Lecture 14: Drug Development and Biosimilars

Question 1

What Constitutes a “Drug”?

Answer 1

A drug is a substance that produces change in cellular or physiologic functioning

Question 2

Drug development influenced by:

Answer 2

High cost of research; complex regulatory environment & legislations;
insurer reimbursements; and patient perspectives

Question 3

Some of factors that influence drug development include

Answer 3

 Development cost (~ $1.3 - $2.8 billion or more) and time (can be as much as or >15 years)
 Regulatory approval process
 Changes in laws
 Patient acceptance
 Insurance reimbursement

Question 4

Investing in new drug development is

Answer 4

expensive and risky

Question 5

FDA Regulates drugs under two legislative acts

Answer 5

• Food, Drug, and Cosmetic Act – for small molecule drugs

- Public Health Service Act – for biologicals

Question 6

The FDA’s mission is to promote and protect the public health by promoting:

Answer 6

safe and effective products reach the market in a timely safe and effective products reach the market in a timely way
- However: once FDA determines a drug is safe and effective, it has little control over
its use in medical practice, such as for non-approved indications (“off-label” use)

Question 7

Specific FDA Function/Role in Drug Development

Process and Drugs in the Marketplace

Answer 7

• Approves drugs on the basis of purity, safety, efficacy
• Regulate all labeling of prescription and nonprescription drugs
• Advertising OTCs the responsibility of the Federal Trade Commission (FTC)
• Regulate manufacturing processes of drugs and institution of drug recalls
• Regulate bio-equivalence for generics and bio-similars
• Monitor safety of US blood supply

Question 8

Conceptualization

Answer 8

performed by independent investigators, small research companies, academic institutions & large pharmaceutical companies

Question 9

Intramural

Answer 9

NIH investigators perform research

Question 10

Extramural

Answer 10

independent investigators win research grants to perform research

Question 11

Drug development has

Answer 11

3 stages prior to approval

Question 12

STAGE 1

Answer 12

Drug discovery
Discovery ( Laboratory based)

5,000 – 10,000 compounds may be synthesized and tested
- 250 “may” make it to pre-clinical testing

Question 13

STAGE 2

Answer 13

Pre-clinical Testing

• Tests performed to determine if candidate molecule safe to test in humans
• Candidates for drugs are first tested in animals
• Very few candidate materials for drugs make it through pre-clinical testing
• < 0.1% of potential candidate drugs go from discovery to clinical testing stage
• Varies in number of years it takes

Question 14

STAGE 3

Answer 14

Clinical testing has 3 DISTINCT PHASES with distinct goals
- Investigational New Drug (IND) application must be submitted to FDA
in order to begin clinical testing in humans

Question 15

STAGE 4

Answer 15

Post approval and post clinical testing (also called Phase IV)

Question 16

To begin clinical testing,

Answer 16

Investigational New Drug (IND) Application must be filed

Question 17

When all clincial testing is complete,

Answer 17

The New Drug Application (NDA) must be filed

Question 18

PHASE IV

Answer 18

addition research post-marketing by FDA

- Used to identify events not detected during clinical testing

Question 19

IND

Answer 19

Investigational New Drug

Question 20

NDA

Answer 20

New Drug Application

Question 21

3 phases before drug approval : Clinical testing

Answer 21

• Phase 1: Learn how the drug works in (small number) of humans – set dosage
• Phase II: Demonstrate efficacy (proof of concept) and safety (toxicity) in patients
• Phase III: Provide strong evidence of efficacy and safety by studying candidate drug
  in a few thousand people with target disease in randomized, controlled trials using
  doses and settings more like “real world” practice

Question 22

Phase I Clinical Testing Goals Include

Answer 22

• Learn how candidate drug works in HEALTHY humans
   Studies of <100 healthy individuals
   Establish dose range, metabolism, excretion, toxicities
   Usually takes one year or less to complete

Question 23

Phase II Clinical Testing Goals Include

Answer 23

• Study candidate drug in a few hundred people with target disease
• Efficacy (proof of concept) and safety (toxicity) in patients
• Single arm studies (No comparison group)
• Usually takes up to two years to complete
  (occurs after Phase I testing is completed)

Question 24

Phase III Clinical Testing Goals Includ

Answer 24

Study a few thousand people with target disease in randomized, controlled trials
 Strong evidence for efficacy and safety
 Use doses and settings more like real-world practice
 Success is necessary to move to the next stage of approval
 Usually takes three to four years to complete
(occurs after Phase I and Phase II testing is completed

