SAS Clinical Trails Phase-I

7/29/2019 SAS Clinical Trails Phase-I

1/70

Design and Analysis of Phase IClinical Trials in Cancer Therapy

Alex A. AdjeiKatherine Anne Gioia Chair in Cancer

MedicineRoswell Park Cancer InstituteBuffalo, NY


2/70

Definition

First evaluation of a new cancer therapy inhumans

First-in-human single agent study

Combination of novel agents

Combination novel agent and approved agent

Combination of approved standard agents ?(pilot study ?)

Combination of novel agent and radiationtherapy

Eligible patients usually have refractorysolid tumors of any type


3/70

Conventional eligibility criteria- examples:

Advanced solid tumors unresponsive to standardtherapies or for which there is no known effective

treatment

Performance status (e.g. ECOG 0 or 1)

Adequate organ functions (e.g. ANC, platelets,

Creatinine, AST/ALT, bilirubin)

Specification about prior therapy allowed

Specification about time interval between prior therapy

and initiation of study treatment

No serious uncontrolled medical disorder or active

infection

Phase I Patient Population


4/70

Agent-specific eligibility criteria - examples:

Restriction to certain patient populationsmust havestrong scientific rationale

Specific organ functions:

For examplecardiac function restrictions (e.g. QTc < 450-470ms, LVEF > 45%, etc) if preclinical data or prior clinical data

of similar agents suggest cardiac risks

For exampleno recent (6-12 months) history of acute

MI/unstable angina, cerebrovascular events, venous

thromboembolism; no uncontrolled hypertension; no significant

proteinuria, for antiangiogenic agents

Prohibited medications if significant risk of interaction

with study drug

Phase I Patient Population


5/70

A New Agent Merits Clinical Study if

It is biologically plausible that the agent may

have activity in cancer (target seems valid and

agent affects it)

There is reason to expect benefit for patients(preclinical or other evidence of efficacy)

There is reasonable expectation of safety

(toxicology)

Sufficient data on which to base starting dose

Hirschfeld S, 2004


6/70

The 3 Basic Tenets Of Phase I Studies

Define a recommended dose : SAFELY (minimum # of serious toxicities)

EFFICIENTLY (smallest possible # of pts) RELIABLY (high statistical confidence)

SAFETY TRUMPS EVERYTHINGELSE


7/70


8/70


9/70

At what dose do you start ?


10/70

Typically a rodent (mouse or rat) and non-rodent(dog or non-human primate) species

Reality of animal organ specific toxicitiesvery few

predict for human toxicity Myelosuppression and gastrointestinal toxicity

more predictable

Hepatic and renal toxicitieslarge false positive

Toxicologic parameters

LD10lethal dose in 10% of animals

TDL (toxic dose low)lowest dose that causesany toxicity in animals

Preclinical Toxicology


11/70

Phase I Trials : Starting Dose

1/10th of the LD10 in rodents,or

1/3rd of the minimal toxic dose in

large animalsExpressed as mg/m2

These have historically been safedoses


12/70

Equivalent Surface Area DosageConversion Factors

MOUSE20g

RAT150 g

MONKEY3.0 kg

DOG8 kg

MAN60 kg

Mouse 1 1/6 1/12Rat 2 1 1/7Monkey 4 2 1 3/5 1/3Dog 6 4 5/3 1 Man 12 7 3 2 1

Freireich EJ, et al, Cancer Chemother Rep 50:219-244, 1966


13/70

What are the endpoints

/ objectives ?


14/70

Phase I Study Endpoints

Dose, toxicity, pharmacology (efficacy ? )

Classical goals

Identify dose-limiting toxicities (DLTs)Identify the maximally tolerated dose

(MTD)

Assess pharmacokinetics (drug metabolismand clearance)

Evaluate target modulation


15/70

Defining Toxicities :NCI Common Toxicity Criteria

Grade 1 = mild

Grade 2 = moderateGrade 3 = severe

Grade 4 = life-threatening

Grade 5 = fatal


16/70

Dose-Limiting Toxicities (DLT)

Toxicities that, due to their severity or duration,

are considered unacceptable, and limit further

dose escalation

Defined in advance of beginning trial

Classically based on cycle 1 toxicity

Examples:

