What’s new for conditional approval of drugs in China?
By Jianqing Chang, Vice President of Drug Regulatory Policy, Tigermed
On Nov 19, 2020, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China issued The Technical Guidelines for Conditional Approval of Drugs. After the two rounds for seeking public comments in Dec 2017 and Nov 2019 respectively, this tentative version was put into force immediately.
In Aug 2015, the State Council issued the Opinions on Reforming the Review and Approval System for Drugs and Medical Devices. One of the primary objectives is to encourage the research and development of innovative drugs. Clinical value-oriented drug innovation is to be encouraged, the review and approval procedures for innovative drugs are to be optimized, the review of innovative drugs with urgent medical needs is to be accelerated. In Oct 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 and Encouraging Innovation in Drugs and Medical Devices. For the first time, the conditional approval was brought up in such high level government document. With respect to drugs and medical devices used for treating severely life-threatening diseases that have no effective treatment at present as well as other drugs and medical devices that meet the urgent needs for public health, if indicators of clinical trials at early and intermediate phase show efficacy and project relevant clinical value, such drugs and medical devices may be granted conditional approval for marketing authorization. The marketing authorization holder shall formulate a risk control plan and carry out study as required.
As one of the great improvements of the newly revised Drug Administration Law that came into effect in Dec, 2019, “protection and promotion of public health” is specified in the 1st article. How to protect and promote public health? To improve the availability of drugs with urgent medical needs, one of the effective measures is to help those patients who have urgent needs to access to the new drugs as early as possible. Therefore, the article 26 says “For drugs used for treatment of severely life-threatening diseases without effective treatment and drugs urgently needed for public health, where the drug clinical trials have data to show efficacy and to project clinical value, conditionally approval may be granted, and, the relevant information shall be specified in the drug registration certificate”.
To support the implementation of the newly revised Drug Administration Law, the State Administration for Market Regulation issued the revised Drug Registration Regulation for implementation since Jul, 2020. The Drug Registration Regulation has clearly established a drug registration system to accelerate the marketing authorization of drugs to support drug innovation oriented by clinical value. For accelerated registration procedures for marketing authorization, four procedures with regard to breakthrough treatment drugs, conditional approval, priority review and approval, as well as special approval are applied.
In Jul 2020, to support the implementation of the Drug Registration Regulation, the NMPA issued The Working Procedures for Review and Approval of Application for Conditional Approval of Drugs (Tentative). In Nov 2020, the CDE issued The Clinical Technical Guidelines for Conditional Approval of Drugs (Tentative). The objective is to shorten the timeline of drug clinical trials and to provide those drugs to patients who are critically ill and cannot afford to wait any longer, or to address the urgent needs of public health.
How to evaluate which drugs meet the application criteria?
- Drugs indicated for treating the severely life-threatening diseases without effective therapeutic options, for which clinical trials demonstrate efficacy and project clinical value;
- Drugs urgently needed in public health, with efficacy evidence and clinical value projected by existing clinical trial data;
- Vaccines urgently needed to respond to major public health emergencies or other vaccines considered urgently needed by National Health Commission with the benefits outweighing the risks.
In addition, one of the following four technical standards needs to be met.
- Compared with the existing treatments, the drugs have significant improvement in the prognosis of the disease;
- Significant efficacy can be achieved for the drugs treating patients intolerant to existing treatments or patients without effective treatments;
- The drugs can be effectively combined with other crucial drugs or treatments that cannot be combined with existing treatments, and, significant efficacy can be achieved;
- By avoiding serious adverse drug reactions of existing therapies or significantly reducing harmful drug interactions, the drugs can improve patients compliance significantly, even though efficacy equivalent to that of existing treatments.
How to confirm efficacy and project the clinical value?
Based on the surrogate endpoints, intermediate clinical endpoints or early phase clinical trial data, the correlation and rationality between the selected alternative endpoints, intermediate clinical endpoints or early clinical trial data and the expected clinical benefits are fully evaluated and explained. Corresponding evidence is provided.
1. Surrogate endpoints that can project very likely the clinical benefits
Surrogate endpoints refer to the endpoints indicators used to reflect clinical benefits indirectly. For drugs that are needed urgently, it is expected that surrogate endpoints can be used to evaluate the efficacy in time-saving way.
The surrogate endpoints might be laboratory tests, radiographic imaging, physical signs or other indicators. To evaluate whether the surrogate endpoints can project clinical benefits and predictive ability, it is necessary to make the judgement based on the biological rationality of the relationship between the diseases, clinical endpoints and the expected efficacy of the drugs, and the evidence or experience that supports such relationship.
For pivotal registration trials, if pre-set surrogate endpoints that are very likely to project clinical benefits are used to evaluate the efficacy, and positive results are achieved, the application for conditional approval may be filed.
2.The interim clinical endpoints for early evaluation of clinical benefits.
The interim clinical endpoints generally refer to the evaluation of clinical benefits in the treatment of chronic or progressive diseases, it is generally assumed that short-term clinical benefits are very likely to project long-term clinical benefits.
In pivotal registration trials, if the study results using interim clinical endpoints indicators can project reasonably that the drug is very likely to have therapeutic efficacy and clinical benefits, the application for conditional approval may be filed.
3.Early phase clinical trial data
Early phase clinical trial data usually refer to the clinical data obtained prior to the confirmative clinical trials. Based on the early phase clinical trial data, if the clinical benefits can be reasonably projected or determined, the application for conditional approval may be filed before the completion of the confirmative clinical trials.
How to manage the post-marketing risk?
Applicants shall discuss with the CDE and reach a consensus on the actions promised to complete after the marketing authorization is granted. It includes the post-marketing clinical study plan, study completion date, final clinical study report submission date and post-marketing risk management plan, etc.
The marketing authorization holder shall complete the new or ongoing clinical trials of the drug within the required time frame as specified by the drug registration certificate. Usually, these trials are confirmative ones with the purpose to confirm the expected clinical benefits therefore the sufficient evidence supporting normal marketing authorization can be provided.
For drugs with conditional approval, if the MAH fails to complete the study within the prescribed time limit in accordance with requirements or its benefits cannot be proved to outweigh risks, the NMPA shall deal with in accordance with laws and even suspend the drug registration certificate.
What are the opportunities and challenges?
To obtain the conditional approval, based on the actual clinical development of the drugs, applicants shall communicate with the CDE before the initiation of clinical trials intended to support the conditional approval. The meeting minutes shall be taken to specify the alternative endpoints indicators selected in the clinical trials or the rationality of interim clinical endpoints indicators or early clinical trial data and the criteria that can reasonably project clinical benefits, as well as the design and implementation plan of post-marketing clinical trials. Again, prior to the application for the conditional approval for marketing authorization, communication with CDE is of importance about the obtained clinical trial data, the intention to apply for conditional approval for marketing, the design and implementation plan of post-marketing clinical trials, and the post-marketing risk management plan, etc.
For the drugs with urgent medical needs that are approved abroad to treat rare diseases, The Clinical Technical Requirements for Drugs approved Overseas but not in China issued by the CDE in Oct, 2020 might be referred. For individual products with different data, specific analysis is necessary. The marketing authorization is granted under the condition of strict risk control, and post-marketing efficacy and safety clinical trials are to be conducted; or, clinical trials are required.
Apparently, the new system of conditional approval can shorten the development timeline of clinical trials. Patients who are in urgent need of treatments may have access to new drugs in a timely way.
Meanwhile, for applicants, only when the drugs have the above-mentioned outstanding clinical value and meet the urgent clinical needs, they may have the opportunity to obtain conditional approval.