NMPA regulation reform – cell and gene therapy products€¦ · Global clinical trial data on gene and cell therapy products – as of 11 Feb, 2019 Gene therapy China US EU # of

© 2019 Parexel International Corporation / CONFIDENTIAL

NMPA regulation reform –

cell and gene therapy products

1

Yuexia Li, Ph.D.

VP, Technical, Regulatory & [email protected]

© 2019 Parexel International Corporation

Update on the NMPA regulatory reform

Advantages for getting into China

The brief history and current status for cell and gene

therapy products in China

Key submission considerations

Challenges and the future

2

Agenda


Update on the NMPA regulatory reform


August 9, 2015, a historic date for China pharmaceutical regulation: for the very first time in history, the

State department issued an announcement on drug and medical device regulation reform. Since then,

the following milestones have happened (in 4 years):

1. New definition for “new drug”: only the drug has not been approved anywhere in the world can be

called “new drug”, many such new drugs have been made available for Chinese patients.

2. Uniformed standard for generic drug approval, i.e.: all generic must be comparing to reference listed

drugs, can’t be to another generic drug.

3. Clinical trial site filing is required (self evaluation) rather than providing the Good Clinical Practice

(GCP) certificate, this has been written into the law. This leaves little room for fake and data

manipulations.

4. The well known “7.22”(7-22-2015) event over 200 teams with over 2000 inspectors sent out to

perform inspection for clinical trial sites associated with 1622 drugs. Over 1000 drugs had voluntary

withdraw of registration and the clinical sites had admitted they were not qualified and wanted to

remove their site from the qualified list. (Proudly: all Parexel China sites and conducted trials

passed inspection).

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Brief background regarding the China regulatory reform, highlights


5. The definition of “drug” has been updated:

Under the new regulation, only drug product (final dosage form, FDF) is considered as

“drug”. Active Pharmaceutical Ingredient (API) is no longer considered as “drug” as it did

before.

6. The definition of “counterfeit drug” has been updated:

Drug approved outside of China and before getting China approval will not be considered

as “counterfeit drug” as it did before, however, it must be approved by CDE/NMPA as

imported drug before it can be marketed in China.

7. Introducing the “market authorization holder” (MAH) concept, previous the MAH is issued

to one who must have a manufacture site; this will pave the road for MAH system

implementation in China, similar to the rest of the world.

8. Officially introducing the “China DMF” system, which allow NMPA to implement the China

DMF regulatory requirements.

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9. Officially introducing the “accelerate approval” and/or “conditional approval”

regulatory pathways in the regulation.

10. Strengthening the NMPA and different local government level drug administration

office’s role & responsibility.

11. The 60 working days (WD) Clinical Trial Application (CTA) review timeline has

been written in the law.

12. Only license is needed to market the pharmaceutical products; previous it is

required that the products can only be manufactured after it gets approval, this

new regulation implies that the PV batch and registration batch is also allowed to

be sold in China once license is issued, i.e., the drug is approved in China.

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Advantages of getting into China

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China is the #2 pharmaceutical market (after USA,

replacing Japan as of early 2019).

Late entry to China will lose new drug designation and

data exclusivity granted by the Chinese regulatory

authority (for biologics, data protection period is 12

years). When a firm is considering global approach,

make sure include China in the plan.

8

Advantages of getting into China-1

At a value of around 137 billion U.S. dollars at the end of 2018, the Chinese pharmaceutical market has surpassed Japan to become the world's second-largest by sales after the United States, the report said, citing data from market research firm IQVIA.


The largest patient pool in the world and fast recruitment

process.

Adapting to ICH requirements started May 2017.

Good infrastructure for clinical sites management and

data is accepted by US FDA and EMA for registration.

Fast CTA & NDA approval timelines.

Foreign clinical data may be acceptable for registration in

China (this needs justification and qualification).

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Development considerations



Largest population in the world

Aging society (detail: next slide)

Cancer Diagnosis and treatment options

Noncommunicable chronic disease (NCD), such as

hypertension, diabetes, etc….

Rare diseases

Others…

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China has huge medical needs…….