ANC < 500 for 5 or 7 days

ANC < 500 of any duration with fever

PLT < 10,000 or 25,000

Grade 3 or greater non-hematologic toxicity

Inability to re-treat patient within 2 wks of scheduledtreatment


17/70

Definition of DLT is Dynamic

Examples: DLTs in 2008 Diarrhea : grade 3 in spite of adequate antidiarrheal

therapy (loperamide)

Nausea and vomiting : grade 3 in spite of adequate

anti-emetic prophylaxis and therapy (steroids, 5HT3antagonists)

Hypertension : grade 3 in spite of adequate anti-hypertensive therapy

Inability to take at least 90% of drug doses in a cycle(continuous oral meds)

Grade 2 chronic unremitting toxicity


18/70

Maximally Tolerated Dose(MTD)

Inconsistently defined as either: Dose at which 33% of pts experience

unacceptable toxicity (DLT in 2 of 3 or 2 of 6)

OR 1 dose level below that

MTD = level @ DLT (in Europe or Japan)

MTD = level below DLT (in US)

6-10 pts treated at the recommended Phase IIdose (MTD or 1 dose level below)


19/70

Recap : Trans-AtlanticDifferences in Terminology

Important to note that:

Maximum tolerated dose (MTD):

Usually means recommended dose in US

Usually means dose level above recommendeddose in Europe and some other jurisdictions


20/70

How many patients percohort?


21/70

Patients per Cohort : Guiding

Principles

Minimum needed to provide adequate

toxicity information

Classically 3 patients per cohort In some designs 1 patient per cohort

until toxicity seen

If correlative studies are a major aim, may

increase up to 6 patients per cohort


22/70

3 pts

Dose

3 pts

3 pts

3 pts

3 pts

3 ptsRecommended dose

DLT

3 pts+

Eisenhauer et al.

DLT

Phase I Standard 3 + 3 Design


23/70

How quickly do youescalate?


24/70

Phase I Trial Design : Dose Escalation

Escalation in decreasing steps (Hansen HH et al.

Cancer Res. 1975)

Attributed to a merchant from Pisa in the 13th century

(Leonardo Bonacci, 1170-1240; aka Fibonacci)

Outlined a number of problems including how many pairs

of rabbits can be produced from a single pair underspecified conditions? (1, 1, 2, 3, 5, 8, 13, 21, 34, 55, 89,

144..) in a book, Liber abacus


25/70

Phase I Trials: Dose Escalation

Cohort Dose % Escalation

1 n first dose

2 2 n 100%

3 3.3 n 67%

4 5 n 50%5 7 n 40%

6 and higher 25-33%

The Modified Fibonacci Schedule


26/70

Cohort Dose Escalation

# of pts w/DLT Action

0/3 Increase to next level

1/3 Accrue 3 more pts at same dose level

1/3 + 0/3 Increase to next dose level

1/3 + 1/3 Stop: recommend previous dose level



2/3 Stop: recommend previous dose level3/3 Stop: recommend previous dose level


27/70

Problems and Pitfalls


28/70

Phase I Study Assumptions

The higher the dose,

the greater the

likelihood of efficacy

Dose-related acute

toxicity is regarded as

a surrogate for

efficacy The highest safe dose

is the dose most likely

to be efficacious

A B

107

107

106 106

105 105

104 104

103 103

102 102

SURVIA

LFRACTION

c d

DOSE DOSE

y

x

z

w

Slope of line c = y/x = k

Slope of line d = z/w = h


29/70

Dose-response: Efficacy and

Toxicity

010

20

30

40

50

6070

80

90

100

0.00

1.25

2.00

2.50

3.00

3.50

4.25

4.75

5.50

7.00

Therapeutic

Adverse

M difi d Fib i D


30/70

Modified Fibonacci DoseEscalation

Problems:

Requires many patients

Takes a long time

May expose a substantial proportion of

patients to low, ineffective doses

Cl i Ph I T i l


31/70

Classic Phase I TrialsDesign Limitations

Wide confidence intervals

Patients treated at ineffective dosesin first cohorts

High risk of severe toxicities at late

cohorts


32/70

Classic Phase I Trials

Design LimitationsChronic toxicities usually cannot

be assessedCumulative toxicities usually

cannot be identifiedUncommon toxicities will be

missed


33/70

Phase I Studies and Infrequent

Toxicities

Probability of NOT observing a serioustoxicity occuring at a rate of:

