Drug Development, FDA and Generic drugs Flashcards
To describe why “Pharma” develops drugs/biologics
profit for shareholders
To describe the process of drug/biologic development
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
To define the FDA’s role in NCE/biologic approval
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
To apply knowledge of generic Rx & drug costs to Rxing
2018 drug development cost ~ $1.3-1.8 B. takes ~ 8-10 yr and the estimated capitalized cost is ~ $2.4 B
To describe the role of biosimilars in clinical therapeutics
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
what are the components of an investigational new drug application
- 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
outline how pre-clinical development of a drug works
(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
what are the components of an investigational new drug application
- 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
What are the phases to a clinical trial?
Phase 0 - “microdose”
Phase I - “first in humans”
Phase II - “ initial efficacy study”
Describe this phase of a clinical trial: Phase 0
“microdose studies” - low dose of <100ng
- endpoint: kinetics and distribution
- labeled with radioisotope
1) AMS –> estimate the quantity (pharmaokinetics)
2) PET –> imaging techniques –> pharmacodynamics
Describe this phase of a clinical trial: Phase I
“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)
Describe this phase of a clinical trial: Phase II
- “initial efficacy study” - does the drug work? [hundreds]
- endpoint: dose-response [exposure-response] - efficacy
- endpoint: toxicity/safety
- population pharmacokinetics
- proof of concept hitting target
Describe this phase of a clinical trial: Phase III
- “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
how is testing for monoclonal antibodies different from the usual drugs and why?
- 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)
what are other kinds of Phase I studies
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)
at what phases in the drug approval process that are go-no go decision making areas?
Phase I
Phase II
components of a NDA
Pre-clinical studies Human clinical studies Long-term safety data Manufacturing details Labeling information Risk management plan Pediatric development plan
why do drugs fail to be FDA approved?
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)
How can drug companies reduce costs by
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
What is the use of “family of compounds” that drug companies make?
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
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?
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.