During the development of innovative drugs, how does the sponsor communicate with CDE?

The development of innovative drugs requires multi-disciplinary work side by side, and requires the integration of experience and innovation.

01Historical experience of "review-communication" of domestic innovative drugs

In 2009, the regulatory authorities issued the "Implementation Rules for the Communication and Exchange Mechanism of Special Approved Varieties", which detailed the requirements for the communication and exchange of special approved varieties, such as procedures, data preparation, communication time limit, and meeting minutes

In 2012, the regulatory authorities issued the "Management Specifications for the Communication Meeting between the Drug Evaluation Center and Registration Applicants (Trial)", which defined the communication meeting between the Drug Evaluation Center and the applicant, and clarified the application of the communication meeting, meeting procedures and requirements, etc.

In 2013, the regulatory authorities issued the "Opinions of the State Food and Drug Administration on Deepening the Reform of Drug Review and Approval and Further Encouraging Drug Innovation", established a network electronic communication platform, and established an appointment-based communication mechanism to ensure that new drug R&D institutions and technical review departments are timely Communication, written records of communication results

In 2015, the regulatory authorities issued the "Announcement on Several Policies for the Review and Approval of Drug Registration", which pointed out that the communication between reviewers and applicants before and during the clinical trial application should be strengthened, and the problems in the registration application and clinical trial process should be solved in a timely manner

In 2016, the regulatory authorities issued the "Administrative Measures for Communication and Exchange of Drug R&D and Technical Review (Trial)"

In 2018, the regulatory authorities issued the "Announcement on Adjusting the Review and Approval Procedures for Drug Clinical Trials" and the "Announcement on Issuing the Management Measures for Drug Research and Development and Technical Review Communication and Exchange"

In 2020, the regulatory authorities issued the "Administrative Measures for Communication and Exchange of Drug R&D and Technical Review", which is currently the main policy document for communication

Figure 1.

02The "review-communication" model of new drugs in the United States

The United States' communication method for innovative drugs in the review process can be reflected in sec.

The key stage meetings of drug development mainly include pre-IND, end-of-phase I (EOP1), end-of-phase II (EOP2) and pre-NDA meetings

➣ Before IND

Contents to focus on: understanding the mechanism of action of the drug, possible study designs, early drug development; especially new drugs, new mechanisms, planned 505(b)(2) pathways, and drugs with special R&D processes; of course, any Any sponsor of an IND can apply for a pre-IND meeting

➣ EOP1

Contents of focus: How existing data can facilitate the review of the design of phase II clinical trials, and discuss the relevant content of drug development plans; FDA especially encourages the EOP1 meeting for drug applications for the treatment of life-threatening and severe debilitating diseases, especially based on phase II clinical trials Trial approval or may be suitable for accelerated approval situations

➣ EOP2

Key contents: how the existing data can clarify whether the drug is safe enough and whether the research is sufficient, and how to fully guide the scientificity of the phase III clinical development plan and design; especially encourage sponsors to apply for new molecular entities or major new uses of marketed drugs Hold an EOP2 meeting; again, any sponsor can request an EOP2 meeting

➣ Before NDA

Contents of focus: Facilitate FDA reviewers' understanding of the format and content of planned marketing applications, studies aimed at uncovering significant issues, determining drug safety and efficacy, discussing pediatric trials, and statistical analysis methods or results; Party shall submit an application for the pre-NDA meeting for all applications that plan to file for listing

The sponsor seeks communication with the FDA, and the content can be based on the following major aspects: regulatory procedures, clinical statistics, safety, clinical pharmacokinetics, non-clinical pharmacodynamics-pharmacokinetics-toxicology, quality control, pediatric trials,

Table 2.
1 Types and contents of FDA communication meetings

03 Key points of "Management Measures for Communication and Exchange of Drug R&D and Technical Review"

First of all, the upper management law of this management method is the "Pharmaceutical Administration Law of the People's Republic of China" and the "Administrative Measures for Drug Registration"; the communication forms of the meeting include: face-to-face meetings, video conferences, teleconferences or written responses, and teleconferences are encouraged; Types are divided into Type I, Type II, and Type III, as detailed in the table below, and it is not difficult to see that most conference types are concentrated in Type II
.
PS: If it is determined to hold a communication meeting, the Type I meeting is generally arranged to be held within 30 days after the application, the Type II meeting is generally arranged to be held within 60 days after the application, and the Type III meeting is generally arranged to be held within 75 days after the application
.

Table 3.
1 Types of Communication Meetings

Before the meeting, according to the management measures, the drug registrar should fully consult with the project management personnel to confirm the time, place, agenda and other information
.
The participants of the Center for Drug Evaluation should conduct a comprehensive review of the meeting materials before the communication meeting, and form a preliminary review opinion
.

During the meeting, the communication meeting is usually presided over by the staff of the Drug Evaluation Center, and it is carried out according to the predetermined meeting agenda.
The issues to be discussed before the meeting are discussed one by one, and new meeting materials, divergent issues and temporary increases are raised during the process.
In principle, the new issues are not within the scope of communication
.
Under normal circumstances, the communication meeting time is within 60-90 minutes
.

After the meeting, the meeting minutes should be written in accordance with the requirements of the "Communication and Exchange Meeting Minutes Template".
If the two parties have reached an agreement, the common views should be stated; if the two parties have not reached an agreement, their respective views should be stated separately
.
The minutes of the meeting shall be finalized within 30 days after the end of the meeting at the latest, and it is encouraged to form the minutes of the meeting on the spot
.
The minutes of the meeting shall be uploaded to the communication system by the project management personnel within 2 days after the final draft, and the applicant can view it through the applicant window
.
PS: Applicants and other participants are not allowed to record, video, take photos, etc.
without permission
.

Table 3.
2 Communication and exchange meeting materials

04 Summary

To sum up, it is not difficult to see that China has tried for many years to explore the process, content and methods of drug research and development communication meetings, and has learned from the existing experience of the US FDA
.
However, at the same time, the policy has also been adjusted according to the current national conditions of new drug research and development in China
.
For sponsors, there are currently very complete procedures to communicate with reviewers at specific research and development time points.
The slight difference is that China's communication methods have not been further refined, and the system has been greatly improved.
space
.

During the actual operation, based on previous project experience, it was found that the sponsor still needs to explore the rhythm and method of communicating with the reviewers to improve the timeliness of communication, especially the use of telephone communication within a limited time; The information of the party must be summarized in place, as far as possible to support the needs of communication and exchange, and it must be different from the content of the IND application information!

But at the same time, it should be noted that key data must not be deliberately concealed, so as to avoid reviewers making wrong judgments and suggestions based on incomplete data
.
In a word, CDE provides a clear communication path.
Applicants must make full use of it and summarize common solutions to individual problems, so as to facilitate the development of more projects and form the hard power of the applicant's project development!

References :

1.
https:// 2.
FDA official website https:// 3.
Introduction and reflection on the communication system for domestic drug registration.
https:// 4.
Research on the U.
S.
Drug Evaluation System.
https:// 5.
Introduction and thinking of the communication mechanism during the clinical trials of new drugs in the United States.
https:// 6.
"Administrative Measures for Communication and Exchange of Drug R&D and Technical Review".
https:// 7.
Discussion on common statistical issues in communication between drug R&D and technical review.
https://