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MIKE FINOMIRACOSTA COLLEGE
Statistical Issues in Biomanufacturing:
Clinical Trials and Lot Acceptance
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The motivation for our discussion
http://news.sciencemag.org/sciencenow/2009/10/30-01.html
SCIENCE covered the results of the 2009 AIDS Thai trial, which resulted in an analysis between the vaccine and placebo group with a p-value of 0.04
A prominent AIDS vaccine researcher declared
The probability that this vaccine didn’t work was only 4%
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Which of these correctly state the p-value?
There's less than a 5% chance that the results are misleading
A p-value of 0.05 means that the null hypothesis has a probability of only 5%
Given a result with p ≤ 0.05, we state that there is a 95% or greater chance that the null hypothesis is incorrect
There's a less than 5% chance that I'm going to say this worked when it really didn't.
The p-value cut off of 5% means we have 95% confidence that this is real.
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A Phase II Clinical Trial
A Study to Investigate the Neuroprotective Effect of PROCRIT (Epoetin Alfa) Versus Placebo in Cancer Patients Who Develop
Chemotherapy-induced Peripheral Neuropathy
The purpose of this study is to evaluate the neuroprotective effect of PROCRIT (epoetin alfa, a glycoprotein that stimulates red blood cell production) versus placebo in patients with cancer who develop chemotherapy-induced peripheral neuropathy due to combination Taxane and Platinum-Based treatment.
SOURCE: http://www.clinicaltrials.gov/ct2/show/NCT00267007
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Study Design5
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The Prevention
Peripheral neuropathy is a debilitating disease of the nerves which can be a dose-limiting toxicity of chemotherapeutic agents.
The symptoms of peripheral neuropathy can lead to considerable patient distress and discomfort, discontinuation of chemotherapy, and limitations regarding the selection of future chemotherapeutic regimens.
Symptoms such as numbness, weakness, burning pain (especially at night), and loss of reflexes may take months before they improve and permanent deficits may remain.
Epoetin alfa, already used in the treatment of chemotherapy-induced anemia, has been shown to have neuroprotective effects in preclinical studies.
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Primary Measure -- Results
Measure Title The Number of Patients Who Developed Peripheral
Sensory Neuropathy (National Cancer Institute Common Toxicity Criteria (NCI CTC) Score >= 1) at Week 12.
Measure Description NCI CTC neuropathy: a descriptive terminology used
to grade the severity of AEs in cancer subjects on a 0-5 scale. A higher score indicates worse peripheral neuropathy.
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Results
PROCRIT Placebo Totals
Developed Neuropathy
5 6 11
No Neuropathy 14 5 19
Totals 19 11 30
PROCRIT Placebo
Developed Neuropathy
26% 55%
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Did PROCRIT have an effect?
Play the skeptic for a second. What could you say about this data? Do you think the researchers could have just
been “lucky” – that just by chance they got these results?
PROCRIT Placebo
Developed Neuropathy
26% 55%
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ACTUAL RESULTS
PROCRIT Placebo Totals
Developed Neuropathy
5 6 11
No Neuropathy 14 5 19
Totals 19 11 30
NO EFFECTNO EFFECTRESULTSRESULTS
PROCRIT Placebo Totals
Developed Neuropathy 77 44 11
No Neuropathy 1212 77 19
Totals 19 11 30
What we would expect, on average, by chance alone
Does the 5/6 split we got seem very different from the 7/4 expected?
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Resampling Activity
We want to know: if the PROCRIT is truly not effective in helping, how often would the random assignment process alone would lead to such a difference between the treatment groups?
We will answer this question by replicating the randomization process all over again, but in a situation where we play the skeptic and assume that PROCRIT therapy is not effective.
We’ll start with 11 “afflicted” and 19 non-afflicted, and we’ll randomly assign 19 of these 30 subjects to the PROCRIT therapy group and the remaining 11 to the placebo group.
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Resampling Activity
Everybody will receive a deck of cards. These cards match the patient outcomes if we believed that the therapy was NOT effective. 11 got neuropathy, 19 didn’t – what group they end up in is random and the “treatment” in the group does nothing to affect their outcome.
