annual conference - · pdf fileperformance of self-auditing and verification for trial data...

SCDM 2017 ANNUAL CONFERENCE

September 24-27 I Orlando

China Regulatory Roundup: Updated Advances of GCP Standards in the landscape of Medicines v

Daniel Liu, PhD Chief Scientific Officer Beijing Clinical Service Center Orlando, FL, USA Sept 25, 2017

Session 5： Dramatic Change in China Clinical Data Management

Landscape of China GCP Standards General procedure of CTA(IND)/NDA in China Updated or new regulations

Agenda

Landscape of China CTA(IND)/NDA foundation

General procedure of CTA(IND)/NDA in China

Updated or new regulations

Agenda

Announcement #117 by CFDA, July 22, 2015

Regulatory Reformation Initiation

Performance of self-auditing and verification for trial data and integrity

Objectives: • Ensure authenticity and reliability

of clinical trial data submitted to CFDA

• Ensure protection of subjects’ right,

safety and well-being • Ensure the compliance of GCP and

regulatory requirements

Chinese Primary Regulations Relevant to CDM

• Guidance of International Multi-center Clinical Trials (2015) • Essential Elements of Clinical Data On-site Inspection (2015) • Statistic Guidance in Clinical Trials (2016) • Technical Guidance of Clinical Trial Data Management (2016) • Directive Principles of EDC Techniques in Clinical Trials (2016) • Directive Principles of DMP and SAP and relevant Summary Report (2016) • Good Clinical Practice of Drug Clinical Trials (2016 amendment) •Good Laboratory Practice (2016 amendment) • Directive Guideline of Clinical Data Inspection for Bio-correspondance Assessment of Generic Drug Quality and Efficacy (2016) • Categorical Requirements of Regulatory Registration for Chemical Drugs (2016) • Administrative Measures of Drug Registration (2016) • Data Management Practice of Drugs (2016) • Law of Criminal Action on Submission of Fake Data for Registration Applications of Drugs and Medical Devices (2017) • ………

CFDA Departments involved in Drug Clinical Trial Review and Approval

CFDA

PFDA

Provincial Institute of Drug Quality Control

CDE National

Institute of Food and Drug Control

CFDI

Department of Drug Registration: Determine whether or not register or issue

approval notice

Center for Drug Evaluation (CDE) Reviews the data for IND/NDA

Center of Food and Drug Inspection (CFDI) Make inspection to sites and sponsors

National Institute of Food and Drug Control (NIFDC) Qualitative and quantitative analysis of drugs

Qualified Applicant

IND/NDA Applicant

Foreign applicant

China facility or

branch office

Entrusted representative

or agent

Domestic applicant

Legally registered corporation with civil

responsibility

Drug Clinical Trials

CFDA approval

Follow up with Chinese GCP

Clinical Trials:

Phase I/II/III/IV

Drug Registration Category——Chem # Definition comments

1 Never launched globally, ie., any definite new structure, bioactivities and valuable clinical significance. New drug Innovative drug

2 Newly modified drug regimen only but never launched in China and other countries and has a distinctively clinical advantages;

2.1 optical isomers with known active principles obtained from isolation or synthesis etc, or known active component esters or salts (including salt with hydrogen bonds and coordination bond) , or modified acid radical, base group, metal elements from known active components, or non-covalent bond derivatives (e.g., complex, chelate or clathrate compounds)；

2.2 new formulation, new recipe process or new dosing route with known active components (including delivery system)；

2.3 new combination preparation with known active compoents；

2.4 preparation for new indication with known active components.

New drug Modified Drug

3 Launched abroad but never in China： The same active components, dosage, size, indications, adm route and dosing regimen as the corresponding brand drugs

Generic drug

4 Launched in China already; The same active components, dosage, size, indications, adm route and dosing regimen as the corresponding brand drugs

Generic drug

5 launched abroad and application to marketing in China; 5.1 brand drug marketed abroad (including raw materials and preparations) with application to marketing in China 5.2 non-brand drug marketed abroad (including raw materials and preparations) with application to marketing in China .

Importing drug

Drugs with great clinical demands or great improvements on quality and efficacy

1. Pediatric drugs and drugs for diseases that specifically and mostly affect seniors.

2. Drugs in great clinical demands or in shortage, and the list will be made by CFDA, National Health and Family Planning Commission, and Ministry of Industry and Information Technology.

3. Advanced formulation technology using targeted-delivery, sustained or controlled release, and other innovative therapies that can significantly improve treatment.

4. Accepted CTA with the patent expiring in 3 years and accepted application for Product Manufacturing License with the patent expiring in 1 year.

5. Domestic CTA sponsor with the product that has been approved for clinical trials in US or Europe; Domestic application for Product Manufacturing License with the same production line that has been used for US or Europe application in parallel and passed the on-site inspection.

6. Applicants have withdrawn the previous generic applications and re-submitted the applications according to the new regulation that demands bioequivalent to the originator drugs; In the campaign of “re-evaluation of generic drug bioequivalence ”, supplemental applications with changes of approved process .

