2. Introduction
The most important aspects in public
health is, the law.
It protect the health of the population as it
ensures quality, safety and effectiveness of
medicines and treatments.
For this reason, more and more healthcare
companies are integrating good regulatory
practices guidelines into their structure.
3. •These good practices prevent and mitigate adverse health
effects and unsafe, poor quality or ineffective medicine.
•The pharmaceutical industry has always adopted good
regulatory practices and has been concerned about
evaluating medicines and technology in a timely and
adequate manner.
4. •
•
Consistency
Implementation of good
regulatory practices, as
well as adaptation to the
current challenges
High ethical and scientific
standards.
Have a positive impact on
public health at the global
level.
5. Good Regulatory practice
legality, impartiality, consistency, proportionality, flexibility,
effectiveness, efficiency, clarity and transparency.
Strong regulatory
systems Regulatory
Affairs Department
High quality
healthcare
products
6. What are biologics ?
Biological products are
comprised of large and
complex protein
structures that are
primarily derived from
living material, including
human, animal, and
microorganisms.
7.
8. History of Regulations of Biologics
• A significant advancement in areas of vaccinology &
immunology resulted in vaccines of small pox, rabies,
typhoid & antitoxins for diptheria & tetanus resulted
in wide use of these products by public but were not
under pressure to ensure safety
• 13 children died after receiving diptheria antitoxin in
1901 at St.Louis, Missouri which was contaminated
with tetanus toxin
• 9 children died due to contaminated small pox
antitoxin at Camden, New Jersey
• Resulted in Biologics Control Act of 1902
9. Provisions of Biologics Control Act 1902
• Licensure requirements for
establishments & products
• Labelling requirements
• Facilities inspection requirements
• Penalties for violation
• BCA authorised Hygienic laboratory to
issue regulations implementing
provisions of act
• In 1934 Hygienic laboratory was
renamed to NIH
• In 1944 BCA was incorporated into
Section 351 of Public Health Service
Act (PHSA) is basis for current FDA
regulations of biologics published in
Code of Federal Regulations -CFR (Title
21 , Parts600-680)
• In 1948, NIH was called as Division of
Biologics Control within National
Microbiological Institute(NMI)
• In 1955, 200 cases of paralytic polio due
to Salk vaccine by Cutter laboratories &
license was issued by NMI
• So Formation of Division of Biologics
Standard (DBS) within NIH
• In 1972 DBS transferred to FDA as
Bureau of Biologics (BB)
• In 1982 BB was merged with Bureau of
Drugs to form National Centre for Drugs
and Biologics (NCDB)
• NCDB was split into CDER ( Centre for
Drug Evaluation and Research) & CBER (
Centre for Biologics Evaluation and
Research)
10. Difference between Biologics and Drugs
Biologics
1. Complex structure
2. Large size
3. Unstable
4. Identical copy cannot be made
5. Manufacturing methods are
many
6. Characterization is impossible
Drugs
1. Simple
2. 2. Small
3. Stable
4. Identical copy can be made
5. Well defined methods
6. Easy
11. Who Regulates Biologics?
CBER
• More complex Biologics
• Gene therapy, Vaccines & Blood
products
• CDER
• Well characterized proteins and
Biosimilars eg: Monoclonal
antibodies
• (Cardio, Oncology & Renal)
12. What products go where at CBER?
• Office of blood research and review:Blood and blood components
used for transfusion, Drugs derived from blood cells and
plasma,Medical Devices used for collection & testing of blood and
blood components
• Office of Vaccines Research and Review: Vaccines for infectious
diseases, Allergens patch tests, Allergenics, Antitoxins and
Antivenins
• Office of Cellular tissues and Gene therapies: Human tissue for
transplantation, Gene therapy products, Cellular products,
Xenotransplantation products
13. Biologics Regulations
Biologics are approved under BLA , under PHS act, Section 351
Same Regulations as that of drug such as GMPs, GCPs, GLPs, FDA
guidance documents , ICH Quality , Safety & Efficacy guidelines, IND
Regulations , NDA/ BLA regulations
14. IND and its types
• IND has to be submitted when studying a new drug & in a new
clinical indication
• Sponsor IND
• Investigator IND
• Emergency IND
• Treatment IND
15. What goes into IND?
• Is it safe?