Pick 11 FACE CARDS to represent those with neuropathy
Pick 19 NUMBER CARDS to represent no neuropathy
We want to simulate what the skeptic believes. That is, how many people might we expect – BY CHANCE ALONE – to be in the PROCRIT Group that developed neuropathy. This is the number that you’re going to be tracking through FIVE rounds of resampling.
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Resampling Activity: Efficacy
1. Count out 11 face cards and 19 non-face cards. Set the remaining cards aside.
2. You will only be resampling the PROCRIT group because the number of PROCRIT-Neuropathy is the only number we’re going to pay attention to.
3. Shuffle, shuffle, then shuffle some more.4. Deal 19 cards out – this will represent the PROCRIT
Therapy group.5. Count how many have neuropathy (face cards) in the
PROCRIT group. Write this number down.6. Shuffle, shuffle, then shuffle some more.7. Repeat (3) through (5) until you have five numbers.
8. Go to the front of the class and mark your numbers on the class graph.
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Resampling Activity
We want to know, if the null hypothesis is true, how often would the random assignment process alone lead to such a large difference between the treatment groups?
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Results with 10,000 resamplings15
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Safety Data with PROCRIT Study
PROCRIT Placebo Totals
Serious Adverse Event Reported
6 1 7
No SAE 13 10 19
Totals 19 11 30
PROCRIT Placebo
SAE Reported 32% 9%
Do we have a safety problem here?
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ACTUAL RESULTS
PROCRIT Placebo Totals
Serious Adverse Event Reported
6 1 7
No SAE 13 10 23
Totals 19 11 30
NO EFFECTNO EFFECTRESULTSRESULTS
PROCRIT Placebo Totals
Serious Adverse Event Reported 4.44.4 2.62.6 7
No SAE 14.614.6 8.48.4 23
Totals 19 11 30
What we would expect, on average, by chance alone
Does the 6/1 split we got seem very different from the 4.4/2.6 expected?
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Resampling Activity: Safety
1. Count out 7 face cards and 23 non-face cards. Set the remaining cards aside.
2. You will only be resampling the PROCRIT group because the number of PROCRIT-SAE events is the only number we’re going to pay attention to.
3. Shuffle, shuffle, then shuffle some more.4. Deal 19 cards out – this will represent the PROCRIT
Therapy group.5. Count how many have an SAE (face cards) in the
PROCRIT group. Write this number down.6. Shuffle, shuffle, then shuffle some more.7. Repeat (3) through (5) until you have five numbers.
8. Go to the front of the class and mark your numbers on the class graph.
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Results with 10,000 resamplings19
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The Outcome20
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Effect of Erythropoietin (EPO) in Kidney After Cardiac Surgery (EPO-CABG)
The purpose of this study is to determine whether erythropoietin is effective in preventing acute kidney dysfunction after coronary artery bypass grafting surgery.
SOURCE: http://www.clinicaltrials.gov/ct2/show/NCT00654992
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EPO and AKI
Acute kidney injury (AKI) occurs in 7% to 40% of patients undergoing cardiac surgery, depending on the definition of AKI used.
Even small increments in serum creatinine have been shown to be associated with increased mortality after cardiac surgery.
However, there are no proven interventions to prevent AKI after cardiac surgery.
Erythropoietin (EPO) has been shown to have tissue-protective effects in various experimental models.
In this prospective, placebo-controlled, randomized trial, we evaluated the effectiveness of EPO in the prevention of AKI after coronary artery bypass grafting (CABG).
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Study Design23
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Study Results
EPO Placebo Totals
AKI Observed 3 10 13
No AKI 33 25 58
Totals 36 35 71
EPO Placebo
AKI Observed 8% 29%
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Here we go again?
EPO Placebo
AKI Observed 8% 29%
PROCRIT Placebo
SAE Reported 32% 9%
Similar disparity between groups.Are we expecting a similar
conclusion?
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ACTUAL RESULTS
EPO Placebo Totals
AKI Observed 3 10 13
No AKI 33 25 58
Totals 36 35 71
NO EFFECTNO EFFECTRESULTSRESULTS
EPO Placebo Totals
AKI Observed 6.66.6 6.46.4 13
No AKI 29.429.4 28.628.6 58
Totals 36 35 71
What we would expect, on average, by chance alone
Does the 3/10 split we got seem very different from the 6.6/6.4 expected?
