Transcript Ensuring Quality Management of PK Samples from Collection to

Ensuring Quality Management of PK
Samples from Collection to Archival and
Selecting the Right Biorepository for Your
Needs
Gina McMullen
Sr. PK Research Associate
ISIS Pharmaceuticals, Inc.
Objectives:

Provide an overview of PK sample collection, processing,
analysis, data reporting, and eventual archival.
 Identify considerations for protocol planning &
Bioanalytical Lab selection to ensure integrity & accurate
data reporting.
 Evaluate key aspects when choosing a commercial
Biorepository for long term storage (of PK samples), in
order to maintain integrity for potential future use, and
ultimately benefit your drug development program in the
long run.
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What is PK?
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Pharmacokinetics (PK) is essentially the study of what the body does
to a drug once it’s been administered by a chosen route (i.e. Topical,
Enteral, or Parenteral).
PK samples are collected at precise time points (per protocol) in a
specific type of biological matrix (typically plasma) & subsequently
analyzed for drug concentrations.
Bioanalytical methods used to analyze these samples should be
selective and sensitive, in order to construct an accurate
concentration-time profile for your drug.
Example of First Order Kinetics
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The Importance of PK Samples

Pharmacokinetic (PK) samples play an integral
role in the drug discovery & development process.
 PK concentration determinations not only allow
for accurate characterization of the drug, but also
assist in establishing the most effective dose
regimen for the intended patient population.
 Ensuring these samples are properly collected,
processed, analyzed, and eventually archived, is
critical to the success of your drug.
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General Overview of
Drug Development Timelines
Stage
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12
Discovery
The Screen
The Lead
Development
Safety Assess Cand
Patents
Dosage Form Dev
IND/IDE
Clinical Trials
Phase 1
Review Safety Data
Phase 2
End Phase 2 Clin Rev
Phase 3
NDA/PLA/PMA
FDA Review
Approval
Product Launch
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Studies published in 2003 indicate the cost to bring a new drug to market is
around $800 million.[1,2] More recent studies estimate that cost to be as high as
$2,000 million, depending upon the therapy or the company developing it. [3]
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PK Component of Drug Development
Timelines
Preclinical
IND Enabling
Toxicology
Studies
Up to1000 PK samples generated for
analysis in a single IND enabling Toxicology
study (nonhuman primate study)
Phase 1,
First in Human
Studies
Up to 1500 PK samples generated for
analysis in a single Phase 1, FIH,
SAD/MAD study design
(35-40 collected per patient)
Around 500-1000 PK samples
generated from a single Phase
2A/2B study depending upon
number of patients enrolled
(25-30collected per patient)
Phase 2A/2B
Studies
1000+ PK samples generated from a Phase 3
study, but only around 5-10 collected per
patient (increased # patients enrolled)
Phase 3
Studies
Time to Market
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General Considerations
The Importance of proper PK
sample collection,
processing, reporting, and
eventual archival
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Overview of PK Sample Collection to
Data Reporting
Two transfer tubes labeled identically:
1) Primary Aliquot for initial analysis
2) Duplicate Aliquot as a backup
Pack sufficient dry ice in shipping
container to ensure samples won’t
thaw in event of delays.
Purple topped
EDTA collection tube
i.e. 1500g for
15 min @ 4oC
Ship to
PK Lab
for
Analysis
Ensure frozen immediately
at appropriate temperature
(i.e. -80oC)
Sample Log-In
Split into
2 equal
aliquots
Freeze
Centrifuge
Collect
Sample
Use validated methods for
PK analysis under GLP
compliance to ensure
quality final data.
Analyze
samples
and report
data
Proper identification at PK
Lab is essential to accurate
data reporting
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PK Life Cycle
Study Considerations in order to ensure sample viability for future use
Protocol Planning for Sample Collection
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Select optimum time points for drug characterization and
identify in the protocol
Communicate sample collection & processing expectations
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Type of collection tube (i.e. K2EDTA)
Centrifugation speed, time, & temperature
Amount to be apportioned to separate transfer tubes
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1) Sample
Collection
Specify information contained on tube labels
Importance of assigning primary & duplicate aliquots for
sample analysis availability
2) PK Analysis
Temperature for storage
PK Analysis
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Ensure bioanalytical method has been validated prior to
analysis
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Verify samples clearly identified at time of collection and are
correctly reported in final data set
Eventual Sample Archival

