The annual report of NMPA drugs after listing, and the comparison with FDA annual report requirements

On Tuesday, April 12, NMPA officially issued the "Regulations on the Administration of Annual Reports of Drugs", more than a year after the release of the draft for comments in December 2020

Enterprises are already submitting various annual reports, such as safety reports during the clinical period, annual reports of original and auxiliary contracting companies, and provincial bureaus may propose some form of annual reports, such as the “risk self-inspection report of drug production and operation enterprises” in Shandong Province

From a regulatory perspective, as a "closed loop" of drug supervision, the post-marketing drug annual report system formally stipulates regular information communication between companies and regulatory authorities

From a practical point of view, companies must formulate a special SOP for the annual report after listing.

The industry is very concerned about this article, and there are many interpretations from various angles.

Post-IPO Annual Report: Similarities and Differences Between China and the U.

1.

Article 37 Theholder of a drug marketing license shall establish an annual reporting system, and report the production and sales, post-marketing research, risk management, etc.

Article 127 Anyonewho violates the provisions of this Law and commits any of the following acts shall be ordered to make corrections within a time limit and given a warning; those who fail to make corrections within the time limit shall be fined not less than 100,000 yuan but not more than 500,000 yuan:

(4) Failure to submit annual reports as required;

"Administrative Measures for Drug Registration"

Article 80 The holder shall report the following changes in the annual report:

(1) Minor changes in the drug production process;

(2) Other changes required to be reported by the State Drug Administration

2.

Annual report refers to the report that the holder collects the production and sales, post-marketing research, risk management,

execution time

It was officially implemented on April 12, and the collection module of the annual drug report was activated at the same time

Responsible subject

The drug marketing authorization holder is the main body responsible for the annual report, and is responsible for its authenticity and accuracy
.
If the holder is an overseas enterprise, the domestic enterprise legal person designated by it shall perform its annual reporting obligations
.
The annual report shall be approved by the legal representative of the enterprise or the person in charge of the enterprise (or its authorized person in writing) to report the report information of the previous year through the drug annual report system
.

report time

Before April 30 every year, report the report information of the previous year through the drug annual report system
.
The deadline for filling in the 2021 annual report information is August 31, 2022
.

Content of report

The information collected by the enterprise includes two aspects: the public part and the product part
.

The public part includes information on the holder, the overall situation of the product held, an overview of quality management, the construction and operation of the pharmacovigilance system, acceptance of overseas commissioned processing, and acceptance of inspection by overseas regulatory agencies
.

The product part, including basic product information, production and sales, post-market research and change management, risk management,
etc.

Major changes compared to the 2020 exposure draft

Emphasize the responsible subject and clarify the supervisory responsibilities: "The holder is the responsible subject of the annual report and is responsible for its authenticity and accuracy"
.
The provincial bureau is responsible for managing the establishment and implementation of an annual report system for MAHs (including domestic agents) within its administrative region.
If the annual report is not compliant, the provincial bureau where the MAH is located shall order the MAH to make corrections and corrections within 20 working days
.

The deadline for submitting annual reports has been revised from March 31 to April 30
.

Added "Overview of Quality Management, Construction and Operation of Pharmacovigilance System, Acceptance of Overseas Entrusted Processing, Acceptance of Inspection by Overseas Regulatory Agencies, etc.

"

The provincial bureau conducted a "spot check" on the content of the annual report and changed it to "check"
.

Other considerations

The annual report cannot replace the approval, filing and other matters that need to be handled in accordance with laws, regulations and rules
.

The drug regulatory department shall use the annual report as the reference material and the basis for research and judgment in the supervision and inspection, risk assessment, credit supervision and other work
.

In principle, one holder writes an annual report every year
.

If the holder fails to submit the annual report as required, it shall be punished in accordance with the provisions of Article 127 of the Drug Administration Law
.

3.
Changes to be submitted in the annual report

Post-marketing research and change management should include:

(1) Post-marketing research conducted in accordance with the drug approval documents and the requirements of the drug regulatory department;

(2) The approved changes in approval, filing and reporting in the post-marketing changes of the drug;

(3) The review and evaluation of the quality of Chinese herbal medicines used in the production of Chinese herbal decoction pieces, as well as the verification of processing or production process changes;

(4) Other circumstances that need to be reported
.

4.
Risk management required to be submitted in the annual report

The risk management situation shall include the following contents of domestically marketed drugs:

(1) The post-marketing risk management plan of the drug;

(2) Investigation and handling of products that do not meet drug standards;

(3) Returns, recalls, etc.
caused by quality problems or other potential safety hazards;

(4) The production, sales, risk management, etc.
of commercial-scale batches of drugs that have passed the compliance inspection of the corresponding pre-marketing drug production quality management standards
.

(5) Other circumstances that need to be reported
.

