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BCOP > Drug Development Process > Flashcards

Drug Development Process Flashcards

1
Q

agencies that regulate and conduct research

A

NIH, NCI, cooperative groups (CALGB, ECOG, COG, alliance group)

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2
Q

accelerated development review

A

unmet medical need (ie. rare type of sarcoma), start early phase I

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3
Q

parallel track

A

Access to life-saving treatment to patients who for various reasons were unable to participate in clinical trials - with IND

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4
Q

treatment IND

A

Expanded access to a drug during phase 2 or 3 trials if it potentially represented a safer or better alternative to treatments currently available for terminal or serious illness

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5
Q

IND approval time

A

FDA approves in 6-9 months, may offer advice on how to develop the drug

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6
Q

IND definition

A 
#investigational new drug application
#submitted prior to starting clinical trials post pre-clinical
#waiting period of 30 days (FDA may signal that review will be longer than 30 days)
#contents, chemistry, pre-clin data, proposed clinical protocol, investigators brochure
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7
Q

when are sponsor /FDA meetings encouraged in drug development process?

A

prior to IND submission, mid phase II or phase I/II, when NDA submitted, when review submitted

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8
Q

which applications go to the FDA advisory committee?

A

NDA and review (NOT IND)

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9
Q

What is FDA ODAC?

A

oncology drug advisory committee - decisions are not binding ->advice goes to full advisory committee

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10
Q

preclinical

A 
#obtain lethal dose in 10% of animals (usually a small animal (mouse, rat) and a larger animal (rabbit, monkey)->determines LD10, initial dose in humans
#define quantitative and qualitative organ tox (single and long term dosing, post mortem's performed)
#same scheduled and route planned for humans
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11
Q

LD10

A

lethal dose in 10% of animals -dose used to start phase I testing is 1/10th of this dose in mg/m2 in the MOST sensitive species (could be mouse of monkey) (this # is controversial, some think it should be higher, new designs bump this dose up quicker)

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12
Q

FDA 1572 form

A 
#preclinical
#statement of investigator who places conduct of all in pursuing the study on investigator 
#signed by all investigators
#basically a CV of investigators
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13
Q

FDA 1571 form

A 
#preclinical
#this is the IND application
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14
Q

IND exempt studies (3pts)

A 
#study not intended to support FDA approval of a new indication or a significant change in pdt labeling
#study not intended to support a significant change in advertising
#study does not involve a ROA or dosage level or use in a pt population or other factor that significantly increases the risks associated with use of the pdt
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15
Q

phase I objectives (6pts)

A 
#SAFETY
#determine PK and PD (pharmacology)
#determine MTD
#describe drug related toxicity
#determination of tx activity is a secondary objective 
#historically in cancer pts with no other options (in panc CA this may be 2nd line but in breast CA this may be 6th, 7th, 8th line)
#15-30pts
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16
Q

phase I limitations (4pts)

A 
#potential for subtherapeutic dose
#extended period for completion
#limited info regarding pt variability and cumulative tox
#pts seen are NOT the patients of interest (heavily pretreated, advanced dz)
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17
Q

cohort determination (5pts)

A 
#standard 3+3
#continual reassessment method (CRM)
#modified CRM
#PK or PD guided design (using preclinical info)
#patient choice method (rare, pt selects dose based on expected ae's)
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18
Q

standard cohort (3+3)

A

3pts per a level, usually 4-8 escalations, if no DLT the whole cohort advances one level, if at 2nd level 1/3 pts has DLT enroll new set of 3 pts at same level, if no new DLT (so 1/6 has DLT) then can move to 3rd level but if one did have a DLT (so 2/6 have DLT) would drop back down to 2nd level with 3 more pts; also if 2/3 have DLT at a particular level you would go back a level and add 3 pts to ensure this is the MTD (ie. level below where 2/3 pts have DLT)

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19
Q

continual reassessment method (CRM)

A 
#estimates probability of MTD at each dose level based on a priori estimates (previously known info)
#uses real time information as trial progresses
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20
Q

modified CRM

A 
#start with standard cohort (3+3), then escalate with a single pt per dose level until toxicity, then begin the 33% rule, so if 1/3 pts DLT add 2pts to that dosing level, if then 1/3 move up, if 2/3 that determines DLT 
#much more efficient as fewer pts but limitation is less pk,pd data collected
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21
Q

dose escalation types (3pts)

