DRAFT ASEAN COMMON GUIDELINE ON RESEARCH OF HERBAL MEDICINES [As part of TM/CAM]

(Rev se! vers o"# $o"s !er "% t&e "p'ts of (')* +,t& -,+.# Co"s')tat ve /or0s&op# t&e Mer$'re# A"$o)1

Fore2or!
It has been realized by ASEAN Member States that research and development pertaining to Traditional Medicine (TM) is an important issue in order to integrate or to synergize TM into the national health care system !esearch and development is a tool or a step to provide scienti"ic evidence #ith regard o" e""icacy and sa"ety "or human use o" TM "or prevention$ treatment$ or rehabilitation$ o" health problems$ acting as either alternatives or complementary modalities In an e""ort to synchronize on ho# research and development o" TM is conducted amongst ASEAN member state in terms o" methodology$ it is important to develop %Common research guideline of herbal medicines. This guideline covers the essential principles o" research methodology on herbal medicines As the document only covers the essential principles$ each ASEAN Member State can or should "urther elaborate the document in order to ad&ust #ith their needs and local conte't based on their uni(ue traditional medicine and their regulations The )rd ASEAN *ocal +oint o" Traditional Medicine (AT*TM) Meeting recommended that development o" guidelines should be prioritised to the need o" ASEAN and to be in line #ith e'isting guidelines$ such as$ ,eneral ,uidelines "or Methodologies on !esearch and Evaluation on Traditional Medicine (-./ ,uideline) and !eseach ,uidelines "or Evaluating Sa"ety and E""icacy o" .erbal Medicine (-+!/) 0eeping in mind that herbal medicines has already been used in the community "rom one generation to the ne't generation$ the research guideline #ill try to pay attention not only to e""icacy research$ but also the usage pattern research -ith regards to the elaboration o" usage pattern$ the methodologies that can be used are ethnomedicine study$ epidemiological study$ and health system study Mean#hile$ "or proving the e""icacies$ the methodologies that can be used are e'perimental study (randomized controlled trials double blind$ randomized trials open label$ outcome study 1 2e"ore A"ter design$ or case report) *or e""icacy study$ the pipeline o" modern drug development should be "ollo#ed The researches begin #ith pre3clinical study$ phase 1$ phase 4$ and phase ) clinical trials$ and then go to mar5eting approval .o#ever$ "or indigenous herbal medicine$ #hich has enough e""icacy and sa"ety data "rom ethnomedicine and observational study$ the trials can go directly to randomized clinical trials (phase ) clinical trial) In this case$ the e""icacy3driven approach o" clinical trial or reverse pharmacology applies "or indigenous herbal medicine

+age *ore#ord 6ontents I INTRODUCTION 11 14 1) 17 1: 19 2ac5ground /b&ective Scope o" guideline 8e"inition o" Terms !eseach priorities in ASEAN Interrelation bet#een ASEAN common reseach guideline #ith guidelines developed by other #or5ing groups under ASEAN Economic 6ommunity ; ; ; ; ; ; = = 1? 1? 1? 1? 11 11 11 11 11 14 14 14 14 1)
)

4 ) 7 7 7 9

II

GENERAL CONSIDERATIONS IN TM RESEARCH 41 44 4) 47 4: 49 4> <egal consideration Ethical consideration Indigenous 5no#ledge o" TM Natural resources +urposes o" research !esearch approaches E'pected level o" evidence St'!* of 'sa%e patter" Ethnomedicine study Epidemiological study .ealth services study (health system study) St'!* of Eff $a$* a"! Safet* <iterature revie# @uality re(uirements o" plant materials and preparation St'!* of eff $a$* a"! safet* of "e2 &er4s / for5')a +re3clinical study 6linical study +hase 1 clinical trial +hase 4 clinical trial +hase ) clinical trial C) " $a) o't$o5e 5eas're5e"t

III

RESEARCH METHODS ON TM .3+ )11 )14 )1) )4 )41 )44 .3. ))1 ))4 ))41 ))44 ))4) .3.3.