Number of patients 10% 20%

1 0.90 0.80

2 0.81 0.64

3 0.73 0.51

6 0.53 0.26

10 0.35 0.11

15 0.21 0.04

Probability of overlooking a toxicity: POT(p) = (1-

p)n; n = sample size,p = true toxicity rate

Al D i


34/70

Alternate Designs

Starting dose

Number of patients per dose level

Method/rapidity of dose escalation


35/70

Starting

Dose

(% of LD10)

# of Dose

Levels to

Reach MTD

# of Unsafe

Trials*

n = 21

# of Unsafe

Drugs*

n = 14

10% 7 (4-14) 0 0

20% 5 (3-11) 5 2

30% 3 (2-9) 11 6

Selection of Starting Dose for Phase I Trials:

Retrospective analysis of 21 trials using

modified Fibonacci dose escalation

*Unsafe defined as reaching MTD in 3 dose levels

Eisenhauer et al JCO (18), 2000

I t ti t d l ti


36/70

Intra-patient dose escalationTreat patients at dose level 1

Dose level 2 is well tolerated and patients

at dose level 1 have no toxicities

Patients at level 1 are escalated to level 2

WHY NOT DO THIS ALWAYS ?

Makes evaluation of chronic toxicitiesdifficult

The proverbial 1 responder at dose level 1

Phase I Trial Design


37/70

First proposed by Simon et al (J Natl

Cancer Inst 1997)

Several variations exist:

usual is doubling dose in single-patient cohorts

till Grade 2 toxicity

then revert to standard 3+3 design using a 40%

dose escalation

intrapatient dose escalation allowed in somevariations

More rapid initial escalation

Phase I Trial DesignAccelerated Titrated Design (Rule-based)


38/70

1 pt

Dose

1 pt

1 pt

3 pts

3 pts 3 ptsRecommended dose

DLT

3 pts+ DLT

Accelerated Titrated Design

Accelerated Titrated Design : Phase


39/70

Accelerated Titrated Design : Phase

I Study of Lonafarnib (SCH66336)

Adjei AA et al, Cancer Research, 2000

Phase I Trial Design


40/70

Bayesian method

Pre-study probabilities based on preclinical orclinical data of similar agents

At each dose level, add clinical data to betterestimate the probability of MTD being reached

Fixed dose levels, so that increments ofescalation are still conservative

Phase I Trial DesignModified Continual Assessment Method

(MCRM Model-based)

Modified Con

tinual Assessment Method (MCRM


41/70

Example: Pre-set dose levels of 10, 20, 40, 80, 160,

250, 400 If after each dose level, the statistical model

predicts a MTD higher than the next pre-set doselevel, then dose escalation is allowed to the next

pre-set dose level

Advantages:

Allows more dose levels to be evaluated with a smaller

number of patientsMore patients treated at or closer to therapeutic dose

Disadvantages:

Does not save time, not easily implemented if without

access to biostatistician support

Modified Continual Assessment Method (MCRMModel-based)


42/70


43/70

EXAMPLE of Probability of DLTs (Bayesian design)

Under-Dosing(This % should be minimal)

Ideal Dosing(This bar should be the highest percentage)

Over-Dosing(This bar should be below 25%)

Excessive Over-Dosing(This bar should be 0%)

7% 60% 30% 3%

44% 52% 4% 0%

Drug at 0.5mg

7% 66% 27% 0%

Drug at 0.75 mg

0% 35% 64% 0%

Drug at 1.0 mg


44/70

0/3

Posterior summaries for probabilities of DLT (in %)

________________________________________________________________

Dose 0-0.16 0.16-0.33 0.33-0.6 0.6-1 Median Overdose

mg Under- Targeted Over- Excessive DLT rate Control/day dosing Toxicity dosing toxicity

________________________________________________________________

2.5 95.7 3.3 0.5 0.4 0.0 ok

5 91.1 5.5 3.1 0.4 0.2 ok

10 82.9 9.1 6.7 1.3 1.9 no3

17.5 62.5 17.7 12.5 7.2 8.8 no2,3

25 40.0 21.2 19.3 19.5 22.3 no1-3

35 15.6 19.7 20.4 44.3 53.7 no1-3

45 9.9 12.5 19.9 57.7 73.0 no1-3

60 5.6 10.9 12.0 71.5 86.5 no1-3

75 3.2 7.7 12.7 76.4 92.8 no1-3

100 2.4 3.3 13.3 80.9 96.6 no1-3

__________________________________________________________________1 Escalation to this dose not possible, overdose control criterion

