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1 What sorts of challenges might occur when using an infusion pump for a study drug delivery in a clinical trial?
Challenges may arise relating to infusion pumps when progressing from Phase 1 to subsequent phases.
Phase 1 clinical trials are typically conducted in a very controlled environment, normally involving only one model of infusion pump and its recommended disposables (eg, syringes or IV administration sets). Trial coordinators can control selection of the infusion pump and disposables at this stage as well as obtain data on the drug’s stability and compatibility with all the parts of the entire delivery system that are in contact with fluid.
Phase 2 or 3 clinical trials are typically conducted at multiple and often multinational study sites, sometimes even across different continents, so it is no longer necessarily possible to control selection of pump or disposables.
This is because there are dozens of established manufacturers of infusion pumps and disposables worldwide offering a large variety of their products to the market. A clinical trial may face using different infusion pumps for delivering the study drug; different pumps have different technical performance characteristics and limitations. This could be a source of bias in the trial data.
Moreover, all pumps require infusion sets to deliver the drug from a fluid reservoir to a patient, and some pumps can operate accurately only when using their own dedicated infusion sets. As each infusion set has different parts (eg, drip chamber, pumping segment, an infusion line) made of different types of materials (eg, PVC, PE, silicone) additional data may be required on the drug’s stability and compatibility with the fluid-contacting parts of different sets.
2 Are there any fundamental differences between different types of infusion pump?
An infusion pump is a device that facilitates fluid flow by pressurizing fluid; all infusion pumps can be divided into two groups, depending on how this is achieved:
- Mechanically powered infusion pumps or so-called “disposable infusers”. They do not need any external energy supply to operate, have fixed applied pressure, fixed flow rates and reservoir volumes, and are mainly used for ambulatory applications.
- Electrically powered pumps. They do need electrical energy (either mains or battery) to operate, offer flexible delivery regimes (eg, a range of selectable flow rates and volumes), offer a wide range of alarms to alert users to situations that can affect therapy provision, and are generally controlled by microprocessors (typically two). Electrically powered pumps can be separated into general ward-based pumps, and portable ambulatory pumps. Both of these can be either volumetric or syringe pumps.
Normally, the delivery accuracy of a mechanically powered infusion pump is lower than that of an electrically powered pump. The mechanical pumps are particularly used for ambulatory delivery of antibiotics and pain control drugs, where their portability is more important than the accuracy of delivery itself.
Therapy provision by an electrically powered ambulatory infusion pump can be affected by variations in battery power. For this reason, electrically powered ambulatory devices are not recommended for delivery of critical drugs, as interruption of delivery in the event of battery depletion can be hazardous.
The most accurate and reliable devices are the ward-based pumps running on mains power (in addition, they all have integral batteries as a back-up in case of mains power failure). For a clinical trial of a new drug, this type of pump would be the most appropriate choice.
3 Which ward-based pump should be chosen: volumetric or syringe?
Volumetric pumps are typically used for large volume infusions. They perform satisfactorily at flow rates from 5mL/h and higher.
Syringe pumps are typically used for small volume infusions requiring lower flow rates. Most syringe pumps accept most commonly used syringe brands and volumes. Some syringe pumps accept large syringes (100-140mL), but for most 50-60mL syringes are the largest they can use.
Syringe pumps are typically more accurate on continuous infusion than volumetric pumps due to the way their pumping mechanism works. Typical hourly delivery accuracy for a volumetric pump is within ±5% of the rate set by the user, and typical accuracy for a syringe pump is ±3%. For some pumps, flow rate can be set up with precision of 0.1mL/h. However, this precision may not be for the entire flow rate range offered by the pump, and this needs to be checked before finalising the dosing and drug delivery protocols in