Evidence supporting Indications Benefits for Consumers and Industry

Kaylene Raynes Director, Listing Compliance Section Office of Complementary Medicines

Why regulate Listed Complementary Medicines?

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Meet consumers expectations for safe, high quality medicines

that are efficacious

Consistent labelling

requirements

Indications & claims are evidence

based

GMP Contain only preapproved ingredients

Listed Medicines Regulatory Framework

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Listed on ARTG •Streamlined online application & validation process

•Sponsor certify meets legislation requirements

•No premarket efficacy evaluation

Retail supply to Australian market place

Compliance review Unique

Regulatory Framework

Evidence sourced from open literature

Regulatory framework consistent with low risk

medicines

Quick & easy market access

Pre-approved ingredients

Market share established

Fully compliant Non compliant

??? Cancelled from ARTG

Listed Medicines - The Challenge

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Reconciling Australian Consumer’s expectations with industry innovation

Innovative marketing strategies to meet demand

Minimal regulatory burden

Industry Consumer

High quality medicines that are safe &

affordable

Type of Compliance Reviews for LMs Investigations • Triage of complaints into highest priority target review

Target Reviews • Often triggered from complaint or intelligence report • Specific information is reviewed to address concerns • Comprehensive evidence reviews

Random Reviews • Newly LMs are randomly selected • Standard set of information is reviewed

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Target Reviews (Narrow scope)

Random Reviews (broad scope)

Investigations (triage)

Listing Compliance Review Process

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Medicine listed on ARTG

Compliance review Request for information (s31 of Act )

Assessment of information against relevant legislative

requirements

Direct cancellation

ss30(1C) or (1A)

Cancel medicine from ARTG

Compliance issues identified

Propose to Cancel (P2C)

Address all non-compliance issues of P2C

Medicine remains on ARTG

Cancellation ss30(2)

Cancel medicine from ARTG

Fully compliant Medicine remains on ARTG

Sponsor review listing & address issues

Traditional Use – Indications & Evidence

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Evidence of Traditional Use: • tradition of use for its intended purpose spanning at least 3 generations Sources include: • National formularies; • Materia medica; • Official pharmacopoeias; and • Monographs. Example of traditional indication: Traditionally used in Western herbal medicine to relieve nasal congestion

Qualifer Context Action Target

Scientific – Indications & Evidence

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Scientific evidence refers to quantifiable data derived from the open public literature. • Due to the quantifiable nature of scientific evidence; scientific indications can imply efficacy. Sources include: • Clinical studies; • Peer-reviewed published articles; • Pharmacopoeias; and • Systematic reviews.

Example of Scientific indication: • May help reduce effects of mild anxiety

Qualifier Action Target

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When evidence isn’t really evidence

Website Disclaimer (2012) ‘information contained in Hyperhealth are based on abstracts of peer-reviewed research. ..... authors of Hyperhealth have not scrutinized the full text associated with the abstracts cited in Hyperhealth ....’

Naturopathic Doctor News & Review Articles to support libido claims

Website database

Website

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Evidential Support Required – GOVERNED by the specificity of the indication

Traditionally used to assist with general health and well being - Non-specific generalised indication and type of evidential support is broad - Unlikely to be dependant on dosage form (tablet vs capsule) - Monographs/pharmacopoeias/written histories of use Traditionally used in Western herbal medicine to reduce the number of hot flushes - Specific traditional indication relevant evidence of traditional use - Evidence: Same preparation type, similar dose - Monographs/pharmacopoeias (combined collection of Evidence of traditional use) May reduce the number of hot flushes - Specific Scientific indication relevant and high quality scientific required - Evidence: Same preparation type, same dose & dosage form - Clinical studies, in vitro studies (collection of scientific evidence) Scientifically tested to reduce the number of hot flushes by up to 20% - Very specific scientific indication relevant and high quality scientific required that demonstrates a

balanced view of the available literature - Evidence: Same preparation type, same dose & dosage form (capsule vs tablet)

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Evidence of Traditional use – Preparations, Dosage form Indication: Traditionally used to increase energy levels (Coffea arabica) Medicine Ingredient: Caffeine, water extract, capsule 100mg/day Evidence: water extract, tablet 200mg/day [justification for different dose & form] General principles of int. GLs are NA for herbal products, but overarching principles could assist for well characterised constituents (eg. Constituents that are highly water soluble) . Considerations: Comparisons of solubility/dissolution characteristics similar? Indication: Traditionally used in herbal medicine to assist with minor inflammatory conditions Medicine Ingredient: Dandelion root (Taraxaci radix), methanol extract, equivalent to 5g fresh Evidence: water extract of root [justification for different preparation] Eg. At same [root extract ]: in vitro inhibitory test leukotriene b4 formation (inflammation marker) methanol or butanol extract 90% ↓ cf. Ethylacetate or water extract 20-30% ↓ (ESCOP) Different Preparations, solvents & manufacturing procedure may affect the spectrum of components obtained from a given amount different therapeutic benefits. http://www.tga.gov.au/industry/cm-herbal-extracts-equivalence.htm http://www.tga.gov.au/pdf/euguide/ewp140198rev1.pdf

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Scientific Evidence and use of the term ‘Clinically’ - depends on the implied meaning of the indication & overall presentation Clinically proven, shown, trialled, tested

- Claims infers a level of scientific certainty that the medicine has been clinically trialled and proven to have therapeutic efficacy. Only acceptable when supported unequivocally by robustly designed, published PR clinical trial(s) conducted upon the actual medicine, or an identical formulation and dose (as a minimum).