(P(overdosing or excessive tox)>25%) violated

2 Escalation to this dose not possible, overdose control criterion

(P(excessive tox)>5%) violated3 Escalation to this dose not possible, increment >100%

No first cycle DLTs

Bayesian model supports dose escalation in cohort 2 (100% doseincrement)

Prior and posterior probabilities of DLT (median and 95%-CI)

dose

ProbabilityofDLT

0.0

0.2

0.4

0.6

0.8

1.0

dose

ProbabilityofDLT

0.0

0.2

0.4

0.6

0.8

1.0

2.5 5 10 17.5 25 35 45 60 75 100


45/70

1/4

Posterior summaries for probabilities of DLT (in %)

________________________________________________________________

Dose 0-0.16 0.16-0.33 0.33-0.6 0.6-1 Median Overdose

mg Under- Targeted Over- Excessive DLT rate Control/day dosing Toxicity dosing toxicity

________________________________________________________________

2.5 48.1 28.4 16.4 7.1 16.5 no2

5 30.5 31.5 27.5 10.5 26.4 no1,2

10 16.5 23.7 37.3 22.4 38.3 no1-3

17.5 8.8 14.7 41.6 34.9 50.3 no1-3

25 6.1 9.9 37.6 46.4 58.3 no1-3

35 5.6 7.7 29.6 57.1 65.6 no1-3

45 3.7 7.6 24.5 64.1 69.6 no1-3

60 3.3 6.5 18.9 71.2 75.1 no1-3

75 2.4 6.1 15.3 76.1 78.1 no1-3

100 2.4 4.9 13.6 79.1 82.3 no1-3

__________________________________________________________________1 Escalation to this dose not possible, overdose control criterion

(P(overdosing or excessive tox)>25%) violated

2 Escalation to this dose not possible, overdose controlcriterion

(P(excessive tox)>5%) violated3 Escalation to this dose not possible, increment >100%

First cycle DLT in first cohort

Bayesian model does not support dose escalation in cohort 2

Prior and posterior probabilities of DLT (median and 95%-CI)

dose

P

robabilityofDLT

0.0

0.2

0.4

0.6

0.8

1.0

dose

P

robabilityofDLT

0.0

0.2

0.4

0.6

0.8

1.0

2.5 5 10 17.5 25 35 45 60 75 100

Challenges to developing novel non-


46/70

General requirement for long-term administration:pharmacology and formulation critical

Difficulty in determining the optimal dose in phase I:

MTD versus OBD

Absent or low-level tumor regression as single agents:problematic for making go no-go decisions

Need for large randomized trials to definitively assessclinical benefit: need to maximize chance of success in

phase III

Challenges to developing novel non

classical cytotoxic agents


47/70

Phase I Trial Design: Non-Cytotoxic Agents

MTD may not be the goal of Phase I sincespecificity of effect may be lost at MTD

Pharmacologic effect may not equal

biologic effectGoal: identify optimal biologically effective

dose (OBED)

Paradox: requires early development andintegration of (usually unvalidated)

measures of biologic effect into Phase I

Do we need correlative studies ?


48/70

Conventional cytotoxic drugs have led to predictable

effects on proliferating tissues (neutropenia,

mucositis, diarrhea), thus enabling dose selection and

confirming mechanisms of action

Targeted biological agents may or may not have

predictable effects on normal tissues and often enterthe clinic needing evidence/proof of mechanisms in

patients




49/70

Therefore, biological correlative studies maybe used to derive the best dose and schedule

of an agent,and

To determine whether the drug is inducing the

intended biological effect in the patient,and

To predict clinical benefit, although this

generally requires testing in large randomized

studies.


