Regulatory– Terms & Definitions רגולציה - מונחים והגדרות WHO – World Health Organization CFR – Code of Federal Regulations תקנות וחוקים פדראליים לגבי כל תחומי החיים מס' 21 קשור למנהל המזון והתרופות - FDA מהווה חלק ממחלקת שרותי בריאות הציבור 21 CFR ___ Department of Health and Human Services FDA –Food and Drug Administration מנהל המזון והתרופות CDER - The Center for Drugs Evaluation and Research To assure that safe and effective drugs are available to the American people. How CDER works to accomplish this mission as it relates to new drug development and review. E. Solomon M.Sc, Lect. No. 1 Lect. No. 1 Eli Solomon

Regulatory– Terms & Definitions רגולציה - מונחים והגדרות ICH = International Conference on Harmonization (ich.org) Technical requirements for demonstrating the quality, safety and efficacy of new medicines have been almost fully harmonized throughout the European Union, United States and Japan. via the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). E. Solomon M.Sc, Lect. No. 1

Regulatory– Terms & Definitions רגולציה - מונחים והגדרות ICH was launched in 1990 as a joint regulatory/industry project to make new pharmaceutical development and registration processes more efficient, in the interests of patients, public health, and cost-effectiveness, e.g. by preventing unnecessary duplication of clinical trials in humans and minimizing animal testing. גוף משותף לממשלות ולתעשייה לייצור תרופה חדשה ורישומה שיהיה יעיל יותר, בעל עניין לחולים, לבריאות הציבור וזול. כל זאת על ידי מניעת כפילויות של ניסויים קליניים והקטנת מספר חיות הניסוי E. Solomon M.Sc, Lect. No. 1

FDA and U.S. Regulations FDA’s mission: “Protect the public health by assuring the safety ((בטיחות, efficacy ((יעילות, and security ((בטחון of human and veterinary drugs, biological products, medical devices, food supply, cosmetics, and products that emit radiation” FDA role in drug development: Regulates most clinical research (IND) Approves drugs (NDA / BLA) Regulates marketing of drugs after approval E. Solomon M.Sc, Lect. No. 1

Basic Disciplines of Drug Development Chemistry, Manufacturing, and Controls (Pre) Nonclinical ( (בעח"י Clinical (בני אדם) E. Solomon M.Sc, Lect. No. 1

(Pre) Nonclinical Studies Pharmacodynamics / Pharmacology Pharmacokinetics Safety pharmacology Toxicology Genetic toxicity Reproductive toxicity Carcinogenicity E. Solomon M.Sc, Lect. No. 1 5 5 5

Pharmacodynamics The blue curve represents the ligand with greater potency E. Solomon M.Sc, Lect. No. 1

Pharmacokinetics Plasma drug concentration vs time after an IV dose E. Solomon M.Sc, Lect. No. 1

Goals of Nonclinical IND Studies Identify starting dose Identify organ toxicities and reversibility Guide dosing regimens and escalation(החמרה) schemes E. Solomon M.Sc, Lect. No. 1 6 6 7

Basic Disciplines of Drug Development Nonclinical Testing in laboratory (in vitro) and in animal models (in vivo) to assess safety and efficacy Objectives: To develop the pharmacological profile To determine the acute toxicity in at least 2 animal species To assess toxicity with studies ranging from 2 weeks to several months Good Laboratory Practice (GLP): Guidelines related to studies in animal models To ensure the quality and integrity of data by establishing basic standards for the conduct and reporting of nonclinical safety studies E. Solomon M.Sc, Lect. No. 1

מונחים והגדרות – Terms & Definition New Drug Development Process- An interactive chart that provides an overview of the new drug development process, with an emphasis on preclinical research and clinical studies conducted by the drug's sponsor. פיתוח של תרופה חדשה תרשים רציף של תהליכי פיתוח המבוססים על מחקרים פרה קליניים וניסויים קליניים המבוקרים על ידי האחראים. כוללת 2 שלבים: IND ו - NDA E. Solomon M.Sc, Lect. No. 1

Regulatory Submissions* IND: Investigational New Drug Application: application to begin testing of a new drug in humans NDA: New Drug Application application to market a new drug in humans * CDER; CBER: INDs & BLAs E. Solomon M.Sc, Lect. No. 1

מונחים והגדרות – Terms & Definition Investigational New Drug (IND) Review Process- An interactive chart that provides an overview of CDER's investigational new drug application process, including how CDER determines if the product is suitable for use in clinical trials. Safety New Drug Application (NDA) Review Process- An interactive chart that provides an overview of CDER's new drug application review process, including how CDER determines the benefit: risk profile of a drug product prior to approval for marketing. Efficiency An interactive chart that provides an overview of CDER's new drug application review process, including how CDER determines the benefit: risk profile of a drug product prior to approval for marketing. New Drug Application (NDA) Review Process- - (http://www.fda.gov/cder/handbook/nda.htm) E. Solomon M.Sc, Lect. No. 1 Lect. No. 1 Eli Solomon

Drug Development Process Stages involved in Regulating Drugs Basic Disciplines of Drug Development Clinical Trials   Preclinical Testing File IND at FDA Phase I Phase II Phase III File NDA at FDA FDA Phase IV Years 3.5 1 - 2 2 - 4 4 - 6 1.5 Total 12 –17 Additional Post marketing testing required by FDA Test Population Laboratory and animal studies 20 to 100 healthy volunteers 100 to 300 patient volunteers 1000 to 3000 patient volunteers Review process / Approval Purpose Assess safety and biological activity Determine safety and dosage Evaluate effectiveness, look for side effects Verify effectiveness, monitor adverse reactions from long-term use Success Rate (%) 70 of IND’S 30 of IND’S 27 of IND’S 20 of IND’S E. Solomon M.Sc, Lect. No. 1

