Core Drug Development Cycle

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Core Drug Development Cycle

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Core Drug Development Cycle

  1. 1. Overview of Drug Development Rajendra.Sadare Senior Software Engineer-Testing and Validation Arisglobal Software Pvt.Ltd
  2. 2. New Drug Development A scientific endeavor, highly regulated because of legitimate Public Health concerns.
  3. 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. 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. 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. 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. 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. 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. 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. 10. Concepts In Clinical Development Dose - Response Relationship Threshold Dose Maximally Effective MinimallyEffective Dose Dose Respons e or Effect Dose
  11. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 24. Good Science + Good Study Logistics = Good Clinical Development  Regulatory authority satisfaction  Public health protection  Marketable product

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