+ost mar5eting surveillance

.3.36 TM IA ANNEB

St'!* of eff $a$* a"! safet* of I"! %e"o's &er4a) 1: 19 1>

USING THE GUIDELINES

2I2<I/,!A+.C

I3

INTRODUCTION

I3+3 Ba$0%ro'"! Traditional medicine (TM) has a long history and used #orld #ide$ ho#ever it varies greatly "rom country to country The practice o" TM is in"luenced by a number o" "actors such as culture$ history$ personal attitudes and philosophy In many cases$ the theory and application o" TM are (uite di""erent "rom those o" conventional medicine Even though it is claimed that TM is sa"e and e""ective as it is used "rom one generation to another generation$ scienti"ic research is still needed "or providing rigorous evidence in relation to e""icacy and sa"ety It has been ac5no#ledged that conventional medicine uses the paradigm o" evidence based3 medicine$ meaning that doctors can only use therapeutic modalities that have been proved by (uali"ied research to apply evidence based medicine principles The (uantity and (uality o" the sa"ety and e""icacy data on traditional medicine are "ar "rom su""icient to meet the criteria needed "or evidence based medicine practices The reasons "or the lac5 o" research data are due not only to health care policies$ but also to a lac5 o" ade(uate or accepted research methodology "or evaluating traditional medicine In order that researchers on herbal medicines have the same perspective and can conduct (uali"ied research$ it is o" importance to establish a common research guideline o" herbal medicines in ASEAN Member States *rom this document$ it is hoped that research on herbal medicines can be synchronized or used as a re"erence in terms o" methodology on herbal medicines research amongst ASEAN Member States DNoteE Addition o" consideration o" -./ and -+!/ guideline This guideline is a mandate "rom the AT*TM .erbal medicine is a modality o" TM16AM I3-3 O47e$t ves To provide Dminimum standards andF common principles in developing ade(uate and accepted research methodology "or researching on herbal medicines as TM16AM modalities in the ASEAN region To provide scienti"ic data to support the development o" appropriate health care system regulation as #ell as a milestone to integrate herbal medicines into the national health care system To ensure the sa"ety and e""icacy o" herbal medicines used in the health care system o" AMS

To strengthen and promote the rational use o" herbal medicines

I3.3

S$ope of G' !e) "e As TM16AM modalities cover a number o" methods such as &erbal medicines$ acupuncture$ massage 1 manipulation$ steam 1 sauna$ spiritual$ e'ercise (yoga)$ and diet$ this guideline is addressing research methodology "or herbal medicines as modalities o" TM16AM

I363

Def " t o" of Ter5s Traditional Medicine is the sum total o" the 5no#ledge$ s5ills and practices based on the theories$ belie"s and e'periences indigenous to di""erent cultures$ used in the maintenance o" health$ as #ell as in the prevention$ diagnosis$ improvement or treatment o" physical and mental illnesses The terms complementary1alternative1non3conventional medicine are used interchangeably #ith traditional medicine in some countries TM16AM consists o" herbal medicine and traditional procedure based therapies .erbal medicine is a medicine that contains either ra# or processed ingredients "rom one or more medicinal plants In some traditions$ materials o" animal origin may also be present .erbs include crude plant material such as leaves$ "lo#ers$ "ruits$ seeds$ stems$ #ood$ bar5$ roots$ rhizomes or others plants parts .erbal medicines in this guideline can be divided into t#o categories$ namelyE

o Traditional herbal medicine is herbal medicine that has been used by a certain community "rom one generation to another generation and become indigenous 5no#ledge and practice o" the community o Ne# herbs or ne# herbal medicine is herbal medicine that is not to be indigenous 5no#ledge and practice o" the community$ or indigenous herbal medicine that is indicated "or ne# symptoms or ne# indication o" health problems D NoteE 6hoice on the use o" GtraditionalH or GindigenousH herbal medicineF

Traditional procedure3based therapies are TM that use various techni(ues primarily #ithout the use o" medication$ i e acupuncture$ massage$ osteopathy$ naturopathy$ chiropractic$ thermal medicine$ etc

!esearch is a systematic investigation to prove the truth by the use o" rigorous research methodology ,uideline is a document to determine a course o" action$ aiming to streamline particular process according to sound practice 6ommon guideline is a principle document to provide common principles that can be elaborated "urther to go more operational

>

I383 Resear$& 9r or t es " ASEAN !esearch priorities "or herbal medicines in ASEAN member states AMS is geared into health problems that to be the priorities in the member states As the characteristics o" herbal medicine are more subtle than modern medicine$ it is advisable that the development o" herbal medicine is to address non communicable diseases and other degenerative diseases$ especilally "or promotive$ preventive$ treatment o" mild to moderate diseases or ad&unctive therapies$ as #ell as pallitaive and rehabilitative therapy

+3:3

I"terre)at o" 4et2ee" ASEAN Co55o" Resear$& G' !e) "e 2 t& G' !e) "es Deve)ope! 4* Ot&er /or0 "% Gro'ps '"!er ASEAN E$o"o5 $ Co55'" t* 9 ))ar [Note: input from the 3rd ATFTM Meeting: To engage other related sectoral working group in the upcoming consultation workshop] [Note: Include one para how this guideline complements other guidelines, another para on the issue of claims in connection with commercial product orientation ]

