NANS I3
Steve Adler
December 6, 2012
Indications for Use
• U.S.– Infumorph
• Europe– Morphine and Baclofen
Accuracy
Definition: Accuracy refers to the correctness of a single measurement. Accuracy is determined by comparing the measurement against the true or accepted value.
For our purposes, the true or accepted value is the programmed dose
Examples of Poor Accuracy
Introduction
• Product development process for accurate pump– Requirements– Solutions – valve gated technology– Bench or verification tests
• Clinical study results• Clinical significance, next steps
Design Considerations for Accurate (Precise, Durable) Pump
• Prior pumps had shortcomings• Important design considerations
– Accuracy of drug delivery– Accuracy of reported volume in reservoir– Consistency of amount received by the patient over time– Limit any variation in flow rate due to programmed dose, battery age,
reservoir volume, temperature or pressure– Ability to accurately deliver micro-doses – No variation in device performance over a wide range of concentrations and
compounds
Product Development
• New technology was required to design a pump with a an accurate dosing mechanism– The challenges were to design
• A completely different flow regulating mechanism• Electronics that would allow precise timing and provide
redundant safety checks• A power supply with exceptional longevity• Communication capabilities that were insusceptible to
interference and able to prevent programming errors
• Dose Accuracy 98%• No temp, pressure,
reservoir volumeeffects
• Longevity >10 years• Designed to deliver
any compound• Can deliver micro-
doses
Prometra Pump
Dose RegulationValve-Gated Dosing Chamber
Bench Testing
• Extensive bench testing was performed to confirm overall accuracy, as well as accuracy under a variety of conditions.
– Pressure extremes– Temperature extremes– Various programmable rates– Various reservoir fill levels– Various environmental exposures
• Temperature cycling• Electric shock exposure• Vibration testing• Multiple sterilization cycles
– Drug flow accuracy was within specification in each testing scenario.
Bench Testing Results
High ex
it pres
sure (1
6.7psia)
Low ex
it pres
sure
(10.1psia
)
High Te
mperature
(40°C
)
Low Te
mperatu
re (35°C
)
Variety
of Enviro
nmental
Exposu
res - m
inimum ac
curac
y
Variety
of Enviro
nmental
Exposu
res - m
axim
um accu
racy
-15%
-10%
-5%
0%
5%
10%
15%
Testing Condition
Ave
rage
Pum
p Pu
lse
Volu
me
Perc
ent D
iffer
ence
Ongoing Life Testing
Pump B0
20
40
60
80
100
120
Ave
rage
Acc
urac
y (%
)aft
er 7
+ ye
ars
PUMP Clinical Study: Accuracy Results
• Accuracy was calculated as the delivered (volumetrically determined) to programmed (DP) drug volume ratio
– Numerator: sum of delivered drug volumes over all (scheduled and unscheduled) valid fill/refill sessions per patient
– Denominator: sum of programmed drug volumes over all (scheduled and unscheduled) valid fill/refill sessions per patient
• Overall accuracy is calculated by averaging the per patient DP ratios
Accuracy Results (%)
Number of Refills = 2,073Number of Patients = 148
Mean 98.4Standard Error 0.5
90% Confidence Interval (97.6 – 99.2)
Accuracy by Flow Rate
•Flow rate range: 0-1.5 mL/day•No statistically significant differences between flow rate categories
(0.0, 0.14] (319) (0.14, 0.24] (347) (0.24, 0.32] (368) (0.32, 0.45] (659) ≥0.45 (380)0
20
40
60
80
100
120
Flow Rate in mL/day (total visits)
Mea
n Ac
cura
cy (%
)
Accuracy by Months Post-Implantation
•No statistically significant differences between any of the time-points
3 (132) 6 (123) 9 (106) 12 (93) 15 (82) 18 (70) 21 (68) 24 (66) 27 (67) 30 (65) 33 (62) 36 (46) 39 (21) 42 (5)0
20
40
60
80
100
120
Months Post-Implantation (total visits)
Mea
n Ac
cura
cy (%
)
Accuracy by Residual Volume
• (12.0-16.0] was lower than [0.0-4.0] (p=0.0119)• (16.0-20.0] was lower than all other categories (p<0.0001) • Mean accuracy was 100% in the lowest residual volume category (0.0, 4.0].
[0.0, 4.0] (488) (4.0, 8.0] (925) (8.0, 12.0] (333) (12.0, 16.0] (246) (16.0, 20.0] (81)0
20
40
60
80
100
120
Residual Volume in mL (total visits)
Mea
n Ac
cura
cy (%
)
Accuracy by Concentration
•Morphine concentration range: 1-50 mg/mL•No significant differences between concentration categories•No pump failures or other complications occurred related to drug concentration
(0.0, 10.0] (636) (10.0, 25.0] (520) (25.0, 50.0] (380) 50 (537)0
20
40
60
80
100
120
Concentration in mg/mL (total visits)
Mea
n Ac
cura
cy (%
)
Ongoing Continued EvaluationLSU Health Science Center
Durability and Longevity
• The only moving parts are the valves• Fewer moving parts and a simpler design mean less opportunity for
complications
• The valves require very little energy • Promotes longer battery life, requiring fewer replacement surgeries over the course of
a patient’s IT therapy.
Accuracy With Other Drugs?
• Proper function of pumps can be affected by the drug being delivered.– Concentration, molecular size, and corrosion of pump materials can have serious effects
• Clinical trial results indicate that the Prometra Pump is very accurate when
delivering morphine sulfate – Experience with both Infumorph® and compounded morphine at a wide range of
concentrations
• What about other drugs?– Accuracy should be unaffected by the type of drug in the pump.1
– The titanium dosing chamber of the Prometra Pump simply measures the exact volume of
the fluid to be delivered.
• This measurement is unaffected by type of fluid in the chamber
1 Yearwood, T. Results of Secondary Pain Medications to Improve Pain Outcomes in The Prometra Programmable Infusion Pump. Poster Presentation at the 11th Annual ASRA Pain Medicine Meeting, November 2012
Clinical Significance?
• Scheduling of refill visits• Possibly avoiding overdose/underdose, withdrawal
symptoms• Drug dependent• Micro-dosing• Future applications
Intraparenchymal (IPa)
Intracranial Drug Administration
ICV
IT
Intracerebroventricular (ICV)
Clinical Need for Accuracy in Drug Delivery to the Brain
• limit exposure to other organs• deliver complex dosing pattern• greatly reduce effective drug dosage
Conclusions
• Achieved design goals– 98% accurate, independent of external factors
• Confirmed in bench tests• Validated in clinical trials• Clinical significance depends on disease/drugs