lecture V: drug development Flashcards
1
Q
Drug development stages
A
- Discovery
- Development
- Review
2
Q
Drug development: Discovery
A
Discover “article” and test in animals.
→few to many years
3
Q
Drug development: Development phases
A
- Pre-clinical
- Phase 1
- Phase 2
- Phase 3
4
Q
Drug development: Development
A
- 7-10 years
- cost ≈ 350-450 million $
most time-consuming and expensive stage
5
Q
Drug development: Development - FDA requirements
A
- Safety
- Efficacy
- Value
6
Q
Drug development: Review
A
- 12 months
7
Q
IND
A
Investigative New Drug.
8
Q
IND application
A
- First application made after pre-clinical phase of development stage
- Request FDA authorization to test drug in humans
9
Q
Definition of a drug according to the FDA
A
The term “drug” refers to “articles” (other than food)
(A) Recognized in an official compendium (USP)
(B) Intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals
(C) Intended to affect the structure or any function of the body
(D) Intended for use as a component of any article above
10
Q
USP
A
United States Pharmacopeia.
11
Q
NCE
A
New Chemical Entity.
12
Q
What can be a new drug?
A
NCE types…
1. Blockbuster drug
2. Increase in therapeutic efficacy
3. Increase in therapeutic efficiency
4. FDA approved, still patented but with a new use
5. Off-patent drug
6. Unapproved, but a known chemical
7. Plants, dirt, bugs, anything!
13
Q
NCE: Blockbuster drug
A
- made >1 million $
- patented
- first-in-class
→tamoxifen, prozac
14
Q
NCE: Increase in therapeutic efficacy
A
→ use of statins over fibrates
15
Q
NCE: Increase in therapeutic efficiency
A
Better ADME!
(can be an easier route of administration, less frequent dosing, more tolerable formulation)
16
Q
NCE: Off-patent drug
A
“New trick for old dog”
→use of thalidomide, originally for nausea in pregnant women, for cancer
17
Q
NCE: Unapproved but a known chemial
A
→use of arsenic for cancer
18
Q
Better than a new chemical, you are looking for _____
A
A viable opportunity!!!!
19
Q
Why do you need an IND?
A
- Legal
→ to allow investigational drugs to be shipped interstate for the conduct of clinical trials - Practical
→sponsor informs FDA of plans for clinical trials and provides to FDA the information to assess safety and merit of the investigations
20
Q
When does the FDA get updates on drug development?
A
Information on the drug development is submitted to the FDA every year that the IND is active.
21
Q
Purpose of an IND
A
The purpose is to show that a product will not expose humans subjects to unreasonable risks.
22
Q
Which parameters must be known before administering an investigational drug to humans?
A
- Duration of exposure
→duration of drug exposure in humans should not exceed duration of exposure in animals - NOAEL
→Maximum initial dose used in humans should not exceed maximum observed no adverse effect level dose studied in animals
23
Q
When is an IND application required?
A
Whenever studies in humans are conducted for the first time in the USA.
24
Q
IND exemptions
A
- Academic research
- Drug is approved in the USA and investigation is not intended to support change in labeling or advertising and does not change the known risk/benefit profile
→i.e. investigate dosage - Bioavailability/bio-equivalence studies
→testing generic drugs
25
IND application content
1. Non-clinical
→animal study data
→sufficient data to support clinical protocol in humans
→basic exposure data
2. CMC
→sufficient information to assure proper identification, quality, purity and strength
→sufficient information whether drug batches can be produced and
consistently supplied
3. Clinical protocol
→specify how to ensure the safety of the subjects in the study
26
CMC
Chemistry, Manufacturing & Controls
27
IND process
1. FDA receives the document and notifies you of receipt (dated)
2. FDA review of the IND
3. The FDA will determine within 30 days whether your study is “reasonably safe to proceed”
4. Clinical hold & letter ?
28
Are INDs approved?
No! Not receiving a letter is a good sign :)
29
Clinical hold
Reasons include...
