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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?
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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
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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?
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1. Defining objectives
2. Selection of plants
3. CMC
4. Pre-clinical studies
5. Safety
6. Clinical Development
Agenda
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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
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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