Reflections on a career in Pharmaceutical Statistical Sciences: My Journey. James R. Johnson, PhD (UD04)

Transcription

1 Reflections on a career in Pharmaceutical Statistical Sciences: My Journey James R. Johnson, PhD (UD04) 1

2 My Journey 7 Different Pharmaceutical Companies 30 years (1983 to 2013) Retired to Consulting and Teaching 7 different Therapeutic Areas Cardiology / Pulmonary Medicine Nuclear medicine / Imaging Dermatology Infectious Diseases Oncology Anesthesia Neurology Worldwide: US, Germany, UK, India, Australia 2

3 My Education BS, MS, PhD I always wanted to be a Marine Biologist or Veterinarian.. and ended up a Pharmaceutical Statistician. With No Regrets! 3

4 Question Can you tell me when and where the first recorded clinical trial was published? 4

5 Brief History of Clinical Trials First Recorded Clinical Trial: BC Book of Daniel 1:1-17 tell the story, Versus describe the experiment The Lion of King Nebuchadnezzar II at the Gates of Babylon 5

6 Daniel 1:1-17 (The Hypothesis) (12) Prove thy servants, I beseech thee, ten days; and let them give us pulse to eat, and water to drink. (13) Then let our countenances be looked upon before thee, and the countenance of the children that eat of the portion of the king's meat: and as thou seeth, deal with thy servants. The Lion of King Nebuchadnezzar II at the Gates of Babylon 6

7 Daniel 1:1-17 (Observation) (14) So he consented to them in this matter, and proved them ten days. (15) And at the end of ten days their countenances appeared fairer and fatter in flesh than all the children which did eat the portion of the king's meat. The Lion of King Nebuchadnezzar II at the Gates of Babylon 7

8 Daniel 1:1-17 (Results) (16) Thus Melzar took away the portion of their meat, and the wine that they should drink; and gave them pulse. (17) As for these four children, God gave them knowledge and skill in all learning and wisdom: and Daniel had understanding in all visions and dreams. The Lion of King Nebuchadnezzar II at the Gates of Babylon 8

9 Drugs By Design What makes a good Drug (or compound)? Highly Selective for Disease Target High Potency, Uniform Dose Low Toxicity Patient Friendly Dosage Form Route of Administration Frequency of Dosage Reliable, Reproducible, Stable Manufacturing Drug Substance Drug Product Container Delivery Systems 9

10 Stages of Drug Development Formulation à Pilot Plant à Stability Testing à Manufacturing Phase I Target ID Disease Biology Chemistry Medicinal Chemistry Assay Dev. HTS Pharmacology Pre- Clinical Dev. Animal Tox ADME Rx Delivery Safety PK PD (~200) Phase II Dose Finding Initial Efficacy Safety (~300) Phase III Efficacy Safety Trials Large Pop. (~1000) FDA Review EMEA Review Indefinite ~3 yrs ~3 yrs ~1 yr ~2 yrs ~3 yrs ~1.5 yrs Approximate Time (Years) 10

11 Stages of Drug Development Costs Probability Probability of Success Total Cumulative Costs 1/10,000 Target ID Medicinal Chemistry Pre- Clinical Dev Phase I Phase II Phase III Regulatory Review Indefinite ~3 yrs ~3 yrs ~1 yr ~2 yrs ~3 yrs ~1.5 yrs Approximate Time (Years) 11

12 Rational Drug Development Plan Marketing Clinical Development CMC Toxicology Label, Target Product Profile Clinical Development Plan Legal Regulatory Preclinical Development Drug Safety 12

13 Randomized Clinical Trials History has lead us to one of the single most important aspects of the history of clinical research: Randomized Controlled Clinical Trials RCT s are the Gold Standard for testing new intervention(s) in a population 13

14 A Way of Thinking Category Traditional View Statistical View Reproducibility of Events View of Experimental Units Precision in Determinations from data Granularity in Examining Data Certainty and Determinism Individuals Certain Knowledge Examine ALL data Randomness and Shochasticism Distributions and Populations Estimation, Variability, and Bias Data reduction 14

15 A Way of Thinking Statistician vs. Clinician: A Clinician treats one patient at a time using an established protocol. A Statistician helps the Clinician treat 1000 s of patients by helping them develop the protocol to treat a single patient. 15

16 Study Design, Methods, Analysis 1. Study Design Ø Sets the ground work for the study. We begin with the end in mind. 2. Study Methods Ø Implementing the Plan outlined in the Study Design. 3. Study Analysis Ø Rational and focused analysis of the planned study design, implemented with solid methodology generally results in observations that are true to the experiment. 4. Feedback Loop Ø The Study Analysis serves to provide a check on the Original Study Design. Is an indicator of how well the design worked in validating the experiment 1 STUDY DESIGN 4 2 STUDY METHODS 3 STUDY ANALYSIS

17 My NDA s: Funny Stories Ceftin (Ceferoxine axetil) Antibiotic Treatment of: Ear Infections Gonorrhea ß How is this related to ear infections? Sinus Infections Fluticasone Ointment Dermatological Treatment of: Skin Rash ß Was that rash really on that part! 17

18 Early on. I could find almost any association if I looked hard enough 18

19 Then I went to replicated Studies.Multiple Trials? 19

20 Where is the profession going.evolve to Bayesian! 20

21 Pharmaceutical Statistician Statistical Programmer Highly rewarding! Never a dull moment! Meet and work with the smartest and nicest people. Always Learning. I would do it again. 21