Clinical trial training course:Botanical new drug development form Clinical points of viewTien-Tzu Tai MD.Center for Drug Evaluation, Taiwan

*This presentation was not officially cleared, and the views offered here do not necessarily reflect official positions of DOH ,including TFDA.DISCLAIMER*

OutlinesFDAFDAEMATGA():

Introduction (Taiwan)- () [99.12.10](98.3)US FDA: Guidance for Industry (Botanical Drug Products) June 2004(62.4-99.8)()

(TW)

(TW)

:Cerenin (Ginkgo Biloba Extract)()016451 ()016459 ()016845 ()Clove oil (Eugenol)0.02 g(): :Castor Oil()()()

US FDA: (OTC)

US FDA OTC monograph VS. NDA approvalWhen a final OTC drug monograph is published for a specific use of a botanical drug, any person may market a product containing the same substance and for the same use, provided the labeling and other active ingredients (if present) are in accord with all relevant monographs and other applicable regulations.In contrast, when a product is approved under an NDA, the approval is specific to the drug product that is the subject of the application (the applicants drug product), and the applicant may be eligible for marketing exclusivity for either 5 years (if it is a new chemical entity) or 3 years from the time of approval, even in the absence of patent protection.

EU: regulation for botanical drugEMA: Article 16h(3) of Directive 2001/83/EC for traditional herbal medicineEMA: Directive 2004/24/EC 2004 AprilAll herbal medicinal product: required to obtain authorization for marketing in EU.Marketing before 2004 April can continue to market their product until 30 April 2011.Committee on Herbal Medicinal Products (HMPC)

HMPC: Community monographs Community monographs are divided into two columns: Well-established use (marketing authorisation) : demonstrated with sufficient safety and efficacy data,Traditional use (simplified registration). : accepted on the basis of sufficient safety data and plausible efficacy.

Directive 2004/24/EC Where the applicant can demonstrate by detailed references to published scientific literature that the constituent or the constituents of the medicinal product has or have a well-established medicinal use with recognised efficacy and an acceptable level of safety within the meaning of Directive 2001/83/EC, he/she should not be required to provide the results of pre-clinical tests or the results of clinical trials. []

EMA: A simplified registration procedure (hereinafter traditional- use registration) Criteria: [16a](a) they have indications exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment;(b) they are exclusively for administration in accordance with a specified strength and posology; (c) they are an oral, external and/or inhalation preparation;(d) the period of traditional use as laid down in Article 16c(1)(c) has elapsed; { 30 yrs worldwide; 15yrs in EU}(e) the data on the traditional use of the medicinal product are sufficient; in particular the product proves not to be harmful in the specified conditions of use and the pharmacological effects or efficacy of the medicinal product are plausible on the basis of long-standing use and experience.

2011.5.2.A4

Why didnt any company from mainland China and Taiwan get approval before 30 April 2011?(15)Note: The European Medicines Agency is not responsible for registering traditional herbal medicinal products in the European Union Member States nor for authorising herbal medicinal products unless the centralised procedure applies.(centralized )

Botanical Drug in Australia: TGA

Botanical Drug Regulation: TGATherapeutic goods are divided into medicines and medical devices. Some medicines are limited to prescription-only while others are available without a prescription. Non-prescription medicines may be complementary medicines or OTC medicines and may be listed or registered in the ARTG.These guidelines are solely concerned with OTC medicines. Some OTC medicines (eg. sunscreens) are normally listable but the majority are registrable.

Risk-Based regulation by TGAHigh Risk Medicines: individually evaluated for quality, safety and efficacy approved by the TGA as Registered medicines. Efficacy is usually assessed by examining data from controlled clinical trials. However, where adequate information is available on each active ingredient, and it is well described in standard textbooks/guidelines, this may be used to support efficacy.Listed medicines are low risk medicines and are included on the ARTG via a low-cost and streamlined electronic application and validation process. Listed medicines may only contain ingredients that have been evaluated by the TGA to be low risk, must be manufactured by licensed manufacturers in accordance with the principles of GMP and may carry indications only for health maintenance and health enhancement or certain indications for non-serious, self-limiting conditions. Most, but not all, complementary medicines included on the ARTG are Listed medicines.