- Imposed if the IND is deficient or if the information about the drug does not support the proposed clinical study
- only on safety issues
- clinical investigators deemed unqualified
30
Clinical hold: letter
- letter details the hold issues
- a response must be sent
- division will respond within 30 days to remove, continue or modify the clinical hold
31
IND phases
1. Phase 1: Clinical pharmacology studies
2. Phase 2: Controlled studies
3. Phase 3: Confirmatory studies
32
IND Phase 1
- First time in humans
- Determine PK and metabolic activity and side effects
- 20-80 subjects
- Used to assess risk
33
IND Phase 2
- Evaluate drug safety and efficacy for a particular indication
- Further evaluate pharmacologic effect
- Dose-response
- Closely monitored
- Up to 300 subjects
- Proof of concept studies
→testing different [drug], patient populations, biomarkers
34
IND Phase 3
- Pivotal studies
- Gather efficacy and safety information needed to evaluate risk-benefit of the drug
- Test under conditions resembling the market
- Address special issues
→drug-drug interactions, contraindications, dependency
- 300 – 5000 subjects
- Large, multicenter
35
Primary endpoint
The main result that is measured at the end of a study to see if a given treatment worked.
36
Why do you only want one pre-determined primary endpoint?
Purely for statistical reasons!
37
What is the purpose of conducting clinical investigations?
To distinguish the effect of the drug from other influences such as...
1. spontaneous change in the course of the disease
2. placebo effect
3. biased observation
38
Name an advantage of controlled trials.
Controlled trials increase the likelihood that the outcome differences are attributed to study drug treatment.
39
Studies are _____ in adequate and well-controlled trials.
Blinded/masked
40
Possible controls in a controlled trial
1. Placebo (inactive preparation)
2. 2 doses of test drug compared
3. Known effective therapy
41
NDA
New Drug Application.
- Second application made during the review phase
- Seek FDA approval and a label for the drug
- A culmination of the studies under the IND and facilitates the review and approval process
42
What advantage does a NDA give?
Allows you to SELL your drug and MOVE it from state to state.
→Prior to this, the article is considered an Investigational Drug
43
NDA content
1. CMC
→Description of the drug and its formulation
2. Pharmacology
→Clinical pharmacology
→Indication and usage
→Dosage and administration
3. Clinical toxicity/safety
→Contraindications
→Warnings
→Precautions
→Adverse reactions
→Drug abuse and dependence
→Overdosage
44
NDA: Grounds for FDA approval
1. Drug is safe and effective as shown in clinical studies
2. Drug manufacturing, processing and packing methods are adequate and reliable
3. Labeling claims are NOT false and misleading
4. Patent life
45
Dry Eye
A very prevalent and chronic disease that is predominantly characterized by symptoms such as:
-dryness of the eye’s surface
-gritty feeling
-redness or irritation
-stinging or burning
-blurred vision or tired eyes
-photophobia
46
In what conditions do dry eye symptoms worsen?
-windy
-low humidity
-prolonged visual efforts
→computer screens
-increased pollution, dryness, air conditioning
-use of certain medications
-diet poor in omega 3s
47
What happens if dry eye is left untreated?
Ocular surface damage.
48
Dry eye prevalence
-14-35% individuals worldwide
-Increases 35% each decade after age 40
-Predominantly female
49
In which populations is dry eye prevalence expected to grow?
-aging population
-people with certain medical conditions
→diabetes, rheumatoid arthritis, thyroid problems
-contact-wearers
-people who had LASIK
50
What causes dry eye?
Tear film instability often due to a lack of blinking!
51
What causes tear film instability?
Disruption of the Lacrimal Functional Unit
52
Tear film
Liquid at the surface of our eye compose of three layers:
1. Mucus layer
2. Watery layer
3. Oily layer
53
Tear film: Mucus layer
Formed by mucin/glycoprotein secretion, making it "sticky"
54
Tear film: Watery layer
Water/"tears" (water, ions) coming out from lacrimal glands
55
Tear film: Oily layer
Oils secreted by meibomian glands which prevents evaporation of tears
56
Lacrimal glands
Produce water
57
Conjunctival cells
Produce mucins
58
Corneal Epithelial cells
Maintain integrity of the surface
59
Meibomian glands
Produce lipids
60
Lacrimal functional unit: nerves
1. Corneal motor nerves
2. Corneal sensory nerves
→ when you leave your eyes open for too long, there are impulses sent to the brain which will send down a message to blink and thus restore teary layer of eyes
61
Approved eye treatments for DED: Drug classes
1. Anti-inflammatories
2. Increase tears
3. Lubricants
4. Secretagogues
62
Side effect of anti-inflammatory drug for DED
pain & burning
63
Existing drug classes for DED
1. Anti-inflammatories
→only ones in Canada...