Question 25

Efficacy

Answer 25

Extent to which a specific intervention, procedure, regimen, or service
produces a beneficial result under ideal conditions
 “Ideal conditions” are achieved in clinical trials

Question 26

Effectiveness

Answer 26

• Measure of success of a therapeutic intervention carried out in a typical
  environment on typical patients
• “real-world” conditions

Question 27

Post-Clinical testing

Answer 27

NDA submitted to FDA upon successful completion of clinical testing (Stage 3)
 NDA specifies the following information about the candidate drug:
 Manufacturing
 Action in the body
 Marketing
 Labeling and toxicologic information

Question 28

Phase IV testing and evaluation

Answer 28

Post-marketing surveillance in larger samples and for longer time frame
 evaluation of safety and effectiveness not detected in earlier trials
 “real-world” settings, “real-world” patients, and very large numbers of people

Question 29

MedWatch

Answer 29

• FDA’s safety information adverse event reporting program
   Health professionals encouraged to report adverse events in their patients
   Manufacturers are required to report adverse events to FDA

Question 30

Adverse Event Reporting System

Answer 30

Supports the FDA’s post-marketing safety surveillance program
 Contains adverse drug event reports FDA received from manufacturers required by regulation

Question 31

ANDA

Answer 31

Abbreviated New Drug Application

Question 32

Abbreviated New Drug Application (ANDA). What is ANDA

Answer 32

• submitted to FDA for a drug already “approved” but required when requesting:

 Change from prescription to over-the-counter status
 Change in ingredients, dosage, manufacturing, formulation, or labeling

Question 33

Who submits to ANDA

Answer 33

Manufacturers of generics or biosimilars
- FDA examines the bio-equivalence, bioavailability, and
pharmacokinetic/pharmacodynamic properties

Question 34

Intellectual Property (IP) rights

Answer 34

protect innovators & provide
incentives for drug development

But: allow Pharma Companies to have a monopoly & charge higher prices

Question 35

Drug Price Competition & Patent Term Restoration Act of 1984

(Hatch Waxman Act) & PPACA

Question 36

Hatch-Waxman Act Characteristics

Answer 36

• Applies to small molecule drugs
  Innovator data exclusivity for 5 years from FDA approval*
   Additional 3 years of data exclusivity for new indications
   Additional 6 months of exclusivity for pediatric applications
   No new clinical trials required for generics (ANDA)
   Regulation pertains to small-molecule drugs

Question 37

Hatch-Waxman Act

Answer 37

established the approval pathway for generic drug products, under which applicants can submit an abbreviated new drug application (ANDA)

Question 38

Biologic

Answer 38

are a large, new part of the Rx marketplace
- Very important uses in major diseases
 Very, VERY expensive medications

Question 39

Majority of Biologicals Use Living Cells to

Produce a Protein Product

Answer 39

Insert gene encoding the protein of interest
 Cells require proper conditions for optimal growth
(temp, pH, oxygen, feeds, etc.)
 Culture and fermentation can take weeks
 Complex Purification Steps
 Safe product with desired potency

Question 40

Small molecule drugs vs. Biological drugs

Answer 40

Biological drugs are large and have a high MW. They are complex. Produced in living cell structure. Unstable and immunogenic

Small molecule drugs are non-immunogenic, stable, produced by chemical synthesis

Question 41

BLA

Answer 41

Biologic License Application- which includes

- Manufacturing info to demonstrate company can properly and consistently manufacture the product

Question 42

The biological product is licensed and can be marketed in the US only if:

Answer 42

FDA determines that the data shows the biological product is safe and effective for it’s proposed use, and
-the biological product can be manufactured in a way that ensures a quality product

Question 43

Biologics Price Competition and Innovation Act (2009)

Abbreviated approval pathway in place under the 2010 Patient Protection and
Affordable Care Act (PPACA)

Answer 43

Allows for licensing with less than full complement of pre-clinical and clinical data
 Focus on the manufacturing process
 “highly similar” with no clinically significant differences in safety, purity, potency,
immunogenicity
 Tested against a reference product, NOT against placebo!
 “The goal is not to independently establish safety & effectiveness of proposed product

Question 44

Biosimilarity”

Answer 44

A biosimilar product is a biological product that is approved based on a showing that it is
highly similar to an FDA-approved biological product, known as a reference product, and
has no clinically meaningful differences in terms of safety and effectiveness [purity,
potency] from the reference product

Only minor differences in clinically inactive components are allowable in biosimilar
products”

Question 45

Interchangeable means

Answer 45

An interchangeable biological product may be substituted for the reference product
by a pharmacist without the intervention of the health care provider who prescribed
the reference product

-They have different brand names,
making their identification more confusing