Registrable disease list in TGA

SUBSTANCES THAT MAY BE USED IN LISTED MEDICINES IN AUSTRALIA (Example: Page 66)

OTC regulation By TGAWell documented active ingredients: Most OTCProducts containing active ingredients that are not well documented [New substance]

Well documented by standard texts

(Draft)

(Draft)1. ()()2. OTC()([OTC monograph])3. OTC monograph(claims for the symptomatic relief of conditions [other than serious disease, disorders, or conditions])

(Draft)4. 5.

*2.OTC monograph(claims for the symptomatic relief of conditions [other than serious disease, disorders, or conditions])

*Types of claimed indications(1)(: Penicillinpneumococci)(2)(:Chlorothiazide)(3)(:Chlorpheniraminevasomotor rhinitis) [OTC level Claims](4)(: )(adjunct to the mode of therapy)

*Low-level Claims for :(claims for the symptomatic relief of conditions [other than serious disease, disorders, or conditions])

*

(Pivotal Trial)

(Pivotal Trial)(Post-marketing Commitment Study)(Post-marketing Requirement Study)

Outlines - Clinical Considerations in draft Guidance for Botanical NDA in Taiwan Adequate and well-controlled Clinical trial.Pivotal Trial: sample size and required number.Different claimed indications. Design issues: Dosage selection, Comparator selection, Study duration, Adequate primary endpoint, Blinding remained.Safety Evaluation.Bridging Issues.Regulatory Consideration for Combination Botanical Drug.

Adequate and well-controlled Clinical trial(general requirement for pivotal trial)(1)(Clear statement of objectives)(2)[](Study design permits valid comparison [appropriate control])(3)(Select patients with disease [treatment] or at risk of disease [prevention])(4)[](Baseline comparability [randomization])(5)(:)(Minimize bias [blinding, etc.])(6)(Appropriate methods of assessment of outcome)(7)(Appropriate methods of analysis)

(multiple batches)(10%15%)

(dose escalation study)(Maximal Tolerated Dose; MTD)(dose response study)(surrogate endpoint)(pharmacodynamic endpoint)

(:)(initial studies)Add-on

*Placebo control?: GI symptom-relief drugPlacebo effect: Psychiatric drug (MDD..etc)Fluctuations: Allergic rhinitisplaceboirreversible injury?

ICH E1A

Drug XABP(C)P(C):(validated)Q12Q(change from baseline Q scores at Week 12)

(final drug product)

PRO (patient reported outcome)validated()(manipulation)GCP

(multiple batches) (I)(multiple batches)Phase III study()(treatment difference by batch)

(multiple batches) (II)6

(10%15%) (10%15%)

Safety EvaluationPrevious Human experience: Dietary supplement in patient population (the same as claimed indication or other conditions) or healthy subjects (the same dosage and the similar duration?)Reduce safety data pool due to reduce requirement of pivotal trial and early trial.No observed or reported safety signal Safe

ICH E3 Structure and Content of Clinical Study Reports(narratives)CCDP (Complete Clinical Data Package)Clinical Summary(overall risk assessment)()(risk management plan)()

(:)(final drug product)()

Regulatory Strategies to facilitate botanical new drug development (I) 1st Approach: depends on clinical background of the claimed indication (Huge Market, Rare Condition or Life-threateningetc.)2nd Approach: depends on the impact of the claimed indication (prescription or OTC)3rd Approach: depends on how significant the result of single pivotal trial is (plus PMC or PMR studies)

Regulatory Strategies to facilitate botanical new drug development (II) Traditional OTC indication: TCM Traditional Formula; Botanical traditional use refer to monograph from worldwide traditional use.New OTC indication: may still need Clinical trial (esp. pivotal trial) may consider to numbers required + PMC or PMR studies. (need SPA with TFDA)Indication for prescription: May be the same requirement as NCE.

Issues needed to considerHTA issues: Evidence-based OTC?Botanical drug: hard to produce generic one as biological product : patent

Issues needed to considerCMC! (Biosimilar)

Issues needed to consider()TGAOTC monograph OTCTGAlow risk listed medicineOTC monograph?OTC PDRXXXLow level claim

Future Directions of Botanical Drug Regulation in TaiwanTraditional use: ()?()Low risk, low-level OTC claim (Traditional use):High risk, prescription level claim: NCE, CMC

THANKS FOR YOUR ATTENTIONS

Appendix

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