Alternative Endpoints


50/70

Alternative Endpoints

Minimum blood levels/AUC or other

PK measure Inhibition of target

In normal tissue

In tumor tissue

Need enough preclinical evidence tosuggest that the above are

reasonable endpoints withsufficient clinical promise

Must also pay attention to toxicity

Phase I Trial Design : Non-Cytotoxic


51/70

Phase I Trial Design : Non Cytotoxic

Agents - Examples

Pre-clinically define target drug exposureMatrixMetalloproteinase Inhibitors

Define pharmacodynamic endpointBortezomib

(70% of 26S proteasome inhibition in PBMCs)

Use functional imaging as endpointVatalanib

(DCE-MRI)

Use cumulative toxicitiesCI-1040 MEK Inhibitor,800mg TID intolerable after 3 cycles of therapy

Problem : If drug works, youre a genius. If it

doesnt, youre a goat

V t l ib (PTK/ZK) VEGF R t


52/70

Adapted from Dvorak H. J Clin Oncol. 2002;20(21):4368-4380.

VEGF-AVEGF-CVEGF-DVEGF-E

VEGF-AVEGF-B

VEGF-CVEGF-D

VEGFR-1/Flt-1 VEGFR-2/KDR VEGFR-3/Flt-4

PTK/ZK PTK/ZK PTK/ZK

Extracellular

Intracellular

Vatalanib (PTK/ZK) : VEGF Receptor

Tyrosine Kinase Inhibitor

PTK/ZK Induced Significant


53/70

Reduction in tumor blood flow through liver metastases

secondary to colorectal cancer at day 2 is significantly

correlated with improved early clinical outcome

PTK/ZK Induced Significant

Reduction in Tumor Blood Flow in

Metastatic Colorectal Cancer by DCE-MRI

Baseline Day 2

Thomas AL, et al. Semin Oncol. 2003;30:32-38.Morgan B, et al. J Clin Oncol. 2003;21:3955-3964.


54/70

Morgan B, et al. J Clin Oncol. 2003;21:3955-3964.

MeanbaselineMRIKi,%

160

140

120

100

80

60

40

20

0

020

40

60

80

100

120

140

160

180

200

Progressors

Nonprogressors

AUC 0-24, hrM

260

240

220

200

180

160140

120

100

80

60

4020

0

Dose, mg

Day 28

0

200

400

600

800

1,0

00

1,2

00

1,4

00

1,6

00

1,8

00

2,0

00

2,2

00

AUC0-24,hrM

Using DCE-MRI to Establish theOptimal Therapeutic Dose for Vatalanib

The Conundrum of Optimal Biologic


55/70

The Conundrum of Optimal BiologicDose : Phase III PTK787/FOLFOX in CRC

PTK787 1250 mg QD

0

25

50

75

100

0 2 4 6 8 10 12

Time since randomization, months

Progres

sion-freesurviv

al,% PTK/ZK + FOLFOX4

Placebo + FOLFOX4

Phase I Trials of Agent Combinations


56/70

Initial dose-finding component often needed if you

are planning a new combination for a phase II trial Patients for dose-finding phase:

Advanced solid tumors (all comers):

Advantage:fast accrual

Disadvantage:may not be representative of your patientpopulation of interest

Specific patient population (e.g. same as phase IIcohort):

Advantage:population of interest, and early glimpse atantitumor activity in disease of interest

Disadvantage:slow down accrual especially if rare/uncommontumors




57/70

Dose escalation:

New drug A + Standard combination BC

Ideally keep standard combo doses and

escalate the new drug (e.g. 1/3, 2/3, full dose)

Need to provide rationale: why add A to BC?

Need to think about overlapping toxicity in

your definition of DLT

Do you need PK assessment to determine if

A, B and C interact with each other?


How are Phase I Studies


58/70

How are Phase I Studies

Designed Now ?

31 targeted agents: representative of most

common targets

Reports (papers or abstracts) of completed single

agent phase I trials in non-hematologic

malignancies

57 phase I reports identified

Parulekar and Eisenhauer JNCI July 2004

Agents/Targets


59/70

Agents/TargetsTarget Agent #Trials

Angiogenesis Endostatin

ZD6474

PTK787

SU6668

SU5416

Bevacizumab

SU11248

3

1

1

3

3

1

1

BCL-2 G3139 2

PKC alpha ISIS 3521 2

raf kinase BAY 43-

9006 ISIS5132

3

3

DNA MTase MG98 2

MEK CI-1040 1

mTOR CCI-779 1

Target Agent #Trials

EGFR/HER2

ZD1839OSI-774

C225

MAB225

EMD7200

EKB569RG83852

trastuzumab

51

1

1

1

11

1

MMP BAY 12-9566

Marimastat

COL-3BMS-275291

3

2

11

Farnesyl

trans-

ferase

BMS-214662

R115777

L778,123

SCH66336

2

3

2

3

Results: Reason for Halting


60/70

Results: Reason for Halting

Dose EscalationReason No. Trials No. Agents

Toxicity 36 20

PK 7 5

Other:Design (max. planned dose)