3) Long Term
Storage
Proper handling & management will allow samples to be
utilized for additional analyses in the future if needed
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Important Roles in Clinical
PK Studies
Clinical Site

Ensure protocol is followed and samples are
properly identified at time of collection.
Clinical Site
Central Lab
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Preparation of PK Kits for Clinical site, including
collection tubes & labels.
Collate samples from multiple Clinical sites for
shipment to designated PK Lab:
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Initial sample identifier reconciliation.
Potential shipment directly to Biorepository.
PK Lab

Maintain information provided by Central Lab
through analysis to preserve integrity of samples
and ensure quality concentration data.
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Central Lab
Additional sample identifier reconciliation if needed.
PK Lab
BioRepository
Subsequent shipment to BioRepository upon
completion of analysis and final data submission.
BioRepository
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Retain value of samples by ensuring proper
storage for potential future use.
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Bioanalytical Considerations during
Protocol Planning
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Matrix Selection
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Clinical: typically plasma or urine, occasionally tissue
biopsies
Preclinical: typically tissue, plasma, and urine for initial IND
enabling studies
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Species selection (i.e. rodent, non-human primate, canine, etc.)
Select appropriate type of assay to analyze PK
samples in specified matrix
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LC/MS
CE
Ligand Binding Assay (ELISA)
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Additional Considerations

Select appropriate bioanalytical facility for future PK
sample analysis
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Ensure viable assay for concentration determination and
efficient method transfer
Establish sample collection, stability & storage
requirements
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Anticoagulant to support analysis
Detailed Processing instructions
Transfer tube type (i.e. polypropylene vs. polystyrene, etc)
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Labels that will adhere to these tubes during freezing process
Storage temperature & light sensitivity considerations to prevent
degradation
Limit number of freeze/thaw cycles to maintain sample viability
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PK Study Considerations

For Clinical Trials, identify suitable central lab to ensure adequate
supervision of clinical sites, sample management, & subsequent shipment
to PK lab for analysis
 Preparation of sample collection kits, forms, labels, supplies, etc.
 For Preclinical Studies, ensure chosen In-Life facility can employ proper
collection/processing/shipping/ and documentation technique.
 Proper information to be included on sample label (based on protocol) to
ensure accurate identification for future use
 Requirements typically include the following:
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Protocol
Accession # barcode
Patient/Animal #
Collection Date & Time (and/or Study Day & Time point per the protocol)
Matrix type (plasma, urine, etc.)
Aliquot assignment (primary vs. duplicate)
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Documentation of Proper PK Sample
Collection in a Clinical Trial
IMPORTANT
Ensure the Laboratory Requisition
Form is complete and legible. If an
error is made, strike-through the wrong
information without obscuring the
original entry, correct it, sign and date
the change.
Once completed, this form must be
faxed to the Central Lab the day of
sample collection. This is for
tracking purposes.
Please use the forms as follows:
Send the white copy of the form with
ambient specimens to Central Lab.
Complete and check all the
information on the
Laboratory Requisition Form
Investigator Information
Barcode Label
Visit information
Patient information and
sampling information
Airway Bill Number and
comments
Number of specimens
collected/ name,
signature and date
Send the yellow copy of the form with
frozen specimens to Central Lab.
Retain the pink copy at clinical site.
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Shipment Details
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Current address of PK facility plus contact information for
individual who will be responsible for sample receipt
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Detailed shipping manifest
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Especially important when procuring specialized shipping
permits.
Preferably electronic to be populated with electronic data
Temperature of sample shipment (wet vs. dry ice)
Estimated shipping schedule (i.e. batching samples
based on collection time points)
Preferred courier for shipping (company who will ensure
temperature is maintained throughout process & will re-fill
ice if shipment is delayed)
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Tracking # allowing you to check status of shipment on-line
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Sample Log-In
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Upon arrival at PK Lab
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Notification to sponsor of safe receipt
Sample log-in (discrepancy reconciliation
between tube label & manifest)
LIMS (Laboratory Information Management
System) for internal sample tracking at PK lab
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Sample Analysis & Data Reporting
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Use validated method for analysis
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Ensure sample identifier information is accurately
reported in the final data (i.e. tracking system)
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Proper handling of samples during analysis can prevent
contamination
If insufficient volume in primary aliquot use duplicate (ensure
accurate identification and reporting).
Can also be used as a manifest for shipping to selected off-site
Biorepository
QC/QA review of data and finalization of report
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Watch for anomalous concentration values which might
otherwise be explained by incorrectly reported sample identifiers
or contamination.
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General Considerations
Choosing the Right
Biorepository for long term
storage needs
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Key Traits to consider:

Interaction
 Identification
 Inventory
 Invoicing
 Integrity
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Interaction (ensuring quality communication
with your chosen Biorepository):
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Communicate with Biorepository to ensure they can
accommodate proper storage requirements:
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Optimal storage temperature (i.e. < -80oC)
Light sensitivity concerns
Length of time for storage requirements:
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Minimum amount of time for which samples need to be stored?
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Maximum amount of time they are allowed to be stored?
What is your established Long Term Matrix Stability for this
compound? How does that compare with industry guidance?
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Interaction (cont.)
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Shipping considerations to Biorepository
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Ensure constant temperature in shipment
Clearly labeled sample tubes
Accurate shipping manifest, (preferably electronic), which can
easily be linked back to information on tube label
Have Biorepository coordinate with Analytical facility to ensure
safe & timely shipment of your PK samples
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Identification (being able to properly
identify a specific sample if/when needed):
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Sample identifiers - how will facility be able to locate
samples if needed in the future?
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Do they affix a specific label upon arrival at their facility
during initial log-in of the samples?
Do they have an in-house tracking system? If so, what
type? (Paper, electronic, etc.)
Policies on discrepancy resolution if samples arrive
and labels don’t match with the shipping manifest.
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Additional cost to sponsor?
Utilize PK lab to prepare shipping documents and QC
labels prior to sending for long term storage?
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Inventory (knowing what you’re storing and
how much):
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Double check policies re. sample inventory:
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Can sample information be accessed on-line?
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Does this feature result in additional charges (i.e. only certain
individuals can access )?
Will hard copy of inventory be sent? If so, how often?
Monthly, quarterly, annually?
Determine in advance how long samples should be
retained (per industry guidelines & established LTS):
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Plan accordingly to have them disposed of at designated
time points to ensure room for new samples.
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Invoicing (budgeting accordingly for your
Biorepository needs):
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Know what you’re being charged for and how often:
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Per sample cost vs. entire shelf/freezer?
Monthly bill vs. quarterly or annually?
Hidden fees?
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Cost to locate/ship samples if needed?
Cost to destroy samples once established LTS has been reached?
In what capacity will you be utilizing your Biorepository?
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Batch shipping samples from ongoing studies for future analysis
vs. long term storage once studies have completed?
$
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Integrity (acknowledging the value of these samples
and ensuring the appropriate measures are in place to retain
their value):
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Samples are irreplaceable and loss or damage to them
would result in delays to your drug development
program.
To ensure sample integrity, your chosen facility should
have measures in place to account for the following:
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Additional freezers for moving/ transitioning samples
Back up generators for power failure
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In case of natural disaster are steps in place for additional
generators/fuel/ manpower?
Sufficient storage space to accommodate new freezers for
future samples?
Multiple locations to accommodate different shipping sites
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Take Home Message

Maintaining sample integrity for potential future can be
achieved by employing proper planning and diligence
in the following areas:
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Sample Collection/Processing
Sample Analysis
Long Term Storage
…which can ultimately add value to your drug development
program!
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References
1.
2.
3.
DiMasi J. "The value of improving the productivity of the drug development
process: faster times and better decisions". Pharmacoeconomics 20 Suppl 3: 1–
10. PMID 12457421.
DiMasi J, Hansen R, Grabowski H (2003). "The price of innovation: new estimates
of drug development costs". J Health Econ 22 (2): 151–85. doi:10.1016/S01676296(02)00126-1. PMID 12606142.
Adams C, Brantner V. "Estimating the cost of new drug development: is it really
802 million dollars?". Health Aff (Millwood) 25 (2): 420–8.
oi:10.1377/hlthaff.25.2.420. PMID 16522582.
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Biorepositories 2008
We hope to see you in Philadelphia!
September 8 – 10, 2008
http://www.iirusa.com/biorepositories
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