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The implementation of China's conditional approval procedures for drugs and related considerations

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China Pharmaceutical Affairs, Vol.
36, No.
10, October 2022

author

YUAN Lijia,CHEN Xiaoming,ZHANG Ning Center for Drug Evaluation of the State Medical Products Administration

summary

Objective: To conduct an in-depth analysis and discussion on the relevant policies and implementation of conditional approval and listing of drugs in China, and to make suggestions
on the implementation and promotion of conditional approval of marketing in China with reference to the conditional marketing policies of the United States and the European Union.

Objective:

Methods: By combing the implementation of the regulations and policies of the National Medical Products Administration (NMPA) for the review and approval of drug conditional approval marketing applications after the issuance of the drug registration management measures, focusing on the access conditions, access procedures, post-market regulatory requirements, revocation situations and revocation procedures in the current regulations, the problems found in the implementation process are summarized by the US Food and Drug Administration (FDA) Drug Accelerated (Accelerate).
Approval) and the European Medicines Agency (EMA) Conditional Marketing Authorisation experience and comparative analysis of conditional policies of various countries, to explore the development direction
of China's conditional drug approval and marketing policy.

Method:

Results and conclusions: In order to accelerate the launch of clinically urgent drugs with outstanding value and shorten the clinical application time of new technologies, the United States and the European Union have established relatively complete conditional marketing regulations, policies and procedures
.
Although China's conditional approval system has been established for a relatively short time, it has the experience of Europe and the United States as a reference, combined with China's clinical practice and regulatory needs, and relevant regulations are also improving
.
In the future, regulators need to consider more refinement of procedures and technical requirements, the connection between systems (such as emergency use authorization and conditional approval system for vaccines), and strengthening post-market supervision
.

Results and conclusions:

keyword

drug evaluation; conditional listing; State Medical Products Administration; U.
S.
Food and Drug Administration; European Medicines Agency

body

China's 2020 version of the "Measures for the Administration of Drug Registration" proposed four drug accelerated marketing procedures: breakthrough therapy drug procedure, conditional approval procedure, priority review and approval procedure and special approval procedure, and for the conditional approval and marketing procedure of drugs, the State Medical Products Administration has issued relevant supporting documents "Working Procedures for the Review and Approval of Drug Conditional Approval Marketing Applications (Trial)" and "Technical Guidelines for Conditional Approval of Drugs for Marketing (Trial)", During drug clinical trials, the treatment of serious life-threatening diseases for which there is no effective treatment and drugs urgently needed in public health, drug clinical trials that have data showing efficacy and can predict their clinical value, as well as vaccines urgently needed to respond to major public health emergencies or other vaccines determined by the National Health Commission as urgently needed, may be conditionally approved when applying for marketing authorization if the benefits are assessed to outweigh the risks.
The purpose of conditional marketing approval is to shorten the development time of clinical trials of drugs and make them available as early as possible to patients with critical diseases or public health imperatives who cannot afford to wait.

Prior to the issuance of the 2020 version of the Measures for the Administration of Drug Registration, China has issued a number of relevant policies to accelerate the review of clinical innovative drugs and conditionally approve the listing or conditionally approve the market, such as in 2015, the State Council proposed to accelerate the review of innovative drugs urgently needed in clinical practice in the "Opinions on Reforming the Review and Approval System for Drugs and Medical Devices" (Guo Fa [2015] No.
44) [1]; In 2016, the former State Food and Drug Administration issued the "Opinions on Solving the Backlog of Drug Registration Applications and Implementing Priority Review and Approval" (Food and Drug Administration [2016] No.
19, now abolished) proposed [2], if based on early clinical trial data, its clinical benefits can be reasonably predicted or judged and has obvious advantages over existing treatment methods, and conditional approval of marketing is allowed before the completion of phase III confirmatory clinical trials, this policy has paved the way for the introduction of the follow-up drug conditional approval listing policy; In 2017, the General Office of the CPC Central Committee and the General Office of the State Council jointly issued the Opinions on Deepening the Reform of the Review and Approval System to Encourage Innovation in Drugs and Medical Devices (Department Fa [2017] No.
42)[3], which for the first time proposed in national government documents that drugs and medical devices that are urgently needed for the treatment of serious life-threatening diseases and public health can be conditionally approved.
The above reform results were finally reflected in the 2019 Drug Administration Law of the People's Republic of China (hereinafter referred to as the "Drug Administration Law") and the Vaccine Administration Law of the People's Republic of China (hereinafter referred to as the "Vaccine Administration Law"), which incorporated conditional approval into the legal provisions.