Investigational New Drug Application (IND) Application to start clinical trials requires 3 main sections: Preclinical and toxicology information CMC: Chemistry, Manufacturing & Control (manufacturing information) Clinical protocol and investigator information Animal data must show drug is likely to be reasonably tolerated in humans E. Solomon M.Sc, Lect. No. 1

IND Phase 1 Initial Introduction into Human (20-100 Healthy volunteers) Dose Ranging determined the maximum - tolerated dose with potential toxicities well-defined Closely Monitoring Safety E. Solomon M.Sc, Lect. No. 1

IND Phase 2 Controlled Clinical Trials Effectiveness (Preliminary) Defines the dose regimen of the drug Closely Monitoring Relatively Small Numbers (100-300 Patient volunteers) E. Solomon M.Sc, Lect. No. 1

IND Phase 2 (Cont’) End-of-Phase 2 Meeting Type “B” meeting with FDA Package received 30 days before scheduled date Outstanding Nonclinical / CMC issues Proposed Phase 3 adequate and well-controlled study design and analysis plan Obtain agreement from FDA on Phase 3 adequate and well-controlled study design and analysis plan Adequate ( מספק) and well-controlled study Has agreed-upon adequate and well-controlled design Provides the data the FDA will base its go / no-go decision on Must meet high scientific standards: controlled, blinded, randomized, adequate size E. Solomon M.Sc, Lect. No. 1

IND Phase 3 Verifying efficacy, establishing safety, and establishing the optimum dosage Larger Studies (1000-3000 Patient volunteers) Controlled Pivotal :((העיקר To provide the data sufficient to convince the FDA of the favorable benefit/risk ratio of the drug under investigation E. Solomon M.Sc, Lect. No. 1

מונחים והגדרות – Terms & Definition By the end of the first phase of ICH activity, which ended at the fourth conference (ICH 4, Brussels, July 1997), tripartite guidelines had been finalized on 45 harmonization topics, in four broad categories: “Quality” topics, which relate to chemical and pharmaceutical quality assurance (e.g. stability testing and impurity testing); “Safety” topics, which relate to in-vitro and in-vivo pre-clinical studies (e.g. carcinogenicity testing and genotoxicity testing); “Efficacy” topics, which relate to clinical studies in human subjects (e.g. dose response studies and good clinical practice); “Multidisciplinary” topics, i.e. those that do not fit uniquely into any of the above categories (e.g. medical terminology and electronic standards for the transmission of regulatory information). E. Solomon M.Sc, Lect. No. 1

Regulatory– Terms & Definitions רגולציה - מונחים והגדרות WHO – World Health Organization CFR – Code of Federal Regulations תקנות וחוקים פדראליים לגבי כל תחומי החיים מס' 21 קשור למנהל המזון והתרופות - FDA מהווה חלק ממחלקת שרותי בריאות הציבור 21 CFR ___ Department of Health and Human Services FDA –Food and Drug Administration מנהל המזון והתרופות CDER - The Center for Drugs Evaluation and Research To assure that safe and effective drugs are available to the American people. How CDER works to accomplish this mission as it relates to new drug development and review. E. Solomon M.Sc, Lect. No. 1 Lect. No. 1 Eli Solomon

מונחים והגדרות – Terms & Definition 2 CBER - The Center for Biologics Evaluation and Research המרכז להערכה ומחקר של חומרים ביולוגים : חיסונים, דם ומוצריו, תאים ורקמות, ריפוי באמצעות גנים. Mission To ensure the safety, purity, potency, and effectiveness of biological products including vaccines, blood and blood products, and cells, tissues, and gene therapies for the prevention, diagnosis, and treatment of human diseases, conditions, or injury. Through our mission, we also help to defend the public against the threats of emerging infectious diseases and bioterrorism. E. Solomon M.Sc, Lect. No. 1

מונחים והגדרות – Terms & Definition תפקיד CBER להבטיח בטיחות, ניקיון, פעילות, אפקטיביות של מוצרים ביולוגים כמו חיסונים, דם , מוצרי דם, תאים, רקמות, וריפוי ע"י גנים למניעה, אבחנה, וטיפול במחלות הומאניות, תנאי תברואה או פציעות. בתוקף תפקידם גם הגנה על הציבור ממגפות מדבקות וביו טרוריזם ב FDA קיימים משרדים נוספים העוסקים באספקטים נוספים של מזון ובריאות הציבור E. Solomon M.Sc, Lect. No. 1

מונחים והגדרות – Terms & Definitions QSR – Quality System Regulations: According to FDA is Part of 21 CFR 807, 820, 862-882 The FDA defines process validation as follows: Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. E. Solomon M.Sc, Lect. No. 1

Links to Web The U.S. Drug Approval Process: A Primer http://www.thememoryhole.org/crs/more-reports/RL30989.pdf (lower the cost of generic drugs) The New Drug Development Process http://www.fda.gov/cder/handbook/develop.htm Content and Format of INDs for Phase 1 Studies of Drugs http://www.fda.gov/cder/guidance/clin2.pdf Center for Devices and Radiological Health http://www.fda.gov/cdrh E. Solomon M.Sc, Lect. No. 1