According to the data of the sixth national population

census in 2010, the population of aged 60 and older is

close to 178 million, 13.3% of the total population, about

20% of the world population for that age group. As such,

China has the highest percentage of aging population in

the world.

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Aging society


The brief history and current regulatory status for cell and gene therapy products in China

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In 2009, The Department of Human Health of China Issued “The Administration of Medical Technologies for Clinical Use”, in there, immuno cell therapy and gene therapy technologies are categorized as “Involving major ethical issues, the safety and efficacy of such technologies need to be verified in clinical trials that are conducted according to standardized procedures”.

On May 22, 2009, T cell and NK cell therapy technology and cell transplantation therapy (except stem cell) were listed as “First Group of Category 3 Medical Technologies Granted to Be Used for Clinical Purpose”.

On July 2, 2015, the National health and family planning commission issued catalogue of “Prohibited Medical Technologies to Be Used in Clinical Setting”. For example, hematopoietic stem cell including umbilical cord blood hematopoietic stem cells and transplantation technology for the treatment of blood system diseases are the prohibited technologies. Cell therapy is required to be "performed in accordance with relevant regulations of clinical research".

On May 4, 2016, after the incident of “Wei-Ce-Xi” (a young college student, diagnosed with synovial sarcoma, went through 4 treatments of cell therapy and still died at age 22), cell therapy is categorized as clinical research, it can only be used for research and can’t be used for paid medical treatment which is against the law.

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China regulatory guidelines for cell and gene therapy products


On December 22, 2017, CFDA (now: NMPA) issued and implemented the “Technical Guidelines for Research and

Evaluation of Cell Therapy Products”. This guideline provided clear instruction for the development, production, and

registration of cell therapy products in China. The following aspects were made clear for the public to follow:

The scope of this guiding principles and the basic requirements for pharmaceutical, non-clinical and clinical.

The purpose is to promote the research and development of cell therapy products, improve the safety, efficacy, and overall quality

controllability of cell therapy products.

This guideline applies to: Human-derived living cell products for the treatment of human diseases. Cell source, manipulation and

clinical trial processes must meet ethical requirements and are developed and registered in accordance with relevant regulations.

This guideline does not applies to: Blood components for blood transfusion, regulated hematopoietic stem cell transplantation

without in vitro manipulation, reproductive-organ derived cells, tissues and organs, etc.

Cell therapy products should meet the regulatory requirements for drug quality.

The entire manufacturing process for clinical used materials must comply with cGMP requirements.

The pre-clinical studies must be conducted under the GLP requirements, or “Quality Management Regulations for Non-Clinical

Testing of Drugs“.

When a cell therapy product enters the clinical trial phase, it should follow the requirements of the GCP.

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China regulatory guidelines for cell and gene therapy products

© 2019 Parexel International Corporation15

Global clinical trial data on gene and cell therapy products – as of 11 Feb, 2019

Gene therapy China US EU

# of Marketed products 2 4 5

Clinical trial % 22% 54%

The first product approval date Gendicine,16 Oct, 2003

Imlygic27 Oct, 2015

Glybera,25 Oct, 2012

CAR-T Therapy (Chimeric Antigen Receptor - T Cell) China US

# of Marketed products none Kymriah (8-30-207)Yescarta (10-18-2017)

Clinical trial % 41% 40%

Selected top 3 investigational companies

HRAIN, Nanjing Legend, CARsgen

Novartis, Celgene (Juno, Bluebird), Gliead (Kite)

(Worldwide)


There are 2025 cell therapy clinical trials registered worldwide as of 25 Jan, 2019

81% in Phase I-III

1% in Phase IV

9% has clinical results (91% does not have results yet)

There are 444 (~22% of global trials) cell therapy clinical trials registered in China

as of 25 Jan, 2019

85% in Phase I-III

2% in Phase IV

None has clinical results

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Cell therapy clinical trial status

Data Source : NIH clinicaltrials.gov


Number of cell therapy clinical trials in China by therapeutic area

370

18

7

6

6

6

5

4

Oncology

Neurology

Endocrinology

Hematology

Cardiology/Vascular Diseases

Infections and Infectious Diseases

Trauma (Emergency, Injury, Surgery)