II3

GENERAL CONSIDERATION IN TM RESEARCH

II3+3 Le%a) $o"s !erat o" AMS should promote the rational use o" herbal TM that has been scienti"ically validated To do so$ AMS should set a national policy "or "acilitating research and rational use o" herbal TM Education and training o" herbal TM either "or health pro"essionals and traditional healers are needed and should be standardized to obtain certain level o" competencies !egistration o" TM practitioners is very important as part o" national policy to guarantee the rational use o" herbal TM DNoteE Include inputs "rom +ro" Agus$ regarding the e'isting situation o" TM16AM #hether tolerant$ inclusive$ or integrative$ as this #ill implicate to research methodsF II3-3 Et& $a) $o"s !erat o" !esearch on herbal TM has to be carried out in accordance #ith all relevant ethical guideline either "or animals and human beings !esearch on animals must be carried out #ith respect to their #el"are !esearch on human sub&ects must be carried out in accordance #ith "our basic ethical principles$ i e &ustice$ respect "or persons$ bene"icence and autonomy It is advisable that "or research in traditional medicine$ including herbal medicines$ the Ministry o" .ealth research institutes could develop special Ethical 6ommitee o" .ealth !esearch "or Traditional and 6omplementary Medicine II3.3 I"! %e"o's 0"o2)e!%e of &er4a) TM .erbal TM has been used by traditional system o" health care "rom one generation to another +rolonged use o" herbal TM may prove the sa"ety and e""icacy There"ore$ the research approach could should be di""erent bet#een indigenous herbal medicines and the herbal medicine that has not been indigenously practiced in the community (ne# herbs or ne# "ormulas) Traditional medicines are usually an integral part o" culture$ #hich #as already established #ithin certain ethnic group be"ore the development o" modern science !espect "or the principle o" TM practice (indigenous 5no#ledge) under study must be ta5en into consideration To appreciate the cultural aspects and local #isdom o" traditional medicine practice$ the ethnomedicine study approach should be done

DNoteE Include inputs "rom +ro" Agus on 2ody o" 0no#ledge$ as basically research on traditional medicine is raise %indigenous medicineI to be %6AM modalitiesI #ith better evidenceF II363 Nat'ra) Reso'r$es ASEAN tropical geographic areas have a #ealth o" biological resources Aarious 5inds o" medicinal plants can gro# and produce the best (uality "or herbal ra# materials ASEAN can be the locomotive o" traditional medicine development not only as support "or the abundant natural resources$ but also as a mar5et having tremendous potential There"ore$ research on medicinal plants should be carried out "or better health o" the people DNoteE Traditional herbs and ne# herbs should be inserted as AMS resourcesF II383 9'rposes of resear$& !esearch on TM may be &usti"ied by a number o" reasons The most important reason to do research on TM is to evaluate the sa"ety and e""icacy o" TM practice *or herbal medicines$ the research is conducted to validate a ne#3"ound plant material or a ne# combination o" herbal medicines$ or even a ne# indication$ a ne# dosage "orm$ or a ne# administrative route "or e'isting herbal medicines$ as #eel as to validate the indigenous practice o" herbal medicine in the community .erbal materials Simplicia$ semi3puri"ied$ or puri"ied herbal medicines may also be used "or research The re(uirement o" evidence (the level o" evidence) to sa"ety and e""icacy o" TM practice should be ad&usted in terms o" research methodologies in accordance #ith the purpose o" research DNoteE To raise indigenous 5no#ledge to 6AM 5no#ledge #ith better evidence$ 6hec5 "or terms o" simplicia$ completed #ith t#o domains o" TM16AM research i e research o" usage and research o" e""icacyF II3:3 Resear$& approa$&es !esearch on herbal TM has generally been carried out by individual researchers #or5ing independently /ne researcher may conduct research on to'icology$ but another researcher may conduct research directly on human studies This un3 systematic$ scattered$ and isolated research approach is not e""ective "or providing evidence o" sa"ety and e""icacy A more systematic approach should be done "or conducting research on TM T&e f rst step is research to collect data (in"ormation) or literature revie# regarding t&e 'se of TM " $o55'" t* #ithin its indigenous system (traditional system) *or this purpose$ the methodologies that can be used$ "or instance$ ethnomedicine study$ epidemiology study$ and health services (health system) study T&e se$o"! step is research to eva)'ate t&e safet* a"! eff $a$* of TM *or this purpose$ research should be conducted in se(uence$ begin #ith pre3clinical study and human study
1?