7. Registration for imported new drugs with manufacturing transfer to domestic.

Fast Track Review Criteria

Landscape of China CTA(IND)/NDA foundation

General procedure of CTA(IND)/NDA in China


Agenda

Module of Reg Submission (published by CFDA on May 2, 2016)

（I）General Information

# 1-8

(II) Summary Materials

# 9-11

（III）Pharmacy Research Materials

# 12-13

（V）Clinical Trial Materials

# 27-34

（IV）Pharmacology /Toxicology Materials

#14-26

Submission Materials

Submission Documents for Clinical Researches

Item Submission Time

27 Summary of Clinical Researches IND/NDA

28 Clinical Protocol and development plan IND/NDA

29 DMP and SAP IND/NDA

30 IB IND/NDA

31 Samples of ICH, IEC approval (NDA)

32 CSR

(NDA)

33 Database of clinical trials

(NDA)

34 Statistical Report and Data Management Report

(NDA)

Registration of all Clinical Trials, Bioequivalence Studies

• CFDA is requiring clinical trial sponsors to register all trials (Phases I, II, III, IV) and bioquivalence testing (chinadrugtrials.org.cn). For approved drugs, the registration must be completed within three months of the date of the notice • The website will be managed by CFDA’s Center for Drug Evaluation • The trial's approval will be revoked if the registration requirements are not complied with within three years. • Chinese version of application package is mandatory

Electronic Submission online

Meeting Types Meeting Objective

Type I meeting Meetings convened to address key safety issues in the clinical trials of drugs and key technical issues in the research and development of breakthrough therapeutic drugs

Type II meeting Milestone meetings in key research and development periods of innovative drugs mainly include the following circumstances: pre-IND meetings, EOP2 meeting/pre-phase 3 meetings, pre-NDA meetings for risk evaluation and control

Type III meetings Meetings other than type I/II meetings for innovative drugs, including those on key issues in the research and development of commonly modified new drugs and generic drugs

Evaluation System Development of Regulatory Meetings with CFDA

Routine Consultation

Reviewer consults with a member of a relevant Expert Advisory Committee by email or in writing, to solve a technical issues encountered during routine evaluation

Expert Consultation Meetings

Meeting organized and held for establishing or amending technical guidelines and standards for drug research and development, addressing issues in new areas, new technologies, new discoveries and new indications, and resolving any evaluation-related disputes within the CDE as well as the issues concerning drug safety, efficacy and quality control evaluation

Expert Open Discussion Forum

A meeting organized and held for resolving any major technical dispute between the evaluation term an applicant, or any major issues concerning the public interest, or any major, complicated scientific and technical problems during the evaluation of drug registration

Evaluation System Development of Public Expert Consultation Meetings by CFDA

Landscape of China Regulatory foundation

General procedure of Drug Regulatory Registration in China


Agenda

• Construction of technical guidelines and standard systems for drug evaluation has been enhanced preparation and review of more than 10 guidelines have been completed; the technical guideline for extrapolation of drug use data from adults to pediatric population and use of relevant information has been released to solicit opinions. 147 international universal technical evaluation guidelines of agencies including WHO have been translated, preliminarily forming a technical guide and standard system for drug evaluation in line with international standards The program for development of CDE review quality management system has been designed and initiated Efforts will be made to ensure all program and products pass WHO international quality supervision system certification in 2019

Regulatory Reform Progress in the past two years

• Establishment of an eCTD system is initiated to cover acceptance of registration application, data collection, assessment, preparation of review reports and processing of review

• Establishment of drug type archive database is initiated to implement full lifecycle management of drugs Type of archive database includes databases of information about registration review and approval, supervision over production, circulation and use and pharmacovigilance.

Regulatory Reform Progress in the past two years

Improvement of clinical trial institutions change drug clinical trial institution qualification system from reviewing and approval system to filing system clinical trial projects shall be registered and filed to drug evaluation agencies study data of clinical trial institutions having passed inspection may be accepted by drug evaluation agencies

Optimization of procedure for review of clinical trials of new drugs applicants are encouraged to communicate with drug evaluation agencies before applying for linical trials of new drugs approval is considered in case of no denial or query within 60 days following submission of an IND application

Acceptance of oversea drug clinical trial data New drug clinical trial data obtained by applicants outside of China and bioequivalence study data of generic drugs approved in US, EU and Japan, if they comply with relevant regulatory requirements in China, may be used to support registration of new drugs and generic drugs in China after on-site inspection

Considerations for the future reformation

Measures for intellectual property rights Protect legal interests of drug patentees: For drugs within patent period, CFDA will not approve marketing of their generic drugs

Improve the trial drug data protection system Applicants, when submitting drug marketing applications, may submit data protection applications at the same time A 6-year data protection period would be granted to innovative drugs approved for marketing

Preparation of a collection of catalogues of approved drugs as the Chinese Orange Book


Legal liabilities of drug marketing authorization holder For all approved drugs, marketing authorization holders shall bear full legal liabilities for pre-clinical studies, clinical trials, drug processing and manufacturing, quality of raw materials and auxiliary materials, distribution and delivery of drugs, and reports of ADRs

Improvement of ADR reporting system The current system mainly replies on medical institutions to report ADR All marketing authorization holder shall assume liabilities for ADR reporting for products they produce and put forward measures to improve their quality control with regard to emerging adverse reactions.