Postmarketing Drug Annual Reporting System in the United States

1.
Legal basis

FDA CFR 314.
81 Other Postmarketing Reports

annual report
.
The applicant must submit 2 copies of the annual report to the FDA department responsible for reviewing the application within 60 days of the end of each year from the date of approval of the application in the United States, each annual report must be accompanied by a fully completed transmission form FDA 2252 ( Transmission of Periodic Reports for Drugs for Human Use), must contain all information received or obtained by the applicant during the annual reporting period (as of the anniversary date following the date of approval of the previous application in the United States) as specified in this section
.
The report should list the following in order:

Summary
.
A brief summary of any significant new information affecting the safety, efficacy or labelling of the drug in the past year
.

(a) Sales data
.
Information on sales quantities of approved medicines, including wholesale quantities from retailers
.
The information must include the National Drug Code (NDC) of the drug, the total number of packaging units in different specifications of drug packaging (eg, 100,000/5 mg tablet, 50,000/10 mL injection), and the number of domestic and foreign drug sales
.
(b) Generic drugs authorized on the market
.
(applicable to new drugs)

label
.
(a) Samples of currently used professional instructions, patient medication booklets or package inserts (if any) and package labels
.
(b) The contents of the label (i.
e.
professional manual or package label) (including all text, tables and figures) must be submitted electronically
.
(c) A summary of all labelling changes since the last report (listed in chronological order in which the changes were implemented) or, if there are no changes, a description accordingly
.

Chemistry, Manufacturing and Controls (CMC) Changes
.
(a) Reports of incidents, studies, experiments, or tests concerning the physical, chemical, or other properties of the drug product (such as the microbial profile or properties of the drug product, including the effects of the drug product on microorganisms and the effects of microorganisms on the drug product)
.
Applicants are only required to submit reports of new information that may affect FDA's previous conclusions about the safety or efficacy of the drug
.
(b) Changes in production and control that do not require the filing of a supplemental application shall be fully stated and all changes listed in chronological order of implementation
.

Nonclinical research
.
Copies of unpublished research reports and abstracts of published research reports of new toxicological findings collected by the applicant from animal experiments and in vitro studies (such as mutagenicity experiments) conducted by the applicant in relation to drug ingredients
.
If requested by FDA, applicants are required to submit copies of complete published studies
.

clinical data
.
(a) Published drug clinical trial results (or abstracts), including clinical trials on safety and efficacy; clinical trials for new uses; studies on biological drugs, pharmacokinetics and clinical pharmacology, as well as other safety-related clinical trials Aspects of research (such as epidemiological studies or analyses of the clinical experiences of a series of monitored patients), the results of which may be conducted or collected by the applicant
.
(b) The applicant's completed but unpublished clinical trial report abstract or pre-published manuscript (the study is deemed completed 1 year after the study is completed) or collected by the applicant (c) The safety and efficacy of the drug in pediatric patients Analysis of sexual data and proposed labeling changes based on the above information
.
Data evaluation should also be included to ensure that pediatric drug labeling is appropriate
.

Progress reports on post-marketing research commitments
.
All relevant clinical safety, efficacy, Progress reports on post-marketing studies of medicinal products in clinical pharmacology and nonclinical toxicology
.

Other post-marketing research projects
.
Progress reports on all other post-marketing studies conducted by or on behalf of the applicant
.
The progress report will include any chemical, manufacturing, and all control studies that the applicant has agreed to conduct with regard to formulation stability studies
.

Pending registered transaction log
.
To improve the efficiency of communication between FDA and the applicant, the applicant may, in its best judgment, include in the report a list of all pending registration matters related to the drug application with FDA (e.
g.
, the FDA has not responded to the applicant's letter).
List of Checklists, List of Letters of Applicants Not Responding to FDA)
.

2.
Changes in the Annual Report and Corresponding Guidance

FDA CFR 314.
70

(d) Description of changes (minor changes) in the annual report
.

FDA Guidance: Annual Report Documents Documenting Manufacturing Changes After CMC Approval

If a change is identified as a minor change, the applicant may make the change directly, but must report the change to FDA in the annual report
.

Appendix A: Examples of post-CMC-approved production changes that can be documented in the annual report if the risk of adverse effects on product quality is minimal

Appendix B: In accordance with FDA's Scale-up and Post-Approval Change Guidance - Immediate Release Dosages, Scale-up and Post-Approval Change Guidance - Extended-Release Solid Oral Dosage, and Scale-up and Post-Approval Change Guidance - Non-Sterile Semisolid Dosages, As well as the Guidelines for Changes to Approved NDAs and ANDAs, examples of post-CMC approved production changes that can be documented in the annual report

FDA Guidance: Format and Content of the CMC Section of the Annual Report

IV.
Format

SECTION 1 SUMMARY OF NEW INFORMATION

Section II Shipping Data [21 CFR 314.
81(b)(2)(ii)]

Section III Labeling [21 CFR 314.
70(d), 21 CFR 314.
81(b)(2)]

Section 4 CMC Changes

FDA Guidance: CMC Post-Approval Manufacturing Changes for Specified Biologics Documented in Annual Reports

III.
RECOMMENDATIONS FOR REPORTING CERTAIN CHANGES IN THE ANNUAL REPORT

Ⅳ.
Contents of the annual report notice

Addendum: Examples of CMC post-approval manufacturing changes that FDA generally considers unlikely to have an adverse effect on product quality