(phase 1$ phase 4A$ phase 4 2 and phase ) clinical trials) .o#ever$ "or indigenous herbal medicine that had have empirical data "rom ethnomedicine study and observational study the approach o" reverse pharmacology or e""icacy driven research can be conducted 6onsider that research on TM re(uires an ade(uate budget$ in accordance #ith the conditions o" each AMS$ it is necessary to "ormulate the !esearch Agenda #hich contains research priorities !esearch priorities on traditional herbal medicine should consider the bene"its o" overcoming ma&or health problemsJ people1communities are able to maintain their health by using medicinal plantsJ medicinal plants that could potentially develop as modern medicineJ and able to accelerate the peopleKs economy and compete in global mar5et The development o" guideline #ill also be supplemented by the needs o" individual AMS consider the need o" ASEAN Member States as #ell as the availability and comprehensiveness o" e'isting guideline DNoteE !esearch approach should capture ob&ectives 3 Ne# herbsE +re clinical study$ phase 1$ phase 4 a (preliminary$ or early e""icacy trial) and 4b (as one shot e""icacy trial$ advance e""icacy trial) 3 Indigenous herbsE use reverse pharmacology$ enough to do one shot e""icacy trial 3 Need to de"ine reverse pharmacology 3 +ut the last sentence in the bac5ground The development bla bla

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II3;3

Appropr ate E<pe$te! Leve) of Ev !e"$e

The are a number o" re"erences on ho# to categorize the level o" evidence as to support clinical decision in evidence base medicine practice .o#ever$ the /'"ord 6enter "or Evidence 2ased Medicine categorize the level o" scienti"ic evidence "or therapy and prevention as "ollo#s (Table 1) Table 1 Leve) ev !e"$e 1A 12 4A 42

of T*pe of ev !e"$e

Systematic revie# o" !andomized 6ontrolled Trials Individual !andomized 6ontrolled Trial (#ell3designed) Systematic revie# o" cohort studies Individual cohort study (including lo# (uality !6T i e !6T open label) 46 /utcome study or study #ithout control (2e"ore1 A"ter design)$ ecological study$ and (uasi e'perimental study )A Individual case control study )2 Systematic revie# o" case control studies 7 6ase series or case reports$ poor (uality o" cohort 1 case control studies : E'pert opinion DNoteE Ac5no#ledge the source 3 Modi"y and ad&ust table 1 #ith the content o" methodology discussed$ so there is a lin5 bet#een the table and the "ollo#ing discussion) 3 2u Indah create another table that can "it level o" evidence o" TM16AM (herbal medicines) 3 Insert ne# para that eventhough the level o" evidence is not as po#er as conventional medicined the status o" TM16AM is e(ual #ith conventional one as TM16AM is indicated more on prevention$ promotion$ mild disease$ and rehabilitati"1 palliative as to complement conventional one As there are many challenges and obstacle o" doing #ell3designed !6T in traditional herbal medicine (due to traditional preparation o" testing materials$ li5e simplicia$ poeders$ etc)$ it is advisable that the level o" evidence to achieve in herbal medicines e""icacy research is #ithin the range o" 42 untill : .o#ever$ i" the preparation o" herbal medicines can be "ormed in modern types (tablets$ capsule$ etc)$ the #ell3 designed !6T research can be conducted$ and there"ore the level o" evidence 1A can be achieved DNoteE Include under e'pected level o" evidenceE relation o" evidence #ith therapeutic claims #hich con"orm #ith *8A regulation$ particularly products that #ill be mar5eted 3 *irst sentence under table to be re#rittenF 3 3
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III3

RESEARCH METHODS ON TM

[Note= 9 $t're " A""e< I to 4e p)a$e! &ere a"! starte! 2 t& so5e para333 as "tro33] III3+3 St'!* of 'sa%e patter"

Study o" usage pattern is basically to identi"y the usage o" TM #ithin indigenous health system This study is very important to collect data (in"ormation) that can be used as base3line data "or "urther research to validate its sa"ety and e""icacy The study o" usage pattern may use ethnomedicine study$ epidemiological study$ and health services study (health system study) III3+3+3 Et&"o5e! $ "e st'!* Ethnomedicine is the study o" ho# di""erent cultures vie# disease and ho# they treat or prevent it$ including the medical belie"s and practices o" indigenous cultures Ethnomedicine study is very importance to collect base3line data regarding indigenous practice o" TM Ethnomedicine can apply either "or herbal medicine practice or "or procedure3based practice 2y conducting ethnomedicine study$ "or herbal medicines$ it can be identi"ied the species medicinal plants that can be used "or traditional medicine practice$ as #ell as$ part o" plants used$ ho# to prepare$ dosage (posology)$ indications$ etc *or procedure3based practice$ it can be identi"ied ho# traditional healers treat the patients #ith procedure3based techni(ue$ "or e'ample$ massage$ energy trans"er$ spiritual$ manipulation$ etc The research methods "or ethnomedicine study basically use (ualitative approach$ #hich utilize indepth intervie#$ "ocus group discussion$ participatory observation$ as #ell as$ arte"act in(uiry$ as data collection methods It sholud be accentuated that #ithin the ethnomedicine study the researchers are the learners and the in"ormans (respondents) are the e'perts .ere (ualitative approach o" in(uiry should be considered seriously

