Drug Development Process

Question 1

agencies that regulate and conduct research

Answer 1

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

Question 2

accelerated development review

Answer 2

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

Question 3

parallel track

Answer 3

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

Question 4

treatment IND

Answer 4

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

Question 5

IND approval time

Answer 5

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

Question 6

IND definition

Answer 6

#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

Question 7

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

Answer 7

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

Question 8

which applications go to the FDA advisory committee?

Answer 8

NDA and review (NOT IND)

Question 9

What is FDA ODAC?

Answer 9

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

Question 10

preclinical

Answer 10

#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

Question 11

LD10

Answer 11

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)

Question 12

FDA 1572 form

Answer 12

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

Question 13

FDA 1571 form

Answer 13

#preclinical
#this is the IND application

Question 14

IND exempt studies (3pts)

Answer 14

#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

Question 15

phase I objectives (6pts)

Answer 15

#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

Question 16

phase I limitations (4pts)

Answer 16

#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)

Question 17

cohort determination (5pts)

Answer 17

#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)

Question 18

standard cohort (3+3)

Answer 18

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)

Question 19

continual reassessment method (CRM)

Answer 19

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

Question 20

modified CRM

Answer 20

#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

Question 21

dose escalation types (3pts)

Answer 21

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

Question 22

dose escalation - fixed-conditional scheme

Answer 22

#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

Question 23

dose escalation - modified fibonacci method

Answer 23

#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

Question 24

dose escalation - dose-limiting toxicity rate

Answer 24

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

Question 25

DLT

Answer 25

``` #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) ```

Question 26

MTD

Answer 26

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

Question 27

33% vs 50% rule

Answer 27

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

Question 28

when MTD does not apply

Answer 28

``` #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) ```

Question 29

phase I/II trials (3pts)

Answer 29

``` #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 ```

Question 30

phase II trials (4pts)

Answer 30

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

Question 31

phase II design categories

Answer 31

``` #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) ```

Question 32

phase II interim analysis

Answer 32

``` #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 ```

Question 33

phase II endpoints

Answer 33

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

Question 34

phase II - randomized phase 2 discontinuation endpoint

Answer 34

``` #drug->responders vs nonresponders ##responders->randomize to further drug vs placebo ##nonresponders-> off study ```

Question 35

phase III trials

Answer 35

``` #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 ```

Question 36

NDA

Answer 36

``` #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 ```

Question 37

how many days dose FDA have to review NDA?

Answer 37

180 days

Question 38

abbreviated new drug application

Answer 38

``` #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 ```

Question 39

fast tract designation - accelerated drug development (3pts)

Answer 39

``` #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) ```

Question 40

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

Answer 40

``` #expedited review (subpart E) #accelerated approval (subpart H) #fast tract (accelerates IND) #priority review ```

Question 41

expedited review (subpart E)- accelerated drug development

Answer 41

``` #approval based on phase II data #ie. imatinib, crizotinib ```

Question 42

accelerated approval (subpart H)- accelerated drug development

Answer 42

``` #approved on surrogate endpoint after phase III #ie. docetaxel, bicalutamide, irinotecan ```

Question 43

priority review- accelerated drug development

Answer 43

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

Question 44

emergency use, compassionate IND

Answer 44

``` #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 ```

Question 45

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

Answer 45

``` #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 ```

Question 46

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

Answer 46

``` #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 ```

Question 47

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

Answer 47

``` #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 ```

Question 48

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

Answer 48

``` #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 ```

Question 49

RESIST criteria

Answer 49

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

Question 50

study endpoints (4pts)

Answer 50

``` #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 ```

Question 51

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)

Answer 51

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

Question 52

AE reporting

Answer 52

``` #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 ```

Question 53

AE - general grading (6pts)

Answer 53

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

Question 54

AE - attribution description (5pts)

Answer 54

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

Question 55

studies that do NOT require IRB approval (5pts)

Answer 55

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

Question 56

studies REQUIRING IRB approval (6pts)

Answer 56

``` #medical devices #radiopharmaceuticals #pk #pd #vax #chart review for research, publishing ```

Question 57

IRB responsibilities (4pts)

Answer 57

``` #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 ```

Question 58

IRB expedited review

Answer 58

``` #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 ```

Question 59

minimal risk definition

Answer 59

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

Question 60

criteria for IRB approval

Answer 60

``` #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) ```