The Construction of a Clinical Trial. Lee Ann Lawson MS ARNP CCRC

Transcription

1 The Construction of a Clinical Trial Lee Ann Lawson MS ARNP CCRC 1

2 Objectives Review Phases of Clinical Research Discuss Orphan Drug Act Discuss regulatory agencies Overview phases of clinical research Overview clinical trial study design Review drug development for Rare Disease 2

3 Phases of Clinical Research 1 Step 1 Discovery Development 6 Step 2 Pre-clinical research Step 3 Clinical Research 12 Step 4 FDA Review New Drug Application 15 Step 5 FDA Post-market Safety Monitoring 3

4 Orphan Drug Act Signed into law January 4, 1983 Created financial incentives for the development of treatments for rare diseases 326 new drugs approved for rare diseases ( ) > 600 drugs and biologics approved since 1983 Office of Orphan Product Development (OOPD) Orphan Products Clinical Trials Grants Program Natural History Grants Program 4

5 Orphan Drug Designation Provides orphan status to drugs, biologics intended for treatment or prevention of a rare disease/diagnosis Affects < 200,000 people Affects > 200,00 people, but not expected to recover the development and marketing costs 5

6 21 st Century Cures Act Designed to help accelerate medical product development Incorporates patient perspective in FDA decision making Modernizes clinical trial design, and clinical outcome assessment Implements policies that require the FDA to respond to all new designation requests within 90 days Rare Pediatric Disease Priority Review Voucher Program 6 default.htm

7 FDA s Accelerated Approval Process Fast track Designation: facilitates development, and review of drugs that treat serious conditions and fill an unmet medical need Breakthrough Therapy: expedites development and review of drugs which demonstrate an improvement over available therapy Accelerated Approval: allow drugs for serious conditions that address an unmet medical need to be approved based on a surrogate endpoint Priority Review: FDA intends to take action on an application within 6 months 7

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9 Important aspects of Drug Development Adequate description of the disease natural history Adequate understanding of disease pathophysiology Adequate understanding of proposed drug mechanism of action - pharmacotoxicology Reliable endpoints and outcome assessment Standard evidence to establish safety and effectiveness Drug manufacturing considerations 9

10 Establish a solid foundation Pre-clinical studies Natural History Proof of concept Mechanism of action 10

11 Pre-Clinical Natural History

12 Pre-Clinical Proof of concept Mechanism of action

13 Pre-clinical studies Human Research Natural history studies: follows a group of people over time Registry studies: observational study that collects data in a uniform way Pilot studies: preliminary small scale study, informs researchers how to plan a larger scale study Lead-in studies: brief stage at the beginning of a study to establish a baseline 13

14 Pre-clinical studies - disease in a dish Modeling human genetic disorders Human embryonic stem cells (hescs) Induced pluripotent cells (ipscs) Gustavo, T., Vivas, E.L., & Izipsua Belmonte, J.C Disease in a dish: modeling genetic disorders using induced pluripotent cells. Nature 17,

15 Pre-clinical studies - animal models Naturally occurring Small animal Murine model Large animal Canine model Primate model Limitations Genotype/Phenotype variation Metabolomics varied Geel et. al Pompe Disease: Current state of treatment modalities and animal models. Molecular Genetics and Metabolism 92,

16 Investigational New Drug Application Investigator Sponsor Pre-clinical studies 16

17 Regulatory Agencies FDA 17

18 Phase I Research Phase I Safety studies Small numbers of participants Unaffected volunteers Evaluate for toxicity Dose finding PK/PD Pre-clinical studies 18

19 Phase II Research Phase I Safety + Efficacy studies Larger numbers of participants Volunteers with condition/disease Biomarkers Primary outcome measures Secondary outcome measures Phase II Pre-clinical studies 19

20 Phase III Research Phase I Phase III Phase II Pre-clinical studies 20

21 Study Design - Scientific Method Remove bias Validated outcome measures Safety parameters 21

22 Classic Study Design vs Alternative Study Design Classic Large number cohorts Multi-center Randomized controlled trial Double blinded Parallel design Alternative small group cohorts (genotype/phenotype specific) Historical comparator cohorts Crossover design Escape design Non-inferiority 22

23 Phase III Research Rare Disease Pivotal clinical trials Randomized placebo controlled Historical cohort comparator groups Clinical outcomes Biomarkers Surrogate endpoints Patient reported outcome measures 23

24 New Drug Application N D A Phase I Phase III Phase II Pre-clinical studies 24

25 Summary Pre-clinical research Early Phase Safety + Efficacy Later Phase Placebo controlled Randomized Blinded Open label expanded access <a href=' from pngtree.com</a> 25

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