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 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

2. 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

3. 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

4. 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

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

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

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

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

9. 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

10. 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

11. 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

12. 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

13. 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- - (
E. Solomon M.Sc,
Lect. No. 1
Lect. No. 1 Eli Solomon

14. 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

15. 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

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

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

18. 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

19. IND Phase 3
Verifying efficacy, establishing safety, and establishing the optimum dosage
Larger Studies ( 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

20. 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

21. 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 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

22. 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

23. 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

24. מונחים והגדרות – Terms & Definitions
QSR – Quality System Regulations:
According to FDA is Part of 21 CFR 807, 820,
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

25. Links to Web
The U.S. Drug Approval Process: A Primer (lower the cost of generic drugs)
The New Drug Development Process
Content and Format of INDs for Phase 1 Studies of Drugs
Center for Devices and Radiological Health
E. Solomon M.Sc,
Lect. No. 1