By analyzing the procedures, requirements and implementation process of the domestic drug conditional approval marketing application, this paper draws on the procedures and experience of the Accelerated Approval and the EU Conditional Marketing Authorization in the review and approval of the conditional approval application for drugs.
In order to improve the review and approval procedures and technical requirements of China's drug conditional approval marketing application, further accelerate the launch of innovative drugs urgently needed in clinical practice, and reflect the orientation of the "patient-centered" drug evaluation system.

1 Procedures and requirements for conditional approval in China

Procedures and requirements for conditional approval in China

On July 1, 2020, the new "Measures for the Administration of Drug Registration" came into effect, which includes conditional approval procedures, breakthrough therapy drug procedures, priority review and approval procedures and special approval procedures in the procedures for accelerated marketing registration of drugs, On July 8, 2020, the State Medical Products Administration (hereinafter referred to as the State Food and Drug Administration) issued the "Working Procedures for the Review and Approval of Drug Conditional Approval Marketing Applications", and on November 19, 2020, the Drug Evaluation Center of the State Food and Drug Administration (hereinafter referred to as the Drug Review Center) The Technical Guidelines for the Conditional Approval of Drugs for Marketing (Trial) were issued.

1.
1 Conditions of Access[4-5]

During drug clinical trials, drugs that meet the following two conditions can apply for conditional approval: first, drugs that are seriously life-threatening and have no effective treatment and drugs urgently needed in public health, and the drug clinical trial has data to confirm the efficacy and can predict its clinical value; Second, vaccines urgently needed to respond to major public health emergencies or other vaccines determined by the National Health Commission to be urgently needed have been assessed to have benefits outweighed the risks.

1.
2 Admission Procedures[6]

1.
2.
1 The applicant submits an application for conditional approval through a communication meeting

During the clinical trial of the drug, the applicant submits an application for communication (type II meeting) before the submission of the drug marketing authorization application, and fully communicates with the drug review center on conditional approval matters.
Those who intend to apply for priority review and approval may submit them together for communication.
Those who have been included in the breakthrough therapy drug program can apply for a Category I conference.

The minutes of the communication meeting shall serve as an important basis for accepting, filing and reviewing listing applications for conditional approval.
In addition, during the review of the marketing application, the applicant can still further communicate with the NMRC and reach an agreement on the above content.

1.
2.
2 The applicant submits the declaration materials

If it is confirmed that the conditional approval requirements are initially met after communication and assessment, the applicant may, at the same time as submitting the application for drug marketing authorization, submit an application for conditional approval of the drug to the Drug Review Center, and submit supporting materials in accordance with the requirements of the relevant technical guidelines.
Applications for priority review and approval may be submitted together.

1.
2.
3 Technical Requirements

Drugs conditionally approved for marketing should be able to provide effective treatment, and should meet one of the following conditions: 1) Compared with existing treatment methods, it has a significant improvement in the prognosis of the disease; 2) For patients who are intolerant or ineffective to existing treatment methods, obvious efficacy can be achieved; 3) It can be effectively combined with other key drugs or treatment methods that cannot be combined with existing treatment methods, and achieve obvious efficacy; 4) efficacy is comparable to existing treatments, but patient compliance can be significantly improved by avoiding serious adverse reactions of existing therapies or significantly reducing harmful drug interactions; 5) Can be used to respond to emerging or anticipated public health needs.

Existing treatment means drugs that have been approved for the treatment of the same disease in China, or standard treatment methods.
In general, these treatments should be the current standard of care for the disease.
Conditionally approved drugs are not used as existing treatments until clinical benefit is demonstrated.

The usual indicator used to evaluate drug effectiveness should be the clinical endpoint.
Clinical endpoints are features or variables that directly reflect the efficacy of a drug, i.
e.
, a direct evaluation of the drug's impact on patient sensation (e.
g.
, symptom relief), function (e.
g.
, improvement in exercise, delaying or preventing functional decline, etc.
), or survival.

