CSIR-New Millenium Initiative for Technology Leadership of India

(NMITLI)
IIIM, Jammu

CSIR-NMITLI, Delhi

VSGH, Ahmedabad

NBRI, Lucknow

Industry Partners:
NIMS, Hyderabad • Zandu, Mumbai
• Dhootpapeshwar, Mumbai
TNMC & Bhavan’s SPARC, Mumbai • NPIL, Mumbai
• AVS, Kottakal
• AVN, Madurai

MDRF, Chennai
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
 Challenges in Herbal Drug
Development:
Experiences of the CSIR-NMITLI
Project (Diabetes)

Urmila Thatte
Professor and Head,
Department of Clinical Pharmacology,
TN Medical College & BYL Nair Ch. Hospital,
Mumbai
 Agenda

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development
 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?

 1. Defining objectives- CSIR
NMITLI
Madhu`meha’ Diabetes mellitus

Diagnosed on the basis of compromises a group of

urinary symptoms common metabolic disorders

- Prabhuta Mootrata that share the phenotype of

hyperglycemia
- Avila Mootrata

- Madhu eva madhuram

meha

Is Madhumeha equivalent to Diabetes mellitus?

6
1. Defining objectives - CSIR NMITLI

9 Soft end-points
Type 2 Diabetes mellitus 9 Adjuvant

Delay the use of OHA/Insulin

Delay/prevent complications

Adjuvant to anti-diabetic agents

 Agenda

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development
8
2. Selection of Plants

Paucity of published data

Indigenous Clinical Practice not
well documented
Information in regional
languages - needs correct
“interpretation”
2. Selection of Plants - CSIR NMITLI

Long history of use

References in Ayurvedic literature

9 Discussion with Ayurvedic Experts

6 plants identified
 Lead Formulations identified -
CSIR NMITLI

• DM-FN 02 Only one reference in

recent nighantu
(single plant) Widely used in
selected regions of
• DM-FN 01 country
A few recent
(2 plant FDC) publications

Ayurvedic literature
plenty: prescribed in
madhumeha
No recent publications
on FDC – single plants
described
 Agenda

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development
12
 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?
 Agenda

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development
17
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

18
4. Pre-clinical Pharmacology
–in vivo

ƒ What doses to test?

ƒ Extrapolation of pre-clinical

data to patients?
4. Pre-clinical Pharmacology - CSIR NMITLI
STZ 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
 Agenda

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development
21
 5. Safety
ICMR Guidelines, 2006: Category I
Plants and herbal remedies used and prepared in the
same way as mentioned in traditional literature
No 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
 Agenda

1. Defining objectives

2. Selection of plants

3. CMC

4. Pre-clinical studies

5. Safety

6. Clinical Development
23
 6. Clinical Development:
Designing the protocol

Study population Test material:

Sample size formulation, dose,
dosing regimen, PK
Study Design
Ethics
Bias
Practices
Efficacy/safety
variables and end
points
 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
ƒ Type of formulation: traditional/new

Method of preparation:

Acceptability?

Palatability:

Compliance?
Drug Interaction: Formulation problem
6f. Study Medication: What
Dose?

ƒ Historical use

ƒ Clinical development
STEP Trial – Saw Palmetto
for 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 2006

 Saw Palmetto for Benign Prostatic
Hypertrophy
(Bent, et al., NEJM 2006)

AUASI RESULTS
“…what the study is
Urological Assoc. Symptom Index

18

telling us is - what
the effect at this
17

dose is, in this

particular
AUASI

population.”
16

(Heather Miller, Tan

Sheet, 2006)
15
14

0 5 10 15
Month

Saw palmetto Placebo

 6g. Ethics

Attitude towards alternative

therapy: safe (therapeutic
misconception)

Commercialisation of folklore
medicine: rights/share of tribe or
community to be given
 6h. Practices

ƒ One medicine vs. “therapy” for

“a” patient

ƒ 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