III3+3-3 Ep !e5 o)o% $a) st'!* Epidemiology is the study o" the "actors determining and in"luencing the "re(uency and distribution o" disease$ in&ury$ and other health3related events and their causes in a de"ined human population Epidemiological approach can be used "or TM in
1)

order to obtain in"ormation regarding the usage pattern o" TM in a de"ined population (community) *rom this study$ #e can identi"y the prevalence o" TM usage in the community and "actors that in"luence the usage o" TM in the community The study covers both descriptive and analytic studies$ depending on the ob&ectives o" the study This data (in"ormation) is very important to provide the magnitude o" issue (the usage o" TM)$ pattern o" usage$ as #ell as$ "actors that in"luence the usage o" TM

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III3+3.3 Hea)t& serv $es st'!* (&ea)t& s*ste5 st'!*1 .ealth services study$ or health system study$ is the study upon health care system$ especially #ith regard o" e""iciency and e""ectiveness o" the health care system$ as integral part o" socio3economic development "or population health as a #hole .ealth system study is very important to get macro perspective o" the health care system and identi"y its role "or improving health status o" the community In these terms$ it includes health policy research .ealth system research usually "ocuses on health problem o" priority$ action oriented$ multi3discipline$ client oriented$ timely conducted$ simple$ and the results are delivered to clients (policy ma5ers) .ealth system research on TM$ "or instance$ are cost3e""ectiveness analysis study$ study on management and policy o" TM$ study on regulation o" TM$ etc$ #hich are o" importance "or policy ma5ers "or the improvement o" program development III3-3 St'!* of Eff $a$* a"! Safet*

Study o" e""icacy and sa"ety is very important to guarantee the rational use o" TM in accordance #ith evidence3based medicine principle Study o" e""icacy and sa"ety begins #ith pre3clinical study (in3vitro and animal study) and continue #ith human study (clinical study) Animal study is important to obtain data regarding the potency o" clinical importance (e""icacy)$ pharmaco5inetics and pharmacodynamic pro"ile$ as #ell as$ sa"ety (acute to'icity$ sub3acute to'icity) .uman study (phase 1$ phase 4$ and phase ) clinical trials) is important to provide data on e""icacy "or certain indication .o#ever$ as herbal medicines constitues o" multiconstituents o" chemical compounds$ pharmaco5inetics study can be ommited or #aived

III3-3+3 L terat're rev e2 In assessing the sa"ety and1or e""icacy o" TM$ #hether herbal medicines or procedure3based therapies$ the "irst step is to conduct an evaluation o" literature reports The literature search should include re"erence boo5s$ revie# articles$ systematic surveillance o" primary sources$ database searches$ and systematic revie# It should be 5ept in mind$ ho#ever$ that re"erence boo5s and revie# articles might contain inaccurate in"ormation Nevertheless$ these sources #ill cite primary re"erences that can be consulted "or in3depth analysis The search pro"ile used should be recorded$ as should be details o" any re"erences cited$ #hether or not they are available *or herbal medicines$ the literature search should then be e'tended to gather in"ormation on closely related plant species "or chemota'onomic correlation [Note= "$)'!e 5eta>a"a)*s s as o"e 5et&o!o)o%* to stre"%t&e" t&e ev !e"$e "serte! after .3.3-363 e% post 5ar0et "% s'rva ))a"$e] III3-3-3 ?'a) t* re@' re5e"ts of p)a"t 5ater a)s a"! preparat o"
1:

!esearch on traditional herbal medicine must speci"y the (uality re(uirement o" plant materials or the prepapartion to be investigated There"ore$ the study results o" one researcher can be veri"ied by another researchers DNoteE Statement on (uality o" plant materials should be "ully pharmaceutically standardized$ stablility test and other re(uirements as e'planation para e'plaining the pictureF The (uality re(uirements o" herbal medicine as testing materials "or clinical research are basically as "ollo#s (+icture 4)

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.eavy metal contaminants (As$ +b$ 6d) Microbe counts

Aalidation o" herbal medicine prepartions

6ontamination o" other subtances /rganoleptic test

+esticide residues Identi"ying components

@uality Assurance o" herbal medicine preparations "or clinical research

Macroscopic and microscopic test 6hemical content Ash content

6hromatographic pro"ile (,6MS *inger printing) E'tract content

9 $t're + @uality re(uirements o" herbal medicine as testing materials "or clinical research DNoteE crude herbs "ollo# hebal pharmacopeia$ modern preparation (tab$ capsule) re(uire standard o" modern preparationF III3.3 St'!* of eff $a$* a"! safet* of "e2 &er4s / for5')a

