Ethical Issues in Traditional and Alternative Medicine (TAM)

Dr. Pathirage Kamal PereraPhD in Pharmacology (P.R.China)

MSc (USJ), BAMS (Hons.), CTHE (SL), SEDA (UK), Dip in Research and Development of Products to Meet Public Health Needs (Japan)

Senior Lecturer Department of Ayurveda Pharmacology and Pharmaceutics

Head of the Department of Allied SciencesInstitute of Indigenous Medicine, University of Colombo, Rajagiriya, Sri Lanka

Presentation @Forum for Ethical Review Committees in Asia and the Western PacificIn Collaboration with the Sri Lankan Medical Association and the National Science Foundation of Sri LankaHuman Subject Protection Course : Resource person

Learning outcomes

• Define and identify TAM and its outcome 1.

• Analyze research based issues in TAM2.

• Analyze ER issues in TAM3.

• Develop research concept pertain to the TAM 4.

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1.1 Traditional and alternative medicine(TAM)

• Broad categorization of systems of Medicine that do not conform to the standards and practices of Allopathic medicine (Conventional medicine) which is universally recognized as the accepted point of reference for medicine in modern science.

Also referred to as:– Indigenous medicines– Oriental medicine– CAM

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1.2 WHO Recognition of TM

WHO has recognized these systems as a part of health care delivery to the world community and had set guidelines in using them and also in further research.

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1.3 Traditional medicine

The sum total of the knowledge, skills and practicesbased on the theories, beliefs and experiencesindigenous to different cultures, whether explicableor not, used in the maintenance of health, as well asin the prevention, diagnosis, improvement ortreatment of physical and mental illnesses (WHO).

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1.4 Global trend

• There is increased investment in herbal medicine and TAM research by public-health bodies in many countries.

– China, India, Nigeria, the United States of America and WHO have all made substantial research investments in traditional herbal medicines.

In USA, the National Center for Complementary and Alternative Medicine at the National Institutes of Health spent approximately US$ 33 million on herbal medicine research in fiscal year 2005.

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U.S. Department of Health & Human Services7

1.5 TAM practiced in Sri Lanka.

• Ayurveda

• Siddha

• Unani

• Acupuncture

• Homeopathy

• Desheeya chikithsa (Indigenous system of medicine in Sri Lanka)

• Folk medicine[Vaddhas, Ahikuntaka].

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1.6 Sri Lankan TAM Ayurveda and Traditional medicine (Desheeya Chikitsa) has been

practiced in Sri Lanka for more than 3,000 years .

Currently Ayurveda, as defined in the Act, encompasses all medical systems indigenous to Asia, including Siddha and Unani in Sri Lanka.

The most important among them is Ayurveda, which also forms part of the national health services provided by the government of Sri Lanka including separate ministry for Indigenous Medicine.

About 60 to 70% of the rural population relies on traditional and natural medicine for their primary health care (WHO).

Herbal drugs are essential components of primary health care system in Sri Lanka ,But there are very few RCTs has been carried.

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The monastic hospital at Mihintale

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Medicine trough

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Bronze Probes

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Surgical instruments

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Buddhist culture was influenced safe use of medicine in traditional medical system in past

The monastic medical practice14

Auschwitz Nazi Camp: 1943Dr. Josef Mengele (known

as the Angel of Death)

× Children injected with chemical

× Prisoners with deformities – brutal surgeries, amputa8ons

× Female prisoners – sterility and shock treatments

King Buddhadasa (4th century A.D.)

Skilled physician ,surgeon & researcher [Mahavamsa XXXVII: 112ff, 145]

Authorship of Sararthasangrahaya

Establishment of village hospitals

Medical seminaries, eg. at Nalanda [Sankalia 1934 : 70]

How ethical TM in Sri Lanka?

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1.7 Common perceptions about TAM

Had developed over time by trial and error.

Now are time tested.

Part of a cultural heritage.

Some times above perceptions of TAM leading to a vacuum of scientific evidence.

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1.8 Established systems

• Many alternative systems of medicines, are not the result of adoption of practices by trial and error.

• Such TAMs are built on strong and logical fundamentals, though they may belong to a different set of paradigms.

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2. TAM research would differ from conventional Research?

2.1 Holistic Approach

• Atma, mans and Shareera

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2.2 Patient Individualized Treatment Model

• Patients Prakruthi ( body constitution).

• Mental state.

• Sattva, Rajas, Thamas.

• Agni- (Digestive power/Metabolism)

• Diet

• Behavioral aspects

• Environmental influences.

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2.3 Incommensurability of etiological explanations and diagnoses.

Ex: Arthritis

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2.4 Dynamic nature of the treatment protocol.

• Differ according to changes in Prakruthi.

• Change in the disease characteristics.

– Ama and Nirama state. Ex: Rheumatoid arthritis (Ama Vata)

• Change in mental state.

• Change in climate.

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2.5 Incommensurability of treatment approaches

• Chikithsa sutras:

Ex: Stroke

• Shodana and Shamana.

