Drug Development, FDA and Generic drugs

Question 1

To describe why “Pharma” develops drugs/biologics

Answer 1

profit for shareholders

Question 2

To describe the process of drug/biologic development

Answer 2

17 years for patent approval (costs: $1.8B)
Preclinical –> [Phase 0] –> Phase I –> Phase II –> Phase III –> Phase IV; FDA regulates each phase of this path

1) Pre-discovery development: drug discovery
- target identification (0.5-1y)
- target validation (0.5-1y)
- lead identification (0.5-1y)
- candidate optimization (2-3y)
2) Pre-discovery development: preclinical (1-2y)
(a) medicinal chemistry & formulation (lead compound optimization)
(b) in vitro - hits target, metabolism, transport, tissue toxicity
(c) in vivo - animal species testing of safety and tolerability in 2 mammalian species
3) Clinical trials (4-6y)
4) For review
5) Large scale manufacturing

Question 3

To define the FDA’s role in NCE/biologic approval

Answer 3

New Drug Application

1) Is this acceptable? Can we file it
2) different reviews (medical, pharmacology, chemistry, biopharmaceutical, statistical, microbiologY)
3) send questions back to company ==> advisory committee meeting (experts in the field)
4) Inspector comes to site to see all original data to confirm data accuracy
5) is labeling review acceptable
6) inspection of manufacturing plant
7) NDA action: yes / no?

8) post-marketing commitment studies ==> for rare ADs and long-term safety data; risk evaluation and mitigation strategy (REMS) – endpoint: expected frequency of fatal ADR; NNT
9) post-marketing requirement studies ==> mostly for safety (drugxdrug interaction, QTc); sometimes further determination of efficacy

Question 4

To apply knowledge of generic Rx & drug costs to Rxing

Answer 4

2018 drug development cost ~ $1.3-1.8 B. takes ~ 8-10 yr and the estimated capitalized cost is ~ $2.4 B

Question 5

To describe the role of biosimilars in clinical therapeutics

Answer 5

biosimilar (generics) = biological product that is highly similar to the reference product not withstanding minor differences in clinically inactive components; no clinically meaningful differences between the biological product and the reference product in terms of safety, purity & potency

Blockbuster model not sustainable ==> increase in generics & biosimilars

Question 6

what are the components of an investigational new drug application

Answer 6

• Investigational plan
• Investigator’s brochure = what is it supposed to do?
• Protocols
• Chemistry and manufacturing = how does it degrade; how to store it
• Drug product
• Labeling
• Environmental assessment
• Pharmacology and drug distribution = only certain individuals contracted with -FDA are able to prescribe investigational drugs
• Toxicology

Question 7

outline how pre-clinical development of a drug works

Answer 7

(a) medicinal chemistry & formulation (lead compound optimization), for first-in-human
(b) in vitro - hits target, metabolism, transport, tissue toxicity
(c) in vivo - animal species testing of safety and tolerability in 2 mammalian species
- NOAEL, (No Adverse Effect Level), TDL (Therapeutic Dose Level), LD10 (Lethal Dose in 10%)
- Estimates of PK parameters, distribution & metabolism
- Teratogenicity, genotoxicity, mutagenicity

Question 8

what are the components of an investigational new drug application

Answer 8

• Investigational plan
• Investigator’s brochure = what is it supposed to do?
• Protocols
• Chemistry and manufacturing = how does it degrade; how to store it
• Drug product
• Labeling
• Environmental assessment
• Pharmacology and drug distribution = only certain individuals contracted with -FDA are able to prescribe investigational drugs
• Toxicology

Question 9

What are the phases to a clinical trial?