III3.3+3 9re>$) " $a) st'!* +re3clinical study on TM is very important to provide in"ormation on sa"ety (to'icity) and pharmacological pro"iles 1) To'icity study is to evaluate the sa"ety o" TM on animals - Acute to'icity$ to evaluate detrimental e""ects o" TM #ithin 47 hours in animal study - Sub3chronic to'icity$ to evaluate detrimental e""ects o" TM a"ter the administration o" TM #ithin 13) months period in animal study - 6hronic to'icity "or long term use herbs ("or e'ample 8M) L 9 months - Special to'icity$ to evaluate mutagenic$ carcinogenic and teratogecic e""ect in animal study *or special to'icity$ it depends on the people to be the target o" indication 4) +harmacological study$ to evaluate pharmaco5inetics and pharmacodynamics pro"ile o" TM in animal study +harmaco5inetics is to evaluate the adsorbtion$ distribution$ metabolism$ and e'cretion o" TM (herbal medicines) +harmacodinamics is to evaluate the e""ect o" TM on human body (clinical importance) .o#ever$ "or compound herbal medicine$ it is di""icult to evaluate pharmaco5inetic pro"ile as there are hundreds o" chemical substances in compound herbal medicines There"ore$ "or herbal medicine the study o" pharmaco5inetics can be ommited or #aived *or ne# compound herbal
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medicines$ it is proposed that the evaluation o" pharmacodynamic e""ects on animal is very importance to identi"y the bene"it o" the compound "or clinical indications III3.3-3 C) " $a) st'!* 6linical study is important to provide data regarding e""icacy and sa"ety o" TM on human beings (on clinical use) III3.3-3+3 9&ase + C) " $a) Tr a)

-ith regards to TM that has been established in traditional health care system "rom one generation to the ne't$ the phase 1 clinical trial can be #aived It means that the clinical trial can go directly to phase ) clinical trial (see reverse pharmacology "or indigenous herbal medicine research) +hase 1 clinical trial is a trial given to 4?3)? volunteers (usually healthy persons) 2asically phase 1 clinical trial is to obtain data o" (i) sa"ety pro"ile o" TM intervention$ (ii) to evaluate the relation bet#een dosage and pharmacological e""ects (posology) *or herbal medicines$ the pharmaco5inetics study can be #aived$ as herbal medicine is consisting hundreds o" chemical substances It #ould be di""icult to decide #hich substances should be traced "or pharmaco5inetic study There"ore$ phase 1 clinial trial o" herbal medicines is to address the issue o" sa"ety and pharmacodynamic e""ects III3.3-3-3 9&ase -A C) " $a) Tr a)

+hase 4 clinical trials are aimed to evaluate the sa"ety and early e""icacy o" TM in human study +hase 4 clinical trial uses a bigger sample (1??3)?? sub&ects) The best design is !andomized 6ontrolled Trial (!6T) double blinds 2y using this design$ the study can control the bias (sampling bias and intervention bias) *or TM$ ho#ever it sometimes di""icult to conduct double blinds !6T design There"ore$ "or TM it is enough to have the design o" !6T #ithout blinding (a randomized open label clinical trial) 2ut$ "or modern preparation types o" herbal mdecinice li5e tablets or capsules$ it is still possible to implement a randomized double blind clinical trial DNoteE 4 options$ 1st option another term "or herbal medicine early e""icacy trial$ 4nd still use the +hase 4a and 4b but rede"ine the terms$ - Add another e'planation paragraph - 4nd option rede"ining phase 4A "or herbal medicinesF III3.3-3.3 9&ase -B . C) " $a) Tr a)s

+hase ) clinical trial is aimed to evaluate the sa"ety and e""icacy o" TM in the real clinical setting In phase 4 clinical trial$ the trial is done in closely controlled setting$ in terms that everything is under strict control /n the contrary$ phase ) clinical trials are done in the real clinical setting$ to obtain the data o" sa"ety and e""icacy "or real health care services *or conducting phase ) clinical trials$ multicenter study is applied The best design is !andomized 6ontrolled Trial (!6T) double blinds As
1;

