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

)
IIIM, Jammu CSIR-NMITLI, Delhi VSGH, Ahmedabad

NBRI, Lucknow

Industry Partners:
NIMS, Hyderabad TNMC & Bhavan’s SPARC, Mumbai • Zandu, Mumbai • Dhootpapeshwar, 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. 2. 3. 4. 5. 6.

Defining objectives Selection of plants CMC Pre-clinical studies Safety 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’ Diagnosed on the basis of urinary symptoms - Prabhuta Mootrata - Avila Mootrata - Madhu eva madhuram meha
Is Madhumeha equivalent to Diabetes mellitus?
6

Diabetes mellitus compromises a group of common metabolic disorders that share the phenotype of hyperglycemia

1. Defining objectives - CSIR NMITLI

Soft end-points

Type 2 Diabetes mellitus
Delay the use of OHA/Insulin Delay/prevent complications Adjuvant to anti-diabetic agents

Adjuvant

Agenda
1. 2. 3. 4. 5. 6.

Defining objectives Selection of plants CMC Pre-clinical studies Safety 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 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

Agenda
1. 2. 3. 4. 5. 6.

Defining objectives Selection of plants CMC Pre-clinical studies Safety 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. 2. 3. 4. 5. 6.

Defining objectives Selection of plants CMC Pre-clinical studies Safety 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
What doses to test? 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. 2. 3. 4. 5. 6.

Defining objectives Selection of plants CMC Pre-clinical studies Safety 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. 2. 3. 4. 5. 6.

Defining objectives Selection of plants CMC Pre-clinical studies Safety Clinical Development
23

6. Clinical Development: Designing the protocol

Study population Sample size Study Design Bias Efficacy/safety variables and end points

Test material: formulation, dose, dosing regimen, PK Ethics Practices

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 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) Urological Assoc. Symptom Index
AUASI RESULTS
18

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

14 0

15

AUASI 16

17

5 Month Saw palmetto

10 Placebo

15

6g. Ethics
Attitude therapy: towards safe alternative (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

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