A 
#fixed-conditional scheme
#modified fibonacci method
#dose-limiting toxicity rate
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22
Q

dose escalation - fixed-conditional scheme

A 
#start 100% increase until minimal tox (often grade II)
#THEN 50% increase until unacceptable tox (grade II-IV depending on lots of factors)
#THEN 25% increase until MTD
#good for honing in on correct MTD
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23
Q

dose escalation - modified fibonacci method

A 
#1st dose increase 100%, then 67%, 50%, 45%, 33% (2x, 3.3x, 5x, 9x, 12x, 16x)
#lots of problems with honing in on correct MTD
#fibonacci=1+1=2, 2+1=3, 3+2=5, etc
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24
Q

dose escalation - dose-limiting toxicity rate

A

estimate before trial begins what the tox is expected to be, usually only have 2-3 dose escalations, can change dose escalations based on real-time information

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25
Q

DLT

A 
#define before trial begins
#as specific as possible for both the drug and the population of interest
#dose at which 2/3 pts experience serious, life threatening tox (grade IV heme, grade II nonheme, depends of many factors) (ie. grade II QT prolongation more concerning than grade II alopecia)
26
Q

MTD

A

1 dose level before DLT occurs and is the phase II dose

27
Q

33% vs 50% rule

A

1/3 pts required pt’s to be added at that level vs 1/2 pts

28
Q

when MTD does not apply

A 
#vaccines (trying for biological active dose)
#anti-sense
#chemoprevention (may or may not apply)
#gene therapy
#cytostatics (arrest growth rather than kill, look at pharmacologic data)
#special populations (when genotypes determine sample size, where pt's can tolerate higher doses, plasma concentrations, target effect in tumor bx, target effect in surrogate tissue (skin punch bx), CT and PET scans)
29
Q

phase I/II trials (3pts)

A 
#MTD determination in pt population with same tumor (major limitation is accruing 1 tumor type, but is useful in specific tumor types like PI3K lung cancer)
#selection based on preclinical and phase I
#more pts at MTD prior to phase II
30
Q

phase II trials (4pts)

A 
#SAFETY AND EFFICACY
#late phase 2 may enroll pts with concomitant dz
#50-100 pts
#starting dose MTD from phase I
31
Q

phase II design categories

A 
#single arm: same tx at same dose (not prefered)
#comparative: experiment vs control
#selection: # of different tx's or doses are compared, with or without a control arm (different doses can be used to determine phase III dose)
32
Q

phase II interim analysis

A 
#goal is to minimize type 2 (false negative, beta) errors as type 1 (false positive, alpha) errors will be identified in phase 3 (type 2 = expected a response when none was really there so avoid giving to more pts ->no further clinical development)
#ie. Simon's Two-stage design->based on response or response and early progression
#minimize likelihood of taking inferior drug forward
33
Q

phase II endpoints

A 
#tumor markers (less favored by FDA, would not allow PSA)
#progression rates
#time to tumor progression
#randomized phase 2 discontinuation
34
Q

phase II - randomized phase 2 discontinuation endpoint

A 
#drug->responders vs nonresponders
##responders->randomize to further drug vs placebo
##nonresponders-> off study
35
Q

phase III trials

A 
#COMPARE NEW DRUG TO PLACEBO OR STD OF CARE
#larger # (often up to 1000)
#evaluate pt response +/- OS, clinical benefit response (OS is not always best endpoints, ie 1st line mets breast CA has many choices for tx so may use PFS at which point pt goes to next tx)
#phase II determines dosing
#long term study 1-5 yrs
36
Q

NDA

A 
#contains all preclinical and clinical data
#FDA determines if application can be filed
#FDA does NOT regulate chemical entities but rather LABELS for which these chemicals are used (intellectual property)
#advisory panels utilized
#decision is: approval, approvable (based of subsequent studies, based on populations of interest ie. need data in renal dysfunction pts for lenalidomide and MM), or not approvable
37
Q

how many days dose FDA have to review NDA?

A

180 days

38
Q

abbreviated new drug application

A 
#generic drug approval
#not required to contain any pharmcology, or tox, or clinical studies
#NEED one bioequivalency study
#results should fall within 20-30% or reference
#therapeutically equivalent
#bioequivalent
39
Q

fast tract designation - accelerated drug development (3pts)

A 
#may be designated fast tract at ANY STAGE
#unmet medical need (severity of dz it will tx, rapidly aggressive dz, lack of other tx avenues)
#payment of fees
#ie. docetaxel (NSCLC), arsenic (APML)
40
Q

mechanisms for faster approval - all subparts of the NDA (4pts)

