Challenges, trends and Strategies in TCM Development

May 17th 2011 | Beijing, China

Unique Potential for Innovation in China

Jing’an, Shanghai, March 2011

Traditional Chinese Medicine Translational Medicine

TCM is One of Fastest Growing Therapy Areas

Kanpo Medicine: System of herbal medicine practiced in Japan by both herbalists and practitioners of modern medicine. Kampo originated in China and is based on Chinese herbal medicine

TCM Rx Is Mostly For CV, Oncology, Gynecology

What is Modernised TCM?

5

Good Agriculture Practice (GAP) certificate:

•Ensures TCM herbs and raw ingredients are clean and fit for human consumption and that they contain the effective ingredients

•TCM medicine manufacturers usually do not need this certificate, but suppliers may be chosen according to whether or not they have this certificate

•>99 GAP bases in 22 provinces covering 49 different herbs.

Good Supply Practice (GSP) certificate:

•Introduced in 2001, it is necessary if a company seeks to develop an internal distribution and supply network

•Foreign companies generally are not able to attain this certificate, but domestic subsidiaries can.

Good Laboratory Practice (GLP) certificate:

•Beginning in 2007, all non-clinical drug research must be carried out in a GLP certified facility

Good Clinical Practice (GCP) certificate:

•Since 1999, GCP certifications are necessary to perform clinical trials on a drug to determine its quality and efficacy

Good Manufacturing Practice (GMP) certificate:

•The requirement for all drug manufacturers to have this certificate came into effect at the beginning of 2004

•All TCM makers must have this certificate or they are subject to suspension.

Good Extraction Practice (GEP) certificate:

•This covers the first step of the TCM manufacturing process, which ensures quality and use of TCM products

“ModernQualityTCM”

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patent applns

patent grants

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CM

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Protect Innovation: Patent Law & Regulations

Before 1st amendment to Chinese Patent Law in 1993, there was no patent protection for pharma product or food

Chinese Patent Law recognises composition of matter, method & use claims

Can be easy to design around (e.g. change composition mix, change extraction method)

Difficult to enforce (e.g. difficult to prove infringer used same method)

2007: A New TCM Standard for Registration

TCM NCE

Pre-clinical safety GLP for short term tox required GLP for long term tox preferredUse of existing data permissible

GLP required

Pre-clinical pharmacology

GLP should be applied “as much as possible”

GLP required

CMC 1 batch tested for CT3 batches tested for NDA

1 batch tested for CT3 consecutive batches tested for NDA

Phase I* 20-30 patients for toleration 20-30 patients for toleration & PK

Phase II/III/IV* Ph II = 100Ph III = 300Ph IV = 2,000

Ph II = 100Ph III = 300Ph IV = 2,000

Endpoints Western (primary) + TCM (secondary)Primary endpoint must be met

WesternPrimary endpoint must be met

*number given/trial group

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SFDA Regulations Revised in 2007P

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ince 2007New TCM drug approvals:

2009: 722010: 10

A New Era of Evidence Based TCMs

Development attrition risk likely lower than NCE : Many promising new chemical drugs have failed to deliver efficacy Efficacy for TCMs based on many years of (anecdotal) clinical experience, Many years of non-controlled clinical use = low risk of unexpected safety issues

Regulatory Clear regulatory pathway for TCM in China and major markets

(SFDA Guidance 2007, FDA Guidance 2004, EU Directive 2004) New requirements for evidence represent significant barrier for most TCM companies Competitors who choose to develop same/similar TCMs must produce data to

support their claims to the same standard as the innovatorSimilar to biosimilars, represents major barrier to entry

Government: 2007 Party Congress support increased role for TCM in healthcare Encouraged private sectors investment, TCM heritage protection TCM innovation/modernization More TCM use for Primary care, Essential Drug List, National Reimbursement Drug

List Global market is an aspiration

TCM/Botanicals: A Global Opportunity

US & EU have regulatory guidelines for botanical drugs US: FDA Guidance for Industry: Botanical Drug Products, June 2004 EU: Directive 2004/24/EC, amending Directive 2001/83/EC, April 30, 2004

• Guideline On Declaration Of Herbal Substances And Herbal Preparations In Herbal Medicinal Products/Traditional Herbal Medicinal Products (EMA/HMPC/CHMP/CVMP/287539/2005 Rev 1), March 11, 2010

• List of Questions and Answers (Q&A) Received During the HMPC Assessors Training on Quality Issues Emerging for Herbal Medicinal Products (EMEA/531300/2008, November 6, 2008

• Guideline on Selection of Test Materials for Genotoxicity Testing for Traditional Herbal Medicinal Products/Herbal Medicinal Products (EMEA/HMPC/67644/2009) November 12, 2009

• Reflection Paper on Markers used for Quantitative and Qualitative Analysis of Herbal Medicinal Products and Traditional Herbal Medicinal Products (EMEA/HMPC/253629/2007) July 15, 2008

• Guideline on the Quality of Combination Herbal Medicinal Products/Traditional Herbal Medicinal Products (EMEA/HMPC/CHMP/CVMP/214869/2006) June 23, 2008

• Guideline on Quality of Herbal Medicinal Products/Traditional Herbal Medicinal Products (CPMP/QWP/2819/00 Rev 1, EMEA/CVMP/814/00 Rev 1), March 30, 2006

• Guideline on specifications: Test Procedures And Acceptance Criteria For Herbal Substances, Herbal Preparations And Herbal Medicinal Products/Traditional Herbal Medicinal Products (CPMP/QWP/2820/00, EMEA/CVMP/815/00) March 30, 2006

Early experience Veregen is the only botanical approved in US (MediGene AG, 2006)

• Green tea extract for condyloma acuminata Hutchinson Pharma’s HMPL-004 for IBD completed Phase II in US Tasly’s Danshen Dripping pill has completed Ph II

1st May 2011: A Watershed for TCM in EU

TCM: Drug Development Challenges

Right Patient Right Drug Right Dose

Western or Chinese

concepts of disease?

Traditional combinations

or select herbs based on

pharmacology

Recipe?Maximum

tolerated dose?Dose ranging?

Placebo control?

Active control?

Randomised?

Individualised?

Double blind?

Clinical Research: 10 Challenges

Evidence Based TCMs

Evidence Based TCMs: Individualised

Evidence Based TCMs: Dementia

Evidence Based TCMs: Stroke

2011 and Beyond………

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Evidence Based TCMs: Rhinitis