- Consumers – implied meanings of different terms are likely to be considered similar - What’s the implied meaning of the indication & presentation ≡ Evidence held?

Clinically tested to reduce body weight by 10% – very specific indication inferring proven results for the medicine (analogous to clinically proven), will need specific evidence to support claim

Clinically tested to support immune function – generic indication where all ingredients would need

to be clinically tested AND shown to have positive results on immune function Clinically proven formula containing ginger to reduce nausea – specific indication where the entire

formulation has been clinically shown to reduce nausea.

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Examples of irrelevant evidence – Evidence of Traditional use Indication: Traditionally used in Chinese herbal medicine to warm the middle burner and assist with nausea (Ginger; Rhizoma Zingiberis; sheng jiang) Medicine Ingredient: Ginger root, 1g equiv dried root /day/capsule, aq ext. Dose 1 capsule/day Evidence: Materia Medica (Chinese Herbal Medicine) – Raw Ginger used traditionally to disperse cold,

exterior cold patterns. Dose 3-9g fresh herb Concern: Dose inconsistency with no justification Consideration: Increase dosage directions of the medicine 3 capsules/day Indi cation: Traditionally used in herbal medicine to help fight infections (Siberian ginseng)

Medicine Ingredient: Siberian ginseng (Eleutherococcus senticosus), 1g equiv dried root /day, aq ext. Evidence: WHO monograph - Siberian ginseng being traditionally used as a tonic for lowered immunity.

Should discontinue use during acute infections, unless used in conjunction with powerful antimicrobial therapy.

Inconsistent: Evidence suggests that herb is contraindicated to fight acute infections. Consideration: Traditionally used in herbal medicine as an immune tonic

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Evidence of Traditional use - formulations Indication: Traditionally used in Chinese herbal medicine to clear heat from the lung, resolve phelgm and relieve cough Indication: Does it refer to pharmacological effects not envisaged within the specified paradigm (eg. Raised haemoglobin levels) Medicine formulation:

• Follows principles of traditional Chinese Medicine composition with Chief, minister, assistant, envoy herbs

• Change in the formulation – is this justified, substituting assistant or envoy herbs • Dose differences can it be justified, ie by the use of a formulation with synergistic herbs • Are the herbs contraindicated for the specified therapeutic benefit

Evidence:

• Materia Medica (Chinese Herbal Medicine), • The practice of Chinese medicine

Example: Scientific Evidence – Systematic review – good quality Evidence: Cochrane Review: Serenoa repens (SR) for Benign Prostatic Hyperplasia (BPH) (2009 and 2012)

• For symptomatic relief of urinary BPH – phytotherapies has been growing steadily in most Western

countries (mainly US and Europe) for the relief of mild-moderate urinary obstructive symptoms.

Results: • 32 studies (>5000 men), 4-72 weeks duration, mean age ~65years with lower urinary tract symptoms • Included studies had low level risks of bias (e.g. randomisation(95%), concealment(48%), double-

blinded(84%), limited attrition bias) • Use of validated international urologic symptoms scoring systems Of the studies included • SR alone (with placebo arm:17 trials) or with other medicines/phytotherapies (pumpkin seeds, nettle root) • 15 RCT Powered trials (n≥100) smaller CI ↑ statistical evidence in 2012 review cf. 2009 review • Use of validated scoring systems in more recent studies, thereby greater confidence in data Conclusions: In clinical studies, SR was not superior than placebo for the symptomatic relief of BPH

15 Tacklind J, et al (2012)The Cochrane Library, Issue 12, Art No. CD001423. DOI:10.1002/14651858.CD001423.pub3

Example: Evidence of Traditional Use Indication: Traditionally used in Herbal medicine to relieve symptoms associated with “medically-diagnosed”

benign prostate hyperplasia

Evidence: Saw Palmetto (Serenoa repens (SR)) for symptomatic relief Benign Prostate Hyperplasia (BPH); Health Canada (2010), Kings (1898); WHO monograph (2004)

• The liposterolic extract of saw palmetto berries (containing 85%-95% fatty acids and sterols) at oral dose of <400mg daily.