Obstetrics/Gynecology (Women’s Health)


There are 1382 gene therapy clinical trials registered worldwide as of 25 Jan, 2019

670 registered in US (48%)

262 Registered in China (19%)

450 registered in other countries (33%)

Phase I-III: 67%

8% has clinical results

The 262 registered gene therapy trials in China:

Phase I-III: 79%

None has clinical results

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Gene therapy clinical trial status

Data Source : NIH clinicaltrials.gov


Number of gene therapy clinical trials in China by therapeutic area

37

9

3

3

2

2

1

1

1

1

1

1

1

1

Oncology

Genetic Disease

Hematology

Psychiatry/Psychology

Pulmonary/Respiratory Diseases

Trauma (Emergency, Injury, Surgery)

Cardiology/Vascular Diseases

Endocrinology

Gastroenterology

Hepatology (Liver, Pancreatic, Gall Bladder)

Immunology

Infections and Infectious Diseases

Obstetrics/Gynecology (Women’s Health)

Healthy Volunteers


Guiding Principles for Cell Therapy Product Development & Evaluation (draft)

Q & A for “Guiding principles for Cell Therapy Product Development & Evaluation

(draft)”

Guiding Principles for Human Cell Therapy Product Development and Quality

Control

Key Considerations of Clinical Trial Application (CTA) Submission for Cell Therapy

Products

Current Thinking for Evaluating Pre-clinical Studies of CAR-T Products

Key Considerations for Quality Control Testing Studies and Non-clinical Evaluation

of CAR-T Cell Therapy Products

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Key reference guidelines/notifications

issued by CDE


Key submission considerations

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The approval process for cell and gene therapy products in China

After 60WD,if no response

from CDE, clinical trialcan start

CDE sends information request for minor issues, applicants respond within 5WD and submit complete

information requested.

Major deficiencies

found by CDE and clinical trial cannotbe started

Conduct Clinical Trials

Pre-NDA(BLA) meeting with

CDE

NDA(BLA) technical review

(> 120WDs)

NDA(BLA) submission

NMPA issues approval letter

Inspections (cGMP, GCP, ) Sample testing

NMPA Drug Registry

Department

Clinical trial application (CTA) submission for Biological Products

CDE Technical Review (60WD)

Pre-CTA meeting with CDE (pharmacology,

pre-clinical, and clinical)


Scale: Should be able to manufacture enough for multiple patients.

Traceability: Unique code should be assigned for the entire life-cycle of the product (e.g.

collection, separation, engineer, harvest, transportation).

Ethical: The whole process, including the disposal must comply with the ethical

requirements.

GMP & GDP: It is important for cell therapy products to be manufactured/distributed

according to GMP and GDP regulations.

Raw Material: the source of all raw materials and their quality must be compliant with

regulations and avoiding antibiotics.

Pharmaceutical Development: Critical Quality Attribute (CQA) and certificate of

pharmaceutical product (CPP) should be established including Pharmacovigilance (PV).

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Cell therapy products:

CMC considerations-1


Product quality: data from relevant to the following aspects must be from representative

batches as part of the CTA submission:

Cell Characterization

Assay

Purity

Safety

Quality Control Strategy: It is mandatory to have the control strategies and using process

control & release control are encouraged.

Post marketing changes: follow the ICH Q5E: Comparability of Biotechnological/Biological Products

Subject to Changes in Their Manufacturing Process

Stability: as part of the CTA submission, it is mandatory to have stability data to support

product transportation methods and product shelf life.

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Risk assessment

It is mandatory to perform a risk assessment for the entire manufacturing process of cell

therapy products.

A customized development plan should be set up to minimize risk.

Backup Plan

The manufacturing & transportation process for a cell therapy product may take several

weeks; this factor should be taking into consideration for the targeted disease

progression.

The manufacturing of a cell therapy product may fail; backup plan must be proposed.

In case of Out of Specification (OOS) occurs when performing product release testing,

backup plan must be proposed.

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Traditional pre-clinical development plan may not suitable for cell therapy

products.

As such, the pre-clinical data for cell therapy products are evaluated on a

case by case basis.