2. Increase tears
3. Lubricants
4. Secretagogues
64
Varenicline
Receptor agonist that activates PS and stimulates the lacrimal functional unit
→causes nose irritation since it is a nasal spray
65
Neurotrophic growth factors
Neurotrophins interact with specific receptors on neuronal and non-neuronal cells to signal survival, differentiation and synaptic plasticity.
66
Nerve growth factor (NGF)
-dimeric polypeptide
-26 kDa
-signalling mediated via TrkA and p75NTR receptors
-core of the NGF monomer formed by a pair of two-stranded, twisted b-sheets with a cysteine knot motif
-L2 and L4 b-turns are important for biological activity of NGF
67
NGF & TrkA expression
Throughout lacrimal functional unit
68
Advantages of NGF & TrkA as a target in DED
- Stimulates mucin secretion
- Improves corneal healing
- Supports survival and differentiation of neuronal cells to improve corneal sensitivity
- Works in patients with neurotrophic keratitis and corneal ulcers
69
Why did rhNGF fail?
Oxervate was approved for neurotrophic keratitis at 13,000$ for 1 week, with 6 weeks of total treatment needed, and it is not stable at room temperature.
70
Neurotrophic keratitis
End-stages of DED, where the condition becomes irreversible.
71
Peptidomimetic drugs
Compounds derived from a peptide which mimic functional or conformational important sites in a protein of interest.
→Usually have a modification of the AAs, peptide backbone, 3D conformation
72
Advantage of peptidomimetic drugs
Bridge the gap from simple peptides to non-peptide synthetic (organic) molecules
73
Strategy to generate NGF peptidomimetics for targeting TrkA
1. Generation of TrkA receptor mAb
2. Activity assays
3. Agonistic mAb developed
4. Pharmacophore identification
→NGF L4 b-turn
5. Design of novel compounds that mimic 3D elements
6. Test bioactivity
7. MIM-D3 became the lead compound!
74
MIM-D3 studies on in vitro conjunctival cells
- Stimulated a 1.5 fold increase in glycoconjugate secretion
- Stimulated MAPK activity
75
MIM-D3 studies on in vivo rat model of dry eye
- Stimulated a 2-3 fold increase in [mucin] in tears
- Reduced ocular surface damage
76
How was an experimental model of DED established in rats?
Use of systemic scopolamine which shuts down all secretion
77
Criteria for MIM-D3 being a viable drug for an IND
1. Clinical: unmet need in DED
2. Regulatory: have preclinical pharmacology data, preliminary chemistry and clinical protocol
3. Commercial: economically valuable (patents!), suitable drug form
4. Operational: hired CROs
78
CRO
Contract research organizations
79
MIM-D3 (Tavilermide) Phase 2 clinical study: Objectives
1. Safety in patients with DED
→toxicity not really an issue, since most of the drug usually does not even reach the target (eye drops)
2.Efficacy
→Dose finding (1% and 5%)
→Duration and dosing schedule (28 days, BID)
→Endpoints: Signs and Symptoms of DED
→Patient populations
80
MIM-D3 (Tavilermide) Phase 2 clinical study: Design
explain it :) slide 36 + NOTES
81
Fluorescein eye stain
This is a test that uses orange dye (fluorescein) and a blue light to detect foreign bodies in the eye. This test can also detect damage to the cornea. The cornea is the outer surface of the eye.
82
MIM-D3 (Tavilermide) Phase 2 clinical study: Results
SIGN: less staining! compared to placebo but
NOT with P < 0.05
SYMPTOM: lower diary score! compared to placebo but NOT P < 0.05
→Did not meet pre-specified primary efficacy endpoints
→Observed significant improvements in exploratory endpoints
→The 1% dose showed significant (p<0.05)
improvements in signs (change from pre-CAE
to post-CAE)
→The 5% dose showed significant (p<0.05)
improvements in symptoms (diary dryness), but
this is chemically difficult to achieve
→Both doses showed excellent safety and tolerability
83
Tavilermide 1% Phase 3 clinical study
- all (3) studies using CAE
- never met a pre-specified endpoint!
84
Tavilermide 5% Phase 3 clinical study
- no CAE
- increased concentration (5%)
- increased duration (85 days)
- RESULT:
→ SIGNS: lowered staining with 5% with P < 0.05, hit primary sight endpoint!!
→ SYMPTOMS: all three arms got better over time (failure)
85
Tavilermide 5% in a defined subgroup Phase 3 clinical study
RESULT:
→SIGNS: works even better and more significantly (P < 0.1)
→SYMPTOMS: works! (efficacious results found)
NOW...6th clinical trial underway in this subpopulation