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2.6 Outcome assessments

• Definition of Health

Aims:– Deergayu (longevity)

– Sukayu (Quality of life)

– Hithayu (Peaceful co- existence with society and Nature)

Ex: 1.Balancing prakruthi may be an outcome.

2.Achieving satvika state of mind may be an objective.

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3. TAM research using the conventional Frame work?

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Note: Investigators should be aware of any potential errors that may occur when studying traditional medicine out of context and without reference to its traditional theories and concepts.

3.1 Selection of patients

Ex: Sampling in a Study

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3.2 Issues in Using Placebo .

Flavour(Taste)/ Smell would interfere with outcomes.

Using an Inert Oil in enema (Vasthi, method of purification) could influence outcomes.

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3.3 Blind assessment

• Blind assessment is a critical component of conventional evaluation of therapeutic interventions.

• However, in the evaluation of efficacy of traditional procedure based therapies, it can be difficult, impractical or impossible for the practitioner to be kept ignorant of what treatment the patients are receiving.

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Blinding

Ex:

• How to Blind when Shodhana is Involved.

• Difficult to Blind the physician when using a patient Individualized treatment model.

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3.4 Methodology

• Methodologies for research and evaluation of TAMs should be based on the following basic principles.

– Methodologies should guarantee the safety and efficacy of herbal medicines and traditional procedure-based therapies.

– However, they should not become obstacles to the application and development of traditional medicine.

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3.5 Outcome measures

• As traditional medicine relies on a holistic approach, conventional efficacy assessment measures may not be adequate.

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4. How to overcome issues?

• Understanding the incommensurability of Sciences and providing room to incorporate the fundamental approaches

– In Planning and protocol developments in research

– In Reviewing research

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4.1 Selection of study design

• When conventional concepts of clinical research design difficult to apply the choice of study design should be adopted to fit the fundamentals of TAM.

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4.1.1 Selection of study design

1. RCTs

2. Single-case design

3. Black-box design

4. Ethnographic designing

5. Observational design

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4.1.2. Single-case design (WHO)

• Single-case designs have the advantage of being adaptable to the clinical needs of the patient and the therapeutic approach of the practitioner, but have limitations due to their lack of generalization to other patients.

• For example, single-case designs can evaluate the effectiveness of various specialized acupuncture methods in patients with a variety of individual differences.

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Why case studies are important in TM?

1. Can target specific indications of a therapy

2. "-omics"-based pharmacology or individualized pattern based medicine

3. Confidence to clinicians in traditional medical systems

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4.1.3 Black-box design (WHO)

• The study of traditional medicine can also be undertaken in a “black-box” manner. This means that the treatment and all of its components are delivered as they would be in the usual clinical situation.

• In this type of study, no component of the treatment “package” is isolated and studied independently. This allows the effectiveness of traditional medicine to be determined either within its own theoretical framework or within that of conventional medicine.

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4.2 Patient selection

• The “double classification” method is where subjects primarily meet Western diagnostic criteria and then are further classified according to the TAM system.

• Treatments are delivered according to TAM classification and outcomes are evaluated by criteria for both systems.

• If a traditional indication is being tested it is advised to mention the underlying traditional theories and concepts in the protocol.

• The key requirement is to have stringent inclusion and exclusion criteria so that the indication as well as treatment can be assessed reliably.

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4.3 Randomization

• A double screening recruitment model has been suggested to allow the practitioner to individualize treatments and to ensure the reliable assessment of therapy.

• This is similar to double classification proposed earlier. The subjects are first screened according to modern medicine diagnosis and then categorized according to traditional classification system. The categories proposed can be defined into strata and patients can be equally randomized to the treatment and placebo arm.

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4.4 Blinding

1. Most of interventions can be single blinding, where the therapist but not the patient knows the treatment allocation.

2. Another proposed approach to ensure blinding is that the therapist does not assess the outcome of treatment. The assessment is done by a third person who, like the patient is unaware of the actual intervention received. The cautionary principle is to ensure that the patient does not give the assessor details of the treatment that might unblind the assessor.

3. The inclusion of self-report inventories to assess the outcome is another suggested approach

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5. Current Rules and Regulations

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5.1 Ethical requirement

1. Collaborative partnership

2. Social value

3. Scientific validity

4. Fair subject selection

5. Favourable risk–benefit ratio

6. Independent review

7. Informed consent

8. Respect for subjects

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Ethical requirement Definition

Collaborative partnership Research leadership must include bilateral representation based on mutual respect between equal partners with community advice. It includes a responsibility to invest in the scientific training and capacity-building for ongoing research in a host country where such resources are not well developed.

Social value Knowledge gained from the research should have the potential to lead to new generalizable knowledge or improvements in health. Partners should specify in advance to whom benefits will accrue and in what way.

Scientific validity Research should be designed to produce beneficial and generalizable knowledge. This includes designing research so that it can be feasibly implemented in the settings where it will be conducted.