ICH S6 requirements need to be followed Preclinical safety evaluation of

biotechnology-derived pharmaceuticals

Drug Metabolism and Pharmacokinetics (DMPK) considerations: special

attention must be paid regarding cell distribution & differentiation and modified

human cell.

Waive: Certain pre-clinical studies can be waived if sufficient human data is

available for evaluating the safety & efficacy in human trials.

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Pre-clinical considerations


Cell therapy products have different clinical development strategies compared to

traditional pharmaceutical products, the following factors are key points for CDE

considerations:

Is it for treating rare or life-threatening diseases?

Drug development stage: early stage (DMPK may not be feasible) & pivotal stage?

Is the surrogate endpoint reliable?

Can less patients in pivotal trial be acceptable?

Are rare SAE & long-term SAE data completed?

Is a strong patient protection system implemented?

Does significant ethnical difference exist?

Is there a risk management plan in place to minimize potential risks? (safety)

Is a robust benefit/risk assessment done? (efficacy and safety)

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Clinical considerations-1

CDE considerations


For risk control:

The severe adverse events (SAE), such as: cytokine storm, may affect the efficacy.

Multiple doses can only be administered with adequate data to support such dosing scheme.

For SAE monitoring:

The monitoring period must cover the entire treatment period;

Patient long term follow up should be needed;

Additional/extra safety monitoring measures may be needed for a specific product;

Risk associated with cell therapy:

Graft versus host disease (GVHD)

Tumor induction

Hyper immune response

Migrate to non-target areas or unintended tissues in the body

Can’t achieve the expected treatment results.

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Clinical considerations-2


Conditional approval can be applied at any stage of the cell therapy product

development if one of the following conditions is met:

Indication: the proposed cell therapy product can treat life-threatening diseases and can

meet the un-med medical needs in China.

Available clinical data obtained from the proposed cell therapy product can reasonably

predict clinical benefit and shows that the proposed product is superior to current

standard of care.

Conditional approval

Upon the conditional approval, all post-approval commitments must be fulfilled, usually,

these commitments are post-marketing safety & efficacy studies.

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Conditional approval


Challenges and the future

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Currently, China has no finalized specific legislation or regulations for gene

and cell therapy products, especially for the following:

Ethical relevant laws and regulations

Human rights protection relevant laws and regulations

No separate regulatory authorities for clinical trial application and marketing authorization

for cell and gene therapy products.

Inexperienced technical reviewers from the regulatory authority.

No global unified regulatory standards to follow.

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Challenges for cell and gene therapy

products in China-1

Incomplete regulatory policies


Getting into clinical trials stage remains a huge challenge as it requires additional

funding for manufacturing of clinical grade reagents, formal toxicology studies in

animals, preparation of extensive regulatory documents, and the high costs of

clinical trials.

As a result of such challenge, many promising product development has been

slowing down due to lack of funding for this critical clinical stage studies.

When the US FDA approved two Car-T treatment products, it provided much

needed encouragement for Chinese cell and gene therapy companies, it also

makes the competition in this field much more intense.

The cost of cell and gene therapy is also very high, this will always remain as a

challenge.

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Challenges for cell and gene therapy

products in China-2


Many indications of gene and cell therapy drugs are for rare diseases. For rare

diseases, there is no clear official definition in China, it is case by case and can be

discussed with CDE/NMPA.

China does not have a clear evaluation standard, and the regulatory reviewers are

inexperienced. Currently, there is no gene therapy product approved under the

new CDE regulations.

Currently, the oversight and approval of cell and gene therapy products are

different from each other globally, and no agreed upon international standards

have been established.

Diseases requires gene therapy are mostly genetic diseases, which the patients

often need to be tested and screened by genetic sequencing. Currently, there is a

lack of commercially available gene screening kit for detection of genetic diseases

in China. 33

Challenges for cell and gene therapy products –regulatory issues and operational difficulties


The new NMPA/CDE reform has created many opportunities and multiple pathways for

oversea companies to get into China. CDE/NMPA is proactively promoting science based

decision and collaborating with many organizations globally.

The recent NMPA reform has transformed the cell and gene therapy field in China, many

companies have joined this arena and the development is at a very fast pace, maybe

even faster than the US and EU.