Answer 9

Phase 0 - “microdose”
Phase I - “first in humans”
Phase II - “ initial efficacy study”

Question 10

Describe this phase of a clinical trial: Phase 0

Answer 10

“microdose studies” - low dose of <100ng

• endpoint: kinetics and distribution
• labeled with radioisotope

1) AMS –> estimate the quantity (pharmaokinetics)
2) PET –> imaging techniques –> pharmacodynamics

Question 11

Describe this phase of a clinical trial: Phase I

Answer 11

“first in humans” (healthy volunteers)

• endpoint: toxicity/safety [10-40]
• placebo treated (n=2-4) ==> blind PI and volunteers from bias
• single / multiple dose cohort escalation – to see if effects seen in animals also seen in humans
• initial human pharmacokinetics
• find recommended phase II dose (RP2D)

Question 12

Describe this phase of a clinical trial: Phase II

Answer 12

• “initial efficacy study” - does the drug work? [hundreds]
• endpoint: dose-response [exposure-response] - efficacy
• endpoint: toxicity/safety
• population pharmacokinetics
• proof of concept hitting target

Question 13

Describe this phase of a clinical trial: Phase III

Answer 13

• “define efficacy in patients” [thousands]
• endpoint: new drug / biologic v. placebo (or v. gold standard)
• less common toxicities observed
• finalized dosing
  ==> new drug application (NDA) to the FDA

Question 14

how is testing for monoclonal antibodies different from the usual drugs and why?

Answer 14

• must test 1 placebo pt + 1 treatment pt – then watch both for 3 days, before you can do it in 6 active v. 2 placebo

TGN1412 Phase-I Study: FIH study of a CD28 agonist mAb (6 active v. 2 placebo). –> T cell activation
- no significant issues in pre-clinical data
- First dose cohort - in <90min == HA, rigors, lumbar myalgia ==> in 2, progressed to ARDS, distal digital necrosis and loss of digits
==> starting dose was too high (100x too high)

Question 15

what are other kinds of Phase I studies

Answer 15

Drug-drug interactions
Food effect == affecting absorption (v. low-fat / high-fat meal)
‘Special Populations’ == renal/hepatic dysfx
New formulation/bioequivalence
Additional safety
Biomarker/imaging
ADME
Thorough ECG (QTc) studies (v. Moxifloxacin)

Question 16

at what phases in the drug approval process that are go-no go decision making areas?

Answer 16

Phase I

Phase II

Question 17

components of a NDA

Answer 17

Pre-clinical studies
Human clinical studies
Long-term safety data
Manufacturing details
Labeling information
Risk management plan
Pediatric development plan

Question 18

why do drugs fail to be FDA approved?

Answer 18

not as efficacious

Phase II: safety
Phase III: safety; no adequate basis to be competing on the market (too many of this drug alreadY0

(definitely most expensive to fail in Phase 3)

Question 19

How can drug companies reduce costs by

Answer 19

Repurposing – look at compounds that they have on the shelf from a family of compounds == to see if they can be used for something else

compress the timeline

“ Tweak” drug development path to reduce cost/gain time

Question 20

What is the use of “family of compounds” that drug companies make?

Answer 20

Repurposing – look at compounds that they have on the shelf from a family of compounds == to see if they can be used for something else

compress the timeline

“ Tweak” drug development path to reduce cost/gain time

Question 21

Phase I study - Jan 2016

Oral FAAH inhibitor
128 subjects in study 90 received the FAAH Inh.

6 participants (29-48 y) daily dosing for 2-3 days
One died -brain dead
4 severe neurological damage (MRI confirmed) ? Reversible
1 minor symptoms; one no symptoms observed

You are a pharmaceutical company VP & Medical Director in charge of the development of a novel chemical entity that inhibits the enzyme which catabolizes the endocannabinoid-anandamide (to extend the “natural high”). In single dose Phase 1 studies in healthy volunteers, oral doses of up to 50 mg were safely given to ~ 90 subjects. At the second dose cohort of the 14 day multi-dose study, after 2-3 days of 15 mg PO /day, one subject presented to the local ER with altered mental status and focal weakness (?CVA). Within 24h the patient was brain dead. Over the next 1-2 days 5 other subjects receiving the drug on a daily basis develop focal neurological symptoms.
MRI –> Lesions in pons & hippocampus (hemorrhagic necrosis)

What do you want to know and what should you do? When and what do you report to the regulatory authorities?
What should be done for subjects who only received one dose of the drug dose?

Answer 21

1) Medical safety –> STOP THE STUDY; removal all drugs as possible from those who were exhibiting sxs
2) Report to the FDA - asap
3) Find all people who had gotten the drug and evaluate them, scan them

4) Go back to pre-clinical studies –> see if there were primates who “died of unclear reasons”
5) Go back to prior studies from other companies who have tested for similar molecules.