again$ it is di""icult to conduct double blinds !6T design$ there"ore$ "or traditional herbal medicine$ it is enough to apply the design o" !6T #ithout blinding (an open label randomized trial) 2ut$ "or modern preparation types o" herbal mdecinice li5e tablets or capsules$ it is still possible to implement a randomized double blind clinical trial DNoteE need to rede"ine phase 42 6linical Trial "or herbal medicineF III3.3-363 9ost 5ar0et "% s'rve ))a"$e -ill be "illed later based on agreement D 8r 0anchitE -here possible and applicable$ post mar5eting surveillance "or drug side e""ect should be applied by the *8A authorityF III3.3.3 C) " $a) O't$o5e Meas're5e"t The proponents o" TM argue that the philosophy o" TM is di""erent #ith that o" modern medicine (allopathic medicine) The philosophy o" TM is holistic medicine 8iseases are seen as imbalance (dis3ease) o" the #hole individuals #ith their environment 8isease is seen as multi"actorial and comple' interaction o" the psycho$ body$ mind$ spirit$ and environments The modalities o" therapy (herbal medicines and procedure3based therapies) are trying to normalize the individuals by promoting the potency o" healing by the individuals themselves *or these reasons$ the clinical outcome variables "or clinical trials should ta5e into consideration not only ob&ective parameters but also ta5e into consideration sub&ective parameters The ob&ective parameters are basically the parameters that are measured by medical devices and laboratory analysis to obtain clinical parameters "rom e'pert vie# (health pro"essionals) *rom anthropological perspective$ this 5ind o" variables are named etic (without h) perspective$ meaning #hat the e'pert vie# regarding %the diseaseI /b&ective parameters$ to mention$ are blood pressure$ body #eight$ body temperature$ radiologic e'amination$ blood pathologic parameters$ chemical analysis$ and the li5e .o#ever$ "or holistic approach$ sub&ective parameters are also o" importance outcome The sub&ective parameters are basically the parameters that are e'plored "rom the perspective o" the patient by structured (uestionnaire$ semi3structured (uestionnaire$ or un3 structured (uestionnaire 8isease score improvement$ (uestionnaire o" (uality o" li"e (-./ @uality o" <i"e)$ as #ell as$ #ellness inde' (uestionnaire (Short *orm )9$ Short *orm 47) are e'amples o" structured (uestionnaire Semi3structured or un3structured (uestionnaire to e'plore %#hat the patient "eel and e'perienceI a"ter obtaining herbal medicine treatment is very important to obtain (ualitative data *rom anthropological perspective$ the in"ormation (not variables as in (uantitative perspective) is veru use"ul to get an emic vie# o" %the illnessI Emic perspective is basically #hat the patients vie# about %the illnessI they are su""ering *or e'ample$ by e'ploring (probing) #hat they "eel a"ter consuming herbal medicine$ ho# is their sleep$ ho# is their appetite$ ho# is their bo#el "unction$ ho# their urinary "unction$ ho# is their "amily li"e$ and so on This narrative in"ormation ((ualitative in"ormation) #ill complement the (uantitative variables (ob&ective parameters)
1=

DNoteE Therapeutic claim to be mentioned here Add more e'planation on etic and emic perspectives as a holistic measurementF

III3.363 St'!* of eff $a$* a"! safet* of "! %e"o's &er4a) TM *or the study o" e""icacy and sa"ety o" indigenous herbal TM$ the method that can be used is e""icacy driven research method In some o" the literatures$ e""icacy driven research method is called reverse pharmacology 2asically$ the study starts #ith ethnomedicine study (study #ithin the conte't that the TM is used and practiced)$ then to see the e""icacy and sa"ety #ithin the conte't o" community is done an observational study$ e g to see the e""icacy and sa"ety #ithin the conte't o" indigenous practice I" there is a potency o" e""icacy and sa"ety$ the study can go directly to phase 4 clinical trial or go directly to phase ) clinical trials It depend to #hat e'tent the evidence obtained "rom obervational study (clinical observation)

4?

The "lo# o" e""icacy driven research in Indigenous herbal herbal medicine as compared to conventional pharmaceutical development is as illustrated in +icture 1

6onventional pharmaceutical development

E""icacy driven research "or indigenous herbal medicine

9 $t're + The "lo# o" e""icacy driven research in Indigenous herbal herbal medicine as compared to conventional pharmaceutical development To conduct a reverse pharmacology study "or indigenous herbal medicine$ the "ollo#ing suggested approach can be considered "or practical implementationE a Ethnomedicine study and anthropological study to obtain the conte't$ philosophical understanding$ dan utilization pattern o" herbal medicines 2asically$ ethonomedicine and anthropological study apply (ualitative approach (constructivism approach) !esearchers are considered as learners$ respondents (in"ormans) as e'perts There"ore$ researchers are to learn the conte't$ the meanings$ the e'perience o" themes being investigated "rom the respondents b /bservational study (clinical observation) "or traditional practitioners to obtain sa"ety data and early e""icacy data The design o" observational study can be e""ectiveness study (#ith more "le'ible design)$ or clinical observation (#ith standardization o" herbal medicine preparation as testing materials)
41