For drugs that qualify for conditional approval, marketing approval can be conditional based on surrogate endpoints, intermediate clinical endpoints, or early clinical trial data.
Applicants should fully assess and explain the correlation, reasonableness and evidence between the selected surrogate endpoints, intermediate clinical endpoints, or selected early clinical trial data and the expected clinical benefit.

1.
2.
4 Review and approval

If a drug is conditionally approved for marketing, a drug registration certificate shall be issued, and relevant matters such as the validity period of the conditional approval drug registration certificate, the research work that needs to be continued after marketing, and the time limit for completion.
If the application for conditional approval of the listing is not approved, the applicant may re-declare according to the normal procedure after completing the corresponding research.

1.
2.
5 Post-market requirements[5]

The applicant shall discuss and reach a consensus with the NMRC on the research promised to be completed after marketing, the applicant shall undertake to complete all clinical trials on time, and the drug MAH shall submit to the NMRC for routine approval for marketing by means of supplementary application after completing new or ongoing drug clinical trials within the specified period.

1.
3 Logout procedure[5]

For conditionally approved drugs, if the holder fails to complete the research as required within the time limit or cannot prove that the benefits outweigh the risks, the NMPA shall cancel its drug registration certificate.
In addition, the holder shall take corresponding risk management measures for existing or identified risks and potential risks in accordance with the formulated post-market risk management plan to ensure the safety of patients' medication.

1.
4 Conversion to regular listing approval[5]

In accordance with the specific conditions attached to the drug registration certificate, the MAH shall submit to the Drug Review Center for routine approval for marketing by means of supplementary application after completing new or ongoing drug clinical trials within the specified period.
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.
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2 Conditional ratifications by China, the United States and the European Union

Conditional ratifications in China, the United States and the European Union

2.
1 Comparison of conditional ratification policies of China, the United States and the European Union

A comparison of China, the United States, and EU conditional ratification policies is detailed in Table 1
.

2.
2 Conditional approval of drugs in China, the United States and the European Union

2.
2.
1 Conditional approval of drugs in China

As of December 31, 2021, 48 varieties have been conditionally approved for marketing
.
Among them, antitumor drugs accounted for 75%, new crown drugs accounted for 11%, hematological disease drugs accounted for 6%, endocrine drugs accounted for 4%, and anti-infection and immune drugs accounted for 2% each, see Figure 1
.
At present, 5 varieties have been officially approved
.

2.
2.
2 Conditional approval of drugs in the United States

From 1992, when the FDA formally established the conditional approval process, to December 31, 2021, FDA approved a total of 278 accelerated approval products, of which 139 were approved for full marketing, 28 were disqualified, and 111 were pending complete marketing[12], as detailed in Figure 2
.

Of the 278 products with accelerated approval, 60% were antineoplastic drugs, 18% were anti-infective drugs, 14% were hematologic drugs, and the rest were endocrine, respiratory, psychotropic and other drugs (Figure 3).

2.
2.
3 Conditional approval of EU medicines

From the issuance of the Conditional Marketing Authorization Regulations in 2006 to December 31, 2020, the EMA approved a total of 59 conditional marketing authorizations for 59 drugs, of which 23 drugs were converted to full marketing and 2 drugs were withdrawn (not suspended or revoked) for commercial reasons, and on average, it took about 3.
5 years for companies to fulfill their post-authorization obligations and obtain full authorization for the product [13-17].

Among the 59 drugs, 50% are antitumor drugs, 20% are anti-infective drugs, 7% are neurological drugs, and the rest are cardiovascular, endocrine, blood, new crown, ophthalmology, transplant immunological drugs (Figure 4).

2.
3 Comparative analysis of conditional approval of drugs in China, the United States and the European Union

2.
3.
1 Distribution of indications for drugs

China's conditionally approved drugs are not as extensive as the United States and the European Union, with anti-tumor drugs accounting for the highest
proportion.

Among the drugs conditionally approved for marketing in China, the United States and the European Union, although anti-tumor drugs account for the largest proportion, China's anti-tumor drugs account for the largest proportion of conditionally approved listed drugs, about 75%, the EU accounts for the smallest proportion, about 50%, and the US FDA accounts for about 60%.

2.
3.
2 Conditional approval of listing to regular approval (full listing).

