Challenges in Herbal Drug Development -Experiences of the CSIR-NMITLI Project Diabetes)

CSIR-New Millenium Initiative for Technology Leadership of India (NMITLI)

IIIM, Jammu

NBRI, Lucknow

MDRF, Chennai

VSGH, Ahmedabad

TNMC & Bhavan’s SPARC, Mumbai

CSIR-NMITLI, Delhi

Industry Partners:• Zandu, Mumbai

• Dhootpapeshwar, Mumbai

• NPIL, Mumbai

• AVS, Kottakal

• AVN, Madurai

NIMS, Hyderabad

Reverse Pharmacology

The science of

integrating documented clinical/experiential

hits into leads by trans-disciplinary

exploratory studies, and

developing these leads into drug candidates

by experimental and clinical research

Urmila ThatteUrmila Thatte

Professor and Head, Professor and Head,

Department of Clinical Pharmacology, Department of Clinical Pharmacology,

TN Medical College & BYL Nair Ch. Hospital, TN Medical College & BYL Nair Ch. Hospital,

Mumbai Mumbai

Challenges in Herbal Drug Development:

Experiences of the CSIR-NMITLI

Project (Diabetes)

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development

Agenda

1. Defining objectives

Reliance on Traditional or Western medicine?

Differences in philosophy

Direct translation – or interpretation?

Are the disease entities even the same???

Can we expect similar end-points?

Hard or soft targets?

6

Madhu`meha’

Diagnosed on the basis of

urinary symptoms

- Prabhuta Mootrata

- Avila Mootrata

- Madhu eva madhuram

meha

Diabetes mellitus

compromises a group of

common metabolic disorders

that share the phenotype of

hyperglycemia

1. Defining objectives- CSIR NMITLI

Is Madhumeha equivalent to Diabetes mellitus?

1. Defining objectives - CSIR NMITLI

Type 2 Diabetes mellitus

Delay the use of OHA/Insulin

Delay/prevent complications

Adjuvant to anti-diabetic agents

Soft end-points

Adjuvant

8

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development

Agenda

Paucity of published data

Indigenous Clinical Practice not

well documented

Information in regional

languages - needs correct

“interpretation”

2. Selection of Plants

2. Selection of Plants - CSIR NMITLI

Long history of use

References in Ayurvedic literature

Discussion with Ayurvedic Experts

6 plants identified

Lead Formulations identified -CSIR NMITLI

• DM-FN 02

(single plant)

• DM-FN 01

(2 plant FDC)

Ayurvedic literature plenty: prescribed in madhumeha

No recent publications on FDC – single plants described

Only one reference in recent nighantu

Widely used in selected regions of country

A few recent publications

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1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development

Agenda

3. Chemistry, Manufacturing, Control

Identification, authentication and

continuous supply of raw material: Good

Agricultural Practice

Quality control systems for raw material,

drug substance and formulation

Specifications not available: which

marker to use?

Bioassay guided standardization?

3. Chemistry, Manufacturing, Control - CSIR NMITLI

Raw material

Identification, collection, authentication

Pharmacognosy

1. Which marker to use and

2. What specs to lay down?

3. Chemistry, Manufacturing, Control –CSIR NMITLI

Drug substance Markers

Heavy metals, microbial load, pesticide residue, aflatoxins

Residual solvents

Stability studies

1. Lack of bioassay

2. What specs to lay down?

3. Chemistry, Manufacturing, Control - CSIR NMITLI

Drug Product (Formulation)Markers

Stability studies

Batch to batch consistency

Storage, transport

1. What is active marker?

17

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development

Agenda

18

4. Pre-clinical Pharmacology –in vitro

Solubility of test substance

Interference of test substance

Complexity of constituents- consistency

and reproducibility of results

What extract and concentrations to use

What cut-offs to consider

4. Pre-clinical Pharmacology –in vivo

What doses to test?

Extrapolation of pre-clinical

data to patients?

4. Pre-clinical Pharmacology - CSIR NMITLISTZ induced hyperglycemia

1. Need for dose finding studies

2. No previous literature to depend upon

3. Cannot compare results as material used varied

4. Expensive

21

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development

Agenda

5. SafetyICMR Guidelines, 2006: Category IPlants and herbal remedies used and prepared in the same way as mentioned in traditional literatureNo need for toxicity studies in animals (prior to Phase II) unless

there are reports suggesting toxicity or when the herbal preparation is to be used for more than 3 months or when a large multi-centric Phase III trial is subsequently planned

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1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development

Agenda

Test material: formulation, dose, dosing regimen, PKEthicsPractices

Study population

Sample size

Study Design

Bias

Efficacy/safety variables and end points

6. Clinical Development: Designing the protocol

6a. Study Population

Target population?

Freshly diagnosed?

On conventional medications?

Advanced cases: to delay

complications?

Ayurvedic concepts: Prakriti

6b. Sample size

Poor documentation

Experiential data

Pilot studies

Animal experiments

6c. Study Design

6c. Study Design

RCT

Which comparator?

Masking

6c: Comparator

Controls: Placebo?

Difficult to match colour, taste, odour,

flavour or formulation of herbal product

Should be truly inert

Robust placebo response

6c. Comparator

Controls: Standard therapy

Stiff competition

Ethics of test and control arms

6d. Bias

Sampling bias

Patients who “opt” for alternative

medications

Not responding to “conventional”

medicines

Prakriti

6e. Defining efficacy variables

Hard vs. soft

targets:

Quality of life

subjective variables

Difference in

philosophy

6f. Study Medication: Formulation

Type of formulation: traditional/new

Method of preparation:

Acceptability?

Palatability:

Compliance?

Drug Interaction: Formulation problem

6f. Study Medication: What Dose?

Historical use

Clinical development

STEP Trial – Saw Palmettofor Benign Prostate

Hypertrophy

225 men, 49+ yrs with moderate to

severe BPH

Randomized

160 mg, twice daily or matching

placebo

8 visits in one year

Bent, et al., NEJM 2006Bent, et al., NEJM 2006

Saw Palmetto for Benign Prostatic Hypertrophy

1415

1617

18A

UA

SI

0 5 10 15Month

Saw palmetto Placebo

AUASI RESULTS

(Bent, et al., NEJM 2006)

Uro

logi

cal A

ssoc

. Sym

ptom

Inde

x “…what the study is telling us is - what the effect at this dose is, in this particular population.”(Heather Miller, Tan Sheet, 2006)

6g. Ethics

Attitude towards alternative

therapy: safe (therapeutic

misconception)

Commercialisation of folklore

medicine: rights/share of tribe or

community to be given

6h. Practices

One medicine vs. “therapy” for

“a” patient

Translating research findings

into clinical practice, concept of

“Evidence Based Medicine”

“Peripheral vision: The ability not only to look straight at what you want to see but also to watch continually, through the corner of your eye for the unexpected. I believe this to be the greatest gift a scientist can have.”

Hans Selye, From Dream to Discovery