Acceleration of review and approval for clinical-urgent drugs For med-unmet drugs, if surrogate indications, interim indicators or early clinical indicators in clinical trials demonstrate efficacy and the clinical value is predictable, marketing may be conditionally approved Applicants shall make risk control and management plan and carry out confirmatory clinical trials as required marketing and post-marketing studies as required in the approval documents


Supports of exploratory drug clinical trials For new drugs that are being tested in clinical trials and indicated for serious life-threatening diseases without effective treatment, if preliminary data in clinical trials show benefits possible and ethic requirements met, the trial drugs may be used in other patients if ICF is obtained, and the safety data may be used to support review and approval

Support of R&D for rare diseases Improve regulations on management of drugs for rare diseases, publish a list of rare diseases and establish a system for registration of patients with rare diseases For drugs approved oversea for rare diseases, marketing may be conditionally approved on the basis of oversea clinical trial data.


Foreign applicant should be the pharmaceutical company that has a legal registration in the local territory

The foreign applicant that is applying import drug registration should transact the process by its Chinese administrative branch or an agency the company entrusts to be the legal representative

Besides the package above, the branch or agency that supports the overseas company to process the drug registration should submit a marketing authorization approval or certificate allowed to be marketing of drugs to be imported into China and GMP certificate as well issued by the mother country of the oversea company and so on

Regulation of Registration Clarification and Submission Materials for Chemincal Drugs (May 2016)

In China when an international multicenter drug clinical trials (IMDCT) is to be conducted, it is not required that the clinical trials should be registered outside the PRC with medicine or has entered the phase II or III clinical trials. Vaccine drugs are included.

After completion of the IMDCT in China, the sponsor can directly submit an application for registration of drugs. When filing the application for a marketing, the requirements for the management of the drug registration administration and the relevant documents shall be carried out.

for applying for import of innovative chemical drugs and biologics, it is not required for the pharmaceutical manufacturers to obtain the marketing license overseas in producing countries or regions.

Prior to the release of this notification, if an importing drug has used the completed IMDCT data to submit a regulatory application and data is satisfied by reviewer and all requirements are conformity in China, it can be approvable to be imported without a China alone clinical trial

Notice for Regulatory Registration of Importing Drugs (for public consensus, Mar 2017)

NDA Priority Review List by CDE CFDA NDA List May 27, 2017

Definition: the drug substances and drug products with active pharmaceutical ingredients, dosage form, strength, indication, route of administration, and dose and method of administration are all the same as that of the original product

Policy change: •November 2015 by People’s Congress and March 2016 by State Council: a goal of equivalency of quality and efficacy to the original product clinically by the end of 2018 for all generic drug in China

Generic Drug Quality Consistence

Adm by China Human Genetic Resources Administration Office (CHGRAO), Ministry of Scientific Technology

Any kind of biosamples collections for clinical trials Any foreign enterprises, including CROs and labs involved 3months or so for the process of review and approval online application http://www.cncbd.org.cn/TColumn/Detail/3428

Executive Guidance of Regulatory Review and Approval for Collection, Trading, Exporting of Human Genetic Sources (Oct 2015)

http://www.cncbd.org.cn/TColumn/Detail/3428

31

Application Package for CHGRAO

# File Name File Type # Paper/E Form Requirements Comments

1 Application Form Original 1 P/E Online fill up and

stamped on paper file for submission

Before initiation of any trials involved in biosample collections

2 Site Code Copy 1 P/E Stamped on paper file Before initiation of any trials

involved in biosample collections

3 ICF Copy 1 P/E Before initiation of any trials


4 IEC Approval letter Copy 1 P/E Stamped on paper file Before initiation of any trials


5 Contract for trials Copy 1 P/E Paper Before initiation of any trials


6 Internationals Cooperative agreement Copy 1 P/E Paper

When foreign parties are involved

7 CFDA Approval Letter Copy 1 P/E Stamped on paper file

Any activities related to clinical trials

8 Trial Files, such as Protocol etc Copy 1 P/E Stamped on paper file

Before initiation of any trials involved in biosample collections

Procedure of Clinical Trials involved with CHGRAO

CTP IEC

Clinical Trial Agreement

Site GCP application

GCP approval

CHGRAO approval

Online registration

0 d 60 – 90 d 30-45d

32

Online application

Any further assistance or inquiries, please contact us:

Daniel Liu, PhD Chief Scientific Officer Beijing Clinical Service Center

China [email protected]

Thank You