(Pre-clinical studies)
• Manufacturing information
• Clinical protocols and Investigator information
16. Required IND Elements
• Cover sheet (Form FDA 1571)
• Table of contents
• Investigatory plan
• Investigators brochure
• Protocol
• CMC
• Pharmacology and toxicology information
• Previous human experience
17. Paper or electronic?
• Electronic format is allowed review required for NDA/BLA
• Electronic submission has following advantages:
1. Publishing & Hyperlinking ease reviews
2. IND amendments easier to track
3. No need to resubmit for marketing application
18. Common Technical
Document (CTD)
It is a format set by ICH agreed by
Regulatory agencies of USA,
Europe & Japan
Information package on clinical,
non- clinical, manufacturing and
technical datas submitted for
registration of new drugs in USA,
Europe & Japan
19. eCTD
• Electronic format of Common Technical Document
• 2 Types: Content specification (ICH) & Technical specification (
Electronic software)
• E-CTD is recommended
20. Is it safe?
• Pre-clinical studies are important because testing of biologics in
animals are difficult and limited
• Human testing materials are immunogenic to animals
• Toxicology studies are carried out on case by case basis
21. How product is made? (CMC)
• Complex manufacturing process
• Processing controls, testing methods and specifications increases its
complexity
• Additional STDs required are:
1. Potency
2. Safety (guinea pigs, mice)
3. Sterility(final container)
4. Purity (Pyrogen testing)
5. Identity( confirms content of product)
22. Clinical Studies
• Phase1:Initial safety, exploring dosing, Identifying adverse events
• Phase2 : Expansion of safety and efficacy profile
• Phase3:Efficacy studies in target population
• Phase4: collection of additional safety information
23. IND Maintenance
• After submission IND application FDA will give 30 days time to review
either to proceed the investigation or put IND on hold
• FDA may ask for revision of clinical protocol
• If answers are insufficient on toxicological & CMC IND will be put on
hold by FDA
• To avoid clinical hold have pre- IND meetings with FDA
24. Meeting with FDA
• CMC
• Pre clinical
• Clinical
• Prepare qs & answers
• Recorded as minutes
• Type A (30 days)
• Type B (60 days)
• Type C (75 days)
25. Updating Files
• Clinical information updates ( new investigators)
• Revised protocols
• IND annual updates
• CMC updates
• IND safety updates
26. Target Product profile
• Begin with end in mind
• Label,Dosage form , Strength
• What type of market to enter?
27. Where to find information?
• FDA CBER website of approved products
• Clinical trials.gov.in
• About similar competitive products so you can plan about your
product development
28. Learning Tools for Product Development
• Licensed Biological products
• Types of Supporting Documents
29. Special programs for Biologics
• Orphan drug designation
• Fast drug designation & Break through therapy
• Accelerated Approval
30. Orphan drug designation
• 7 years exclusivity
• No User fees
• No need to follow pediatric regulation
• Grants (1 million dollars) for clinical study
31. Fast track designation & Break through
therapy
• Sometimes approval of drugs may be delayed
• Fast track designation helps in this
• Short clinical program & frequent FDA interactions for approval for
break through therapy
32. Accelerated Approval
• Based on surrogate end point like tumour shrinkage
• But still proof of efficacy is needed but done on post approval
33. What’s needed for the BLA??
• Preparing BLA Content & Format
• Pre BLA meeting to discuss suitability data for licensure, Draft
product label & Final contents of BLA
• Module1(Product Labelling, Package inserts)
• Module2 ( Summaries of Mfging, Pre clinical & clinical studies)
• Module3 ( Details of Mfging & Stability data’s)
• Module4 ( All completed & approved preclinical datas approved)
• Module 5 ( All completed & approved clinical datas approved)
34. BLA review & outcomes
• PDUFA Review starts once all data’s have been received
• Outcomes are approvable, non approvable & complete response letter to
indicate deficiencies & Recommend actions for BLA to get approval
35. What to do after Biologic get approved??
• Post approval reporting requirements for Biologics
1. Safety reporting ( adverse effects – Quarterly intervals for 3 years
from date of approval)
2. Labelling & promotion- advertising
• Materials to be reviewed
• CBER review whether the report on Product risk & benefit data’s are
truthful , non misleading & Balanced manner
36. Most post approval requirements of Biologics
Any changes in CMC
• Submission of deviation report ( notify to FDA within 45 days)
• Post approval clinical studies
1. Risk evaluation & Mitigation strategies
2. Increase in Patient & Clinician education
3. Accessing of new drug only by approved clinician
37. Summary
• What are Biologics?
• What goes in IND/BLA?
• What is different about Biologics development?
• What programs Biologic products could be eligible for?
• What to do during and after BLA approval ?