The cell and gene therapy clinical trials are taking place at a faster pace too in China.

The CDE/NMPA approval speed has improved dramatically in the last a few years and the

China national reimbursement list is getting updated quickly.

In the foreseeable future, we will see many new cell and gene therapy products reach to

the patients who need them desperately.

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The future of cell and gene therapy

products in China


Victor Cheng – VP Technical (Clinical), ex-CDE/NMPA

Mingping Zhang – VP Technical (CMC), ex-CDE/NMPA

Frank Gao – PCST (CMC and Compliance), ex-CDE/NMPA

Vincent Duan – PCST (Clin Pharm), ex US FDA

Liwei Dong – SCST (Compliance)

Zeck Huang – SCST (Non-clinical) – US based

Changting Haudenschild – (Clinical), Europe based, ex US FDA

Yuexia Li – VP Tech (Compliance and Reg) – US Based, ex US FDA

35

China team – regulatory consulting

services

Remember: Parexel also has very strong clinical service team


For Greater China region, there are total 35 regulatory experts located in Taiwan

(16) and China (16) to fully support clients facilitating product development from

China to global and global to China.

Parexel Consulting China expertise

16 China regulatory experts including:

4 VP (Tech.) Consultants

2 Principal Consultants

2 Senior consultants

A team of regulatory affairs experts

To support:

Regulatory strategy, new drug registration and life cycle management of approved drugs

Clinical and non-clinical

CMC (gap analysis, and regulatory pathways for CMC changes pre- and post approval)

Compliance including pre approval inspection, cGMP remediation, staff training etc…



19 different CTA submissions for biosimilars, biologicals and chemical products of different phases

7 CTAs on green channel (priority review)

4 NDAs (2 ongoing, 2 upcoming) to date

2 DMF standalone applications

30+ regulatory consultation meetings:

Covering different therapeutic areas and development stages including medical devices

13 consultation meetings are still under preparations

30+ regulatory consultation discussions (no formal meetings took place)

Covering different therapeutic areas and development stages including medical devices

Performed due diligent for the clients

6 cGMP trainings and mock inspections, GSP audit, performed cGMP remediation services in China

and US

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Accomplishment during the past 2 years (2017~2019):


Management of regulatory document:

eCTD (electronic common technical

document)

CDISC (Clinical Data Interchange

Standards Consortium)

Gateway system

Translation

Manage external vendor

Proofreading

QC process

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Project Management

Seasoned experts have excellent skills

Communication

Strong skill of communicating in both

English and Chinese

Understands both cultures

Knowledgeable of both regulatory

requirements


Inspection Readiness for cGMP

Remediation plan, implementation, and is a qualified “third party consultant” for

FDA, EMA and other regulatory authorities.

Mock Pre-Approval Audits/inspection (PAI)

GxP Audits (GLP, GMP, GCP etc…)

“For Cause” Audits

Quality Systems (Q9, Q10) implementation and gap analysis

Outsourcing Advisory, Third Party Audits

Inspection Readiness for Clinical Sites

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Parexel strategic compliance services


Global companies � China (new drug registration or new drug importation)

Parexel can be the China agent for these companies:

Drug registration

Interact with CDE/NMPA for all communications

Product lifecycle management in China.

Parexel can perform facility readiness inspection before the NMPA comes to inspect.

Chinese companies� US or EU or other parts of the world

Parexel can be the US or EMA agent for these Chinese companies (especially for API firms):

Drug registration

Interact with FDA/EMA etc for all communications

Product lifecycle management.

Parexel can perform facility readiness inspection before the FDA/EMA comes to inspect.

Warning letter/Import alert remediation etc..

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Parexel Consulting team: Can be the “double agent” �


Victor Cheng, VP Tech, Parexel

Frank Gao, Principal Consultant, Parexel

Mingping Zhang, VP Tech, Parexel

Bob Iser, VP, Parexel

Beijing Regulatory Affairs Team

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Acknowledgement


Thank you!Any questions?

Documents

NMPA regulation reform – cell and gene therapy products€¦ · Global clinical trial data on gene and cell therapy products – as of 11 Feb, 2019 Gene therapy China US EU # of