotherapy, chemotherapy, immuno-checkpoint inhibitors, etc., and the applicant should develop appropriate risk control measures based on the toxic response observed in the relevant drug literature and preclinical studies.
3. Risk control the current lysovirus is a replicable living virus that can be transmitted from treated patients to individuals in close contact with the patient, including relatives and health care providers, and may fall out into the natural environment.
although lysovirus is often genetically modified to limit its pathogenicity, virus shedding is still possible and attention should be paid to the biosecurity risks of such drugs.
Therefore, the rationality of the selected virus strain should be considered at the product project stage, and the prevalence distribution, biological characteristics, host vectors, infection and pathogenicity of the pro-virus strain, including the possible biosecurity hazards and environmental impact of the strain response mutation, and its suitability for clinical applications, should be fully investigated.
In the non-clinical research stage, the dosage and dosage methods of the product should be fully explored, and clinical trials should be considered only after obtaining safety data for the product's biological transmission, acute toxicity, long toxicity, tumor-caused, reproductive toxicity, genotoxicity, etc.
before entering clinical trials, the replication of viruses at non-targets should be considered, depending on product characteristics, including different sources of parent-based strains, different gene modifications, and different dosing methods.