Core Drug Development Cycle

1. Overview of Drug Development
Rajendra.Sadare
Senior Software Engineer-Testing and Validation
Arisglobal Software Pvt.Ltd

2. New Drug Development
A scientific endeavor,
highly regulated because
of legitimate Public Health concerns.

3. Clinical Trials: Major Questions
 What happens to the drug in the body? (PK)
 What happens to the body when given the
drug? (PD)
 Is the drug clinically effective? (E)
 Is the drug clinically safe / tolerable? (S)
 How should the drug be taken? (dosage /
dose-response)

4. Concepts In Clinical Development
 Pharmacokinetics (PK): Evaluation or quantification
(absorption, distribution, of what the body does to a
metabolism, elimination - drug substance over time.
A.D.M.E.)
Evaluation or quantification
of what a drug substance
 Pharmacodynamics (PD): does to the body over time,
(effects on organs or systems) and over drug
concentrations.

5. Concepts In Clinical Development
 Efficacy
- A treatment is considered ineffective unless
scientifically / clinically proven efficacious.
 Safety
- A treatment is considered unsafe unless
scientifically / clinically proven safe / tolerated.
Key is risk / benefit ratio!

6. Clinical Development
Trial #1 Overall summary assessments
of:
• Pharmacokinetics
Trial #2 • Pharmacodynamics
• Biopharmaceutics
Trial #3 • Dose-response (risks /
benefits)
• Clinical efficacy
• Clinical safety
Trial #k
• Special populations
• Generalization

7. The History of Clinical Trials
 First controlled clinical trial
 1753 – Lind’s study comparing the use of
different treatments for scurvy (on 12
patients)
 Treatment - lime & oranges, seawater etc.
 2 patients per group
 Two patients on lime & oranges were cured

8. The History of Clinical
Trials
 First randomised controlled clinical trial
 1948- First use of a randomised control
group: streptomycin treatment of pulmonary
tuberculosis
 Treatments: streptomycin (antibiotic) versus
bed rest
 Patients received streptomycin OR just bed
rest at random (randomised clinical trial)
 Outcome: streptomycin was effective

9. Selecting The Population For Clinical
Trials
Concepts: Study Population
 Each patient is unique
 Drug trials need to assess representative groups
 Conclusions related to: average of tested
population specifics of
tested population
Generalization to other population?

10. Concepts In Clinical Development
Dose - Response Relationship
Threshold Dose Maximally Effective
MinimallyEffective Dose
Dose
Respons
e
or Effect
Dose

11. Standards Of Clinical Development
Key concepts in clinical trial design
• Control: active (positive)
placebo (negative)
others
• Randomization: treatment assignment left
to chance
• Stratification: balancing relevant subset of patients
• Blinding: double-blind, single blind, open
• Parallel groups vs. cross-over vs. others
(simultaneous) (sequential in time)
• Dose titration vs. fixed dose

12. Patient Control Groups: Why?
• To provide a standard for comparison of new therapy
• To eliminate positive bias toward new therapy, including
“placebo” effect
• To protect new therapy against negative bias concerning
adverse experiences
• To increase scientific and regulatory acceptance of study
results

13. Essential Elements of a “Rigorous” Clinical
Trial
 Appropriate study design (treatment structure)
 Concurrent control group
 Randomized (and blinded) assignment of subjects
 Double-blind (unless not possible/not necessary)
 Appropriate and well-defined population
 Standardization (and optimization) of treatment regimens,
measures, and procedures
 Symmetry in study conduct across treatment groups
 Clinically meaningful and well-characterized End-points
 Appropriate statistical methods, defined a priori
 An adequate sample size (based on a clinically important

14. Standards of Clinical Development
US law requests “substantial evidence” to support
claim of effectiveness for new drugs.
Basis for determining the claim is to evaluate if a
clinical investigation is “adequate” and “well
controlled”.

15. Major Stages of Drug Development –
as per US-FDA
Preclinical Testing
IND Application
Clinical Testing – Phase I
Clinical Testing – Phase II
Clinical Testing – Phase III
New Drug Application
Clinical Testing–Phase IV

16. Clinical Testing –
Phase I
 Involves giving the drug to a small number of healthy
volunteers
 Determines the safety of the drug as well as the safe
dosage range
 Takes a year or less to complete

17. Phase I trials (Volunteer studies)
OBJECTIVES
 metabolic and excretory pathways (impinges on toxicity
testing in animals)
 variability between individuals; effect of route;
bioavailability
 tolerated dose range
 indication of therapeutic effects
 indication of side effects

18. Clinical Testing –
Phase II
 Involves giving the drug to a large group (100-300) of
patients who have the disease that the drug is
expected to treat
 Purpose is twofold….
- Does the drug work in the disease population?
- At what dosage does the drug demonstrate efficacy?
 Takes about 2 years to complete

19. Patient studies (Phase II trials)
OBJECTIVES:
 indication for use
 type of patient
 severity of disease
 dose range, schedule and increment
 pharmacokinetic studies in ill people
 nature of side effects and severity
 effects in special groups

20. Clinical Testing – Phase
III
 Involves administering the drug to a large number of
patients (1000-3000)
 Purpose is to….
- Confirm earlier efficacy results
- Identify adverse events which occurs when the drug is
given to a larger population over a longer period of time
 Takes about 3 years to complete

21. Phase III trials
 more certain data for the objectives of phase 2
studies
 interactions between drugs start to become
measurable in the larger population
 sub-groups start to be established
 special features and problems show up

22. Clinical Testing – Phase
IV
 Once the NDA is approved and the drug is available,
post-marketing studies are conducted to further
confirm safety and efficacy during long-term use
 Can include mail-in questionnaires and personal
interviews
 Mandated in the US. FDA requires a 2 year safety data
from PMS studies

23. Major Stages of Drug Development – as per
US-FDA
Preclinical I Clinical NDA Review Post-Marketing
N Phase I
D Adverse
Initial Reaction
Synthesis Phase II Reporting
A
P Phase IV
Animal P Phase III Surveys/
Testing L Sampling
I Testing
C
A Treatment Use
T
I
O Inspections
Range 1-3 Yrs. N Range 2-10 Yrs.
Avg:18 Mos. Avg: 5 Yrs. NDA Approved
FDA Time Range 2 Mon – 7
30 Day NDA Submitted Yrs.
Safety Review Avg:24 Mos.
Average of Approximately 100 Months From Initial Synthesis to Approval of NDA

24. Good Science + Good Study Logistics
=
Good Clinical Development
 Regulatory authority
satisfaction
 Public health protection
 Marketable product