From the above data, it can be seen that the conversion rate of conditional approval to conventional approval in China is 10.
41%, the United States is 50%, and the EU is 38.
98%, of course, this is related to the short implementation of conditional approval in China, and subsequent drug regulatory agencies should continue to pay attention to the research work and supplementary application declaration of
conditional approved varieties after marketing.

2.
3.
3 Conditional approval of deregistration of listings

Since FDA formally established the conditional approval process, 28 conditional approvals have been revoked, and FDA has specific circumstances and specific procedures
for the cancellation of conditional approved marketing varieties.
Periodic assessments based on specific obligations under renewal applications and passive assessments based on non-compliance by applicants also cover the transfer of
conditional marketing authorization products.
However, China has provisions on the cancellation of conditional approval of listing, but has not yet clarified the specific circumstances and procedures, and only requires holders to submit post-listing research materials
in the form of supplementary applications within the specified time limit.

3 Reflections on the implementation of conditional approval for listing in China

Reflections on the implementation of conditional approval for listing in China

The purpose of conditional approval is to shorten the development and registration time of drugs under the premise of controllable risks, so that drugs with potential clinical benefits can be used in patients as soon as possible.
It brings both opportunities and challenges to applicants, requiring applicants to have an in-depth understanding of the disease background and therapeutic areas, as well as a forward-looking approach to drug development.
At the same time, government departments need to standardize the review scale, improve the review path, strengthen post-market supervision, guide applicants to fully understand the requirements for conditional approval, balance risks and benefits, better promote drug innovation, accelerate drug development and market speed, and provide patients with more valuable drugs.
Referring to the regulations and policies of conditional listing in the United States and Europe, there are the following thoughts on the domestic conditional approval policy.

3.
1 Regarding the types of conditionally approved drugs for the treatment of diseases

U.
S.
FDA accelerated approval is primarily applicable to new drugs that treat serious or life-threatening diseases, whose safety and efficacy have been studied to have significant therapeutic advantages over existing therapeutic products, and that need to meet "surrogate endpoint" requirements.
Among them, severe disease refers to a disease that affects survival or daily functioning and is characterized by persistent recurrence, while "treatment of serious disease" requires that the drug must have a direct or expected relief effect on the serious disease.
Accelerated approval focuses on the type of disease on the one hand, and the basis for evaluation on the other.
The former mainly includes severe life-threatening diseases, drugs with a long course of disease and rare diseases that require a long time to measure the expected clinical benefit, and in terms of evaluation basis, the drug is required to have a significant advantage over existing therapies, and based on incomplete validation of alternative endpoints or intermediate clinical endpoints that can reasonably predict clinical benefit.

The EU Conditional Marketing Authorization (CMA) mainly applies to the following three classes of drugs: drugs used to treat severely damaged or life-threatening diseases, drugs used in emergencies and drugs for the treatment of rare diseases.
Among them, for Class I drugs, the clinical outcome of severe damage or life-threatening should be a prominent feature of the target disease and drug indication, and the applicant needs to prove the severity of the disease based on objective and quantifiable medical or epidemiological information, and consider the impact of disease incidence on the patient's daily functioning.
For Category II medicines, applicants should determine whether they are recognized by WHO or the European Union as a public health threat and state the reasons for use in emergencies.

The scope of application of conditional approval has been detailed in the Technical Guidelines for Conditional Approval of Drugs (Trial) issued by China in 2020, that is, for diseases that are seriously life-threatening and there is no effective treatment, drugs urgently needed in public health, and vaccines to respond to major public health emergencies.
A serious life-threatening disease is a disease or stage of a disease that, if not treated early, would kill a patient for months or less, such as advanced malignancy [5].
However, the guiding principles do not limit the indications, and although anti-tumor drugs are mainly anti-tumor drugs in China, the United States and the European Union, anti-tumor drugs in China account for the largest proportion of conditionally approved drugs.
It can also be noted that non-serious, life-threatening drugs, such as injectable tetacept for the treatment of systemic lupus erythematosus, have also been conditionally approved [18].

Conditional approval is to encourage clinical value-oriented drug innovation and accelerate the launch of clinically urgent drugs with outstanding clinical value.
It is recommended that conditional approval comprehensively consider the severity of the disease and the urgent need for drugs, and regulatory agencies need to help applicants have a deeper understanding of the scope of application of conditional approval and appropriately develop drugs for indications other than anti-tumor drugs.