A 
#expedited review (subpart E)
#accelerated approval (subpart H)
#fast tract (accelerates IND)
#priority review
41
Q

expedited review (subpart E)- accelerated drug development

A 
#approval based on phase II data
#ie. imatinib, crizotinib
42
Q

accelerated approval (subpart H)- accelerated drug development

A 
#approved on surrogate endpoint after phase III
#ie. docetaxel, bicalutamide, irinotecan
43
Q

priority review- accelerated drug development

A 
#NDA reviewed in 6 months
#any oncology drug (mandate from federal gov't, also includes HIV drugs)
44
Q

emergency use, compassionate IND

A 
#drug use for life-saving effort
#registered with the NCI as an investigator (only MD's)
#NCI must have an IND
#IRB must be notified
#informed consent
#final report to NCI
45
Q

criteria for obtaining an investigation drug outside of a clinical trial (4pts)

A 
#all reasonable and standard therapies exhausted
#ineligible for clinical trials (if eligible need to go on study)
#investigational agent is active
#pt is likely to benefit
46
Q

Group C Mechanism - obtaining an investigation drug outside of a clinical trial

A 
#def: phase 3 completed
#pts/protocol: 1
#protocol: std guidelines for use
#informed consent: written by NCI, approved by FDA and local IRB
#FDA involvement: prospective FDA approval
#availability: any MD
47
Q

Special Exception- obtaining an investigation drug outside of a clinical trial

A 
#def: phase 2-3
#pts/protocol: 1
#protocol: 2 pg form completed by investigator
#informed consent: written by PI, approved by local IRB
#FDA involvement: retrospective review by FDA
#availability: any MD
#example agents: any IND in phase 2 or 3
48
Q

Treatment referral Center- obtaining an investigation drug outside of a clinical trial

A 
#def: NCI designated protocol for CCC
#pts/protocol: multiple
#protocol: std protocol
#informed consent: written by NCI, approved by FDA and local IRB
#FDA involvement: submitted to FDA
#availability: selected cancer centers
#example agents: various
49
Q

RESIST criteria

A 
#response evaluation criteria in solid tumors
#currently on use CT and MRI imaging, not yet PET
50
Q

study endpoints (4pts)

A 
#RR: anatomical
#OS: rigid endpoint, least subject to bias, most impt to pts
#DFS: curve, used for approval for CA with high rates of recurrence OR when strongly correlates with OS
#PFS: curve, do not necessarily have to have a strong link between PFS and OS to obtain approval
51
Q

RESIST criteria responses -usually measured q2 cycles or 6-8 weeks. (impt that each measurement defines baseline, so if obtain PR, next image will be compared and judged on that PR as reference)

A

CR: disappearance of all target lesions
PR: 30% dec of sum of longest diameter (LD) taking as reference baseline sum LD
PD: 20% inc
SD: does not qualify for PR or PD

52
Q

AE reporting

A 
#ultimately PI has primary responsibility for AE identification, documentation, grading, and assigning of attribution (to drug, dz, or other cause) with help of clinical investigators
#CTCAE is currently version 4: common terminology criteria for adverse events
53
Q

AE - general grading (6pts)

A

0: no AE
1: mild AE
2: moderate AE
3: severe and undesirable AE
4: life-threatening or disabling AE
5: fatal AE

54
Q

AE - attribution description (5pts)

A

unrelated: clearly NOT
unlikely: doubtfully related
possible: may be related
probable: likely related
definite: clearly related

55
Q

studies that do NOT require IRB approval (5pts)

A 
#stability and compatibilty studies
#animal and tox
#susceptibility
#bench-top not involving pt data
#retrospective chart review for quality / internal (non-published)
56
Q

studies REQUIRING IRB approval (6pts)

A 
#medical devices
#radiopharmaceuticals
#pk
#pd
#vax
#chart review for research, publishing
57
Q

IRB responsibilities (4pts)

A 
#reveiw and approve research
#ensure informed consent (all AE reported even if CLEARLY not related to experiment tx)
#provide written notification to investigators
#continuing review
58
Q

IRB expedited review

A 
#minimal risk (surverys, educational procedures, chart reviews, additional testing on existing, nonidentified samples)
#minimal change from an existing study
#consists of review by IRB chairman and 1-2 other members
59
Q

minimal risk definition

A

probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psych exams or tests

60
Q

criteria for IRB approval

A 
#risks to subjects minimized
#risk to subjects are reasonable to benefits expected
#selection of subjects is equitable
#informed consent is obtained (pt needs time to review and all questions answered, translated if non-English)
#additional safeguards for vulnerable populations (children, prisoner, special needs)

BCOP (32 decks)

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