Fair subject selection Subjects should be selected on the basis of scientific importance, not based on convenience, vulnerability or bias.

Favourable risk–benefit ratio The potential benefits of individual participation should outweigh the risks of participation. Benefits to the community or population being studied should also be optimized. Compelling societal benefit can justify risks to individuals in certain circumstances.

Independent review To maintain the integrity of the research, bodies not tied to the investigators must agree that the risks and potential benefits of the research are justified.

Informed consent Investigators must obtain valid permission for study participation from subjects in a manner that is sensitive to the cultural context in which the study is conducted.

Respect for subjects Researchers should have a plan for how the research results will be disseminated; ensuring participants know their right to withdraw, and monitoring the research for relevant adverse events. 46

Table 1. A comprehensive framework for research ethics

5.2 Experimental studies – Toxicity studies

Category 1: Indigenous herbal medicines

•These can be used freely by the local community or region•No safety data would be required.• If the medicines in this category are introduced into the market or moved beyond the local community or region, their safety has to be reviewed by the established national drug control agency.

Category 2: Herbal medicines in systems

•Used for a long time and have been officially documented.•Review of the safety category is necessary. •If the medicines are in safety categories safety data would not be needed.

Category 3: Modified herbal medicines

•Modified in any way including dose, dosage form, mode of administration, herbal medicinal ingredients, methods of preparation, or medical indications base on categories 1 and 2.•Have to meet the requirements of safety of herbal medicines or requirements for the safety of ‘herbal medicines of uncertainsafety’

Category 4.Imported/exported products with a herbal medicine base

•Require safety data, which have to meet the requirements for safety of herbal medicines or requirements for safety of ‘herbal medicines of uncertain safety’, depending on the safety requirement of the importing/recipient countries.

Ref: Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region, World Health

Organization (WHO), 2004

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5.3 “Operational guidance: information needed to support clinical trials of herbal products” (OG – CTHP)

Ref: World Health Organization. Operational guidance: Information neededto support clinical trials of herbal products. 2005. (document referencewho /TDR/GEN/Guidance/05.1)

OG – CTHP -Conventional modern allopathic medicinal drugs containing a chemically-defined pharmaceutical ingredient, herbal products are, almost always, mixtures of partially or wholly uncharacterized constituents; and that being a mixture provides putative therapeutic advantages of one constituent enhancing the efficacy of one or more others in an additive or synergistic fashion, or of one constituent minimizing the side-effects of others.

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Declaration of theOG – CTHP

1. CTHP has asserted that assessing their efficacy does not require attempts to purify herbal medicines down to single constituents or chemical entities.

2. Phase 1 studies in healthy volunteers are generally unnecessary for most herbal medicines if their substantial prior human use conveys reasonable confidence that these regimens can safely be administered to small numbers of carefully monitored clinical participants in phase 2 trials.

3. Crucial stipulation of the CTHP is that, notwithstanding historical evidence of safety, in both phase 2 clinical trials with small numbers of participants and large phase 3 trials (which include several hundred to several thousand), safety of participants should be assured by a comprehensive literature review as well as by specified protocol provisions .

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5.4 GMP Specified for Crude Substances

(Example in Japan)

(Ref: Course Materials: Research and Development of Products to Meet Public Health Needs ,Nagasaki University)

Appointment of crude drug control manager at each manufacturing plant

SOP for specific procedures for natural products.

Pharmaceutical GMP TM GMP+

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5.5 Clinical Product Development - Overview

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PHARMACEUTICAL INSPECTION CONVENTIONPHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTSANNEXES

ANNEX 7 MANUFACTURE OF HERBAL MEDICINAL PRODUCTSPRINCIPLE

PREMISES

Storage areas

Specifications for starting materials

SAMPLING

QUALITY CONTROL

PIC/S' mission is "to lead the international development, implementation and

maintenance of harmonized Good Manufacturing Practice (GMP) standards and quality

systems of inspectorates in the field of medicinal products."

http://www.picscheme.org/

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The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

Ref: http://www.ich.org

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Conclusion

• Performing RCTs, testing herbal interventions, concepts that go beyond western medical technology and understanding fundamentals may be relevant.

• There is a need to develop and validate a range of measures applicable to modern medicine and TAM

• It could in addition introduce new research methodologies and concepts to the TAM.

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Ethical Review Committee of

Institute of Indigenous Medicine

Established : 2011

(Ref: http://iim.cmb.ac.lk)

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References

UNICEF/UNDP/World Bank/WHO. Operational guidance:

information need to support clinical trials of herbal products.

WHO Special Programme for Research and Training in

Tropical Diseases. TDR/GEN/Guidance/ 05.1.WHO, 2005

C Tilburt , Ted J Kaptchuk. Herbal medicine research and

global health: an ethical analysis. Bulletin of the World Health

Organization 2008; 86:594–599

Guidelines for the Regulation of Herbal Medicines in the

South-East Asia Region, World Health Organization (WHO),

2004 Natural Medicines 8, 57-61

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Thank you!

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