3.
2 Provide reference for the selection of surrogate endpoints and intermediate clinical endpoints

In terms of drug effectiveness evaluation, drugs that meet the conditions of conditional approval can be conditionally approved for marketing based on surrogate endpoints, intermediate clinical endpoints or early clinical trial data.
The selection of surrogate endpoints must be scientifically sound, and should demonstrate relevance to clinical benefit and biological plausibility.
In recent years, for many diseases, especially tumors, surrogate indicators such as progression-free survival (PFS) and objective response rate (ORR) have been established.
To help applicants select potential surrogate endpoints and facilitate product development, FDA publishes recommended or recognized surrogate endpoints every six months based on the latest scientific research and review considerations [19].
At present, the selection direction of surrogate endpoints and intermediate clinical endpoints has been explained in the domestic guidelines, but according to scientific progress, the recommended endpoints for specific diseases may be more helpful for applicants to refer to in the design of clinical studies.

3.
3 Improve communication with conditional approval

The communication exchange of conditional approval involves three stages: early clinical research, pre-marketing application and review period, which provides a good information exchange bridge between the applicant and the regulatory authority.
In terms of time frame, except for drugs that also include breakthrough therapies, the current communication meetings related to conditional approval are Class II meetings, which are generally held within 60 working days after application [20].
Consistent with the deadline for other drugs that apply for communication at the critical stage of development.
To expedite the launch of drugs, consideration may be given to shortening the communication period for conditional approval.
In addition, since a large amount of research work on conditionally approved drugs is carried out post-marketing, post-marketing communication procedures and policy support in terms of time limits can be considered to help drugs be routinely approved for marketing as soon as possible.

3.
4 Improve the review path and make a good connection with the emergency authorization of the Vaccine Administration Law

Article 20 of the Vaccine Administration Law clarifies that if the benefits of vaccines urgently needed to respond to major public health emergencies or other vaccines determined by the competent health department under the State Council to be urgently needed after assessment outweigh the risks, the drug regulatory department under the State Council may conditionally approve the vaccine registration application.
In the event of a particularly serious public health emergency or other emergency that seriously threatens public health, the competent health department under the State Council shall put forward a proposal for the emergency use of vaccines according to the needs of infectious disease prevention and control, and may be used urgently within a certain scope and period of time after the drug regulatory department under the State Council organizes demonstration and approval [21].

In the Vaccine Administration Law, there are two ways to accelerate the marketing of vaccines: conditional approval and emergency use authorization.
Taking Zhifei Biotech's recombinant new coronavirus protein vaccine as an example, it was approved for emergency use in China on March 10, 2021, and conditionally approved in China on March 1, 2022[22], but the linkage procedure between emergency use authorization and conditional approval has yet to be clarified.

3.
5 Strengthen post-market supervision

Although China, the United States, and the European Union will all require applicants to continue to complete post-marketing clinical trials after the drug is approved for marketing, and submit relevant materials for these clinical trials within the specified time.
However, there have been reports that some applicants in the United States willingly or unintentionally delay the submission of post-marketing clinical trial data, allowing these conditionally approved products to remain on the market without meeting the full approval requirements and not being revoked [23].
Therefore, how to ensure that after the drug is launched, it is still a challenge for companies to complete clinical trials within the specified time.

In addition, as mentioned above, in the current regulations and policies issued by China, the circumstances and procedures for the cancellation of conditional approval are not clear, and it is far from enough to generally describe "the failure to complete the study as required within the time limit or the failure to prove that the benefits outweigh the risks, and the State Medical Products Administration shall deal with it in accordance with the law until the cancellation of the drug registration certificate".
It is recommended to clarify the specific circumstances and procedures for conditional approval of deregistration.

4 Outlook

prospect

Although China's conditional approval system has only been established for two years, there are the experience of FDA and EMA in Europe and the United States as a reference, combined with China's drug clinical practice and regulatory needs, relevant regulations are also improving
。 In the future, it is recommended that regulators need to consider more issues such as the refinement of procedures and technical requirements (such as the evaluation criteria for conditional approval of various indications), the connection between systems (such as emergency use authorization and conditional approval system), and strengthening the post-market supervision of conditional approval of drugs, so as to ultimately achieve the original intention
of encouraging clinical value-oriented drug innovation and accelerating the launch of clinically urgently needed drugs with outstanding clinical value.

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