6linical trial study to obtain the e""icacy and sa"ety data in more rigorous method 8epending on the strength o" evidence in observational study$ the trials can go to phase 4 or phase ) clinical trials The consideration o" design is depending on the prior evidence obtained$ the practicality o" trials$ as #ell as the types o" herbal medicine preparation as material testing (crude herbs 1 poeder$ tablets$ capsules$ etc) *or practicality$ a pragmatic clinical trial can be used as an optional design *or crude herbs (simplicia) a randomized$ open label$ clinical trial can be used In "acts$ "or modern preparation (tablets$ capsules)$ a randomized$ double blind$ controlled trial can be conducted .ere$ there is a "le'ibility o" selecting the design depending on the level o" evidence to achieve

44

IA3

USING THE GUIDELINES

This research guideline on TM "or ASEAN countries is a %common guidelineI As a common guideline$ this document is proposed to be used "or synchronizing the research methodology amongst ASEAN member states$ in terms o" basic principles .o#ever$ as the common guideline document$ this document is only covering the important essential principles under agreement amongst ASEAN member states There"ore$ to use this common guideline$ the ASEAN member states can or should "urther elaborate the guideline$ depending on local needs and conte't$ in line #ith member statesH traditional medicine and culture In "acts$ "or researchers o" herbal medicines must elaborate the credible re"erence or te'tboo5 regarding the method being used *or e'ample$ "or ethnomedine method$ the investigator should elaborate the detail method in ethnomedicine methodology resource materials *or epidemilogocal study$ the investigator should e'plore the detail method in epidemiology te'tboo5 *or randomized clinical trial$ the investigator should re"er to randomized clinical trial te'tboo5$ and so on Note= I"p't fro5 I4' I"!a& re%ar! "% a"ot&er ta4)e

4)

A""e< + Steps of Resear$& o" TM St'!* of Use 9atter" Ethnomedicine study Epidemiology study .ealth services research study (health system study)

Indigenous *ormulas /bservational study "or sa"ety and e""icacy +hase 4 clinical trial +hase ) clinical trial +ost3mar5eting survaillance

St'!* of safet* a"! eff $a$*

Ne# .erbs 1 *ormulas +re3clinical study +hase 1 clinical trial +hase 4 clinical trial +hase ) clinical trial +ost3mar5eting survaillance

Evidence o" sa"ety and e""icacy

Integration into national health care system

[Note= I"$)'!e a"ot&er se$t o" o" "for5at o" s&ar "% 4et2ee" AMS]

47

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1 4 ) 7 : 9 > ; = 8esigning and 6onducting .ealth System !esearch -orld .ealth /rganization ,eneva$ 4??) .o""mann$ 8 Medical .erbalism$ The Science and +ractice o" .erbal Medicine .ealing Art +ress$ !ochester3Aermont$ India$ 4??) <ast$ Mohn M +ress$ 4??1 A 8ictionary o" Epidemiology (7ed) Ne# Cor5$ NC /'"ord Nniversity

<e#ith$ Monaa O -alach 6linical !esearch in 6omplementary TherapiesE +rinciples$ +roblems and Solutions 6hurchill <ivingstone$ Eastbourne <ondon$ 4??: Murchison$ M M Ethnography EssentialsE 8esigning$ 6onducting$ and +resenting Cour !esearch Mossey32ass San *rancisco$ 4?1? National +olicy on Traditional Medicines and !egulation o" .erbal Medicines -orld .ealth /rganization ,eneva$ 4??: Scharter$ 2 The Ne# Medicines$ .o# 8rug are 6reated$ Approved$ Mar5eted$ and Sold ,reen#ood +ublishing ,roup -esport$ 6onnecticut$ <ondon$ 4??9 Tang$ M < and <eung$ + 6 An e""icacy3driven approach to the research and development o" Traditional 6hinese Medicine$ .0MM Aol >$ 4??1 -./ ,uidelines on ,ood Agricultural and 6ollection +ractices (,A6+) "or Medicinal +lants -orld .ealth /rganization ,eneva$ 4??)

1? -./ Traditional Medicine Strategy 4??434??: -orld .ealth /rganization ,eneva$ 4??4 11 -./3T8! /perational guidanceE In"ormation needed to support clinical trials o" herbal medicines 14 -isnes5i < A O Anderson < The Scienti"ic 2asis o" Integrative Medicine 6!6 +ress$ Ne# Cor5 4??=

[Overa)) $o55e"t= 5prove t&e "'54er "% te$&" @'e# $ tat o"# $o"s ste"$* of ter5s TM/CAM# &er4a) 5e! $ "es] Note= !'e !ate for f "a) C "% !raft s A'%'st +,t&# -,+.

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