Drug Supply

Other phase I results

Active dose

3

4

2

1

3

2

2

1Not stated 4 4

TOTAL 57

Basis for Recommending Phase II Dose


61/70

Basis for Recommending Phase II Dose

Recommended phase II dose? No. Trials No. Agents

Recommended 50 27

Basis: Toxicity

PK (blood levels)Other trial toxicity

Clinical activity

PBMC findings

Tumor measuresConvenience

35

92

1

1

11

19

72

1

1

11

Not stated 5 5

Not recommended 2 1


Secondary Information to


62/70

ySupport Dose Recommendation

No.

TrialsPrimary

Basis

No. Trials Secondary Support From:

Toxicity PK Tumor

measures

Surrogate

measures

Other

Toxicity 35 - 12 2 7 8

PK 9 - - 1 1 3Tumor

measures

1 - - - - -

Surrogate

measures

1 - - - - -

Other 4 2 1 1 -

TOTAL 50 1 12 4 9 11

Other includes: clinical effects, results other trials, convenience, etc.

Laboratory and Imaging Studies


63/70

y g g

Total

No. Trials

Primary

Basis ofDose

Supportive

of dose

No

Help

Tumor Tissue 5 1 4 -

Surrogate

Tissue:

PMBC

Skin

Buccal

11

2

2

1

-

-

5

2

2

5

-

-

Imaging 6 - 1 5

15


Summary Review


64/70

Summary: ReviewPhase I Trials Targeted Agents

Toxicity

Most common reason to halt escalation and primary

basis for dose recommendation (35/50 trials)

PK (Blood levels) Second most common basis for dose

recommendation (9/50 trials)

Laboratory studies May provide information to support dose

recommendation



65/70

Phase I Study - Ethics

Phase I Study Ethics


66/70


Patient benefit or antitumor activity is not aprimary goal of the study, but therapeutic intent

is an important feature

Desperate patients cannot make a truly informed

decision

Historically low probability of response in Phase I

trials

< 5% response rate Majority of responses occur within 80%-120% of the

recommended phase II dose

Response Rates and Toxic Deaths in Phase I OncologyTrials (Horstman et al NEJM 352; 2005)


67/70

Trial No. ofTrials

# of PtsAssessed

forResponse

OverallResponse Rate*

%

No. ofPatients

Assessed forToxic Events

Deathsfrom Toxic

Eventsno. %

TotalFirst use of an agent inhumans

117 3164 4.8 3498 9 (0.26)

Cytotoxic chemotherapyFirst use of an agent inhumans

43 1298 5.0 1422 7 (0.49)

ImmunomodulatorFirst use of an agent inhumans

16 404 7.4 431 1 (0.23)

Receptor or signaltransductionFirst use of an agent inhumans

27 742 3.8 853 1 (0.12)

AntiangiogenesisFirst use of an agent inhumans

8 200 7.0 228 0

Gene transferFirst use of an agent inhumans

0 0 0 0 0

Vaccine

First use of an agent inhumans

23 520 3.1 564 0

Trials (Horstman et al, NEJM 352; 2005)


68/70


Investigators have an inherent conflict ofinterest

Funding

Academic promotion

Publicity

Phase I Study Ethics : Partial


69/70

ySolutions to the Dilemma

Youre the patients physician 1st and a scientist 2nd

Scientific goals should never take precedence overthe patients best interest

Only pts for whom no life-prolonging or curativetherapy exists are eligible for Phase I trials

Informed consent is obtained from every patient

No new agent can hit the pharmacy shelveswithout going through Phase I clinical evaluation

Phase I Clinical Trials - Summary


70/70

y

Most drugs tend to follow the MTD/DLT

paradigm Alternative designs continue to be explored.

Most times they are more complex.

Correlative studies are increasingly importantin the comprehensive evaluation of new agents

Patient benefit/wellbeing trumps all the science

Being a good phase I trialist is not as simple asyou may think

Documents

SAS Clinical Trails Phase-I