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The Approach to Hypothesis Testing27
Model what the data would like, if the null were true
Compare our actual results to the nullAsk whether our data would be expected or
unexpected in the model Expected data consistent with null (e.g. p-value
greater than 5%) Unexpected data rejects the null (e.g. p-value less
than 5%)
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Results with 10,000 resamplings28
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Quality Control for a Cell-Based Therapeutic
BREAK
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Tissue Engineering30
Processes which combine
living cells and biomaterials
to generate tissue in vitro or in vivo
for therapeutic implantation
or as diagnostic reagents
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Process Overview31
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Diabetic Ulcers32
People with advanced diabetes generally suffer from poor circulation in their extremities
Small cuts cannot resolve themselves due to inadequate delivery of nutrients
Neuropathy, an attendant complication, often allows the patient to “live with” the ulcer
It is not uncommon for patients to finally visit the doctor after having the ulcer for many months – sometimes years!
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Angiogenic Foundation33
0
200
400
600
800
1000
Mic
rove
ssel
Mic
rove
ssel
Den
sity
Den
sity
(ves
sels
/ s
qu
are
mm
)(v
esse
ls /
sq
uar
e m
m) *p < 0.05*p < 0.05
Dermagra
ft
Dermagra
ft
NonNon--V
iable
ViableDerm
agraft
Dermagra
ft
ShamSham
0
200
400
600
800
1000**
Mic
rove
ssel
Mic
rove
ssel
Den
sity
Den
sity
(ves
sels
/ s
qu
are
mm
)(v
esse
ls /
sq
uar
e m
m) *p < 0.05*p < 0.05
Dermagra
ft
Dermagra
ft
NonNon--V
iable
ViableDerm
agraft
Dermagra
ft
ShamSham
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DERMAGRAFT® Growth Time Course34
2 Days
1 Day
8 Days
3 Hrs
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DERMAGRAFT® & Diabetic Foot Ulcers
35
Week 0
Week 5
Week 1
Week 8
Week 3
Week 10
Dermagraft implanted weekly for eight weeks
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Batch Production36
Scale-up
Physician cutting piece
of skin
Manifold: 96 units
Each batch: Four manifolds
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Dermagraft Production Overview37
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Product Quality38
The FDA mandates that quality attributes are tested against pre-determined specifications to ensure
Purity Potency Consistency Identity Stability
Safety
Efficacy
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Product Quality39
Safety and efficacy were both proven during the final (Phase III) clinical trial
Quality Control is the group that’s responsible for conducting the laboratory tests to demonstrate the product made today is the same as the Phase III material
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Assays Related to Efficacy40
MTT A metabolic assay that’s generally viewed as a
measure of the number of viable cells
Sirius Red Colorimetric stain measuring collagen content – an
essential EM protein
DNA For a populated neo-dermis this is a relatively stable
measure of cell count
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Assays Related to Safety41
Sterility A measure of asepsis
Endotoxin A measure of LPS from gram (-) bacteria
Mycoplasma Cell culture contaminant
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Assay Specifications42
Each assay had its own specified limits of what’s acceptable
To measure the product against the specifications acceptance sampling is used A composite percent defective score from the
ANSI/ASQ Z1.9 Acceptance Sampling for Variables is calculated
This standard is a measure that’s making a check on the batch’s central tendency and its variability relative to the defined limits
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Acceptance Sampling43
The idea is rooted in inferential statistics Get a random sample from a large population (batch
of product) Analyze it (assays) Make a decision on the properties of the larger batch
based on the sample
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So what’s involved44
Determine sample size code based on batch size
Determine the maximum allowable percent defective, M (based on AQL)
Randomly sample and analyzeCompute sample mean and std devCompute quality indices: QU and QL
Find their associated percent defective: pU and pL
Compare pU + pL to M
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QU and QL45
s
XUQU
s
LXQL
U is the upper limit of the specification for the assay
L is the lower limit of the specification for the assay
X is the sample average
s is the sample std deviation