History of use (>75 years):

• In traditional texts references are made to its ability to reduce hypertrophy of the prostate (King’s); remedy for prostatic irritation and relaxation of tissue rather than for a hypertrophied prostate.

• Symptoms include: weak urine flow, incomplete voiding, frequent night time urination

• Postulated MOA Increase tonus of bladder better bladder contraction ↓ irritation

Inconsistent:

• With current balanced view of scientific evidence carefully worded traditional indications are only applicable to ensure that evidence supporting indication is clearly articulated to consumer.

16 King's American Dispensatory, 1898, was written by Harvey Wickes Felter, M.D., and John Uri Lloyd, Phr. M., Ph. D.

Guidance documents for Evidence reviews Clinical Practice National Health & Medical Research Council (2003). Clinical Practice Guidelines for the Management of Overweight and Obesity in Adults. Canberra. National Health & Medical Research Council (2009). Levels of evidence and grades for recommendations for developers of guidelines. Canberra. Schulz, KF et al (2010). CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomized Trials. Annals of Internal Medicine. 152. Kirby A et al (2002). Determining sample size in a clinical trial. Med J Aust 177(5): 256-257. Lovejoy JC and Sinsbury A (2008). Sex differences in Obesity and the regulation of energy homeostasis. Obesity Reviews 10: 154-167. Therapeutic Goods Administration (international and national guidelines) – website for Therapeutic Goods Administration Note for guidance on Good Clinical Practice (CPMP/ICH/135/95) & Note for guidance on Quality of Herbal Medicinal Products Various EMEA guidelines adopted by the TGA Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Guidelines for levels and kinds of evidence to support indications and claims (2011) Monographs European Scientific Co-operative on Phytotherapy (ESCOP) series (1996) – The scientific foundation for herbal medicinal products, ESCOP, Exeter. Health Canada Monographs. Blumenthal M et al (eds) (2000). Herbal Medicine – Expanded Commission E monographs, American Botanical Council, Austin, Texas. World Health Organization (WHO) (1999). Monographs on Selected Medicinal Plants, Vol 1-4, WHO, Geneva.

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Does the indication match the evidence? Scientific indications are supported by scientific evidence Traditional indications are derived from a tradition of use within a paradigm Format of 2 types of indications are different on the medicine label According to the current Evidence Guidelines1

Is the evidence relevant? • Equivalent doses; plant part

Is it high quality evidence?

• Systematic reviews, methodological sound

Is it a balanced view?

• Positive evidence > equivocal/negative

19 1 Guidelines for levels and kinds of evidence to support indications and claims (2011)

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Indication: Scientifically trialled to suppress appetite and assist weight loss (Caralluma fimbriata) Evidence: RCT designed to measure the effect on appetite and weight loss in overweight individuals (t=60d)

Results:

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T = 60 days Treatment [baseline] Placebo

Bodyweight (kg) -2kg [-2.5%] (not ss) -1kg [-1.3%]

% hunger cf baseline -47.6±22.6% -27.9±18.8%

Methodologically deficiencies:

• Appetite studied as a composite of 4 parameters: Hunger, urge to eat, fullness of stomach & thought of food using a validated VAS. Timing of scoring was different (t=0, 30, 60d). Only %hunger ss ↓ at d=60 (not d=30). No ss ↓ in other parameters (all relevant to appetite)

• No run-in period reported thus stability of baseline characteristics of groups are unclear

• The effect of altering 3 variables; treatment/diet/exercise

Considerations: Change indications to be consistent with the evidence held

Kuriyan R, Raj T, Srinivas SK, Vaz M, Rajendran R, A Kurpad. (2007) Effect of Caralluma fimbriata extract on appetite, food intake and ant hropometry in adult Indian men and women. Appetite 48. 338-344.

Example: Poorer Quality Evidence: Methodological deficiencies

Example: Methodological deficiencies and clinically proven claims Indication: Clinically proven to reduce BMI (Svetol®, green coffee extract ) Evidence: RCT to examine the effects of Svetol® (similar formulation) on weight loss and BMI in overweight subjects

(BMI >25kg/m2, t=60 days); Clinical proven claims = exact formulation

Results:

Methodologically deficiencies: • No run-in period - effects of diet/exercise unclear, no dietary or treatment compliance data • Baseline characteristics; age, sex comparability between groups not reported • Clinical significance of 2.52 kg weight loss over 2 months (300g/wk) compared to control

Options: Remove ‘Clinically proven to reduce BMI’ or provide further evidence to support the indication

21 Dellalibera et al (2006) Svetol, green coffee extract, induces weight loss and increases lean to fat ration in volunteers with overweight problems. Phytotherapie, 4, 1-4.

T=60 days Treatment (Svetol®, 200mg; 2/day) Placebo (maltodextrin)

Bodyweight (kg) -4.97±0.32 -2.45±0.37

BMI (kg/m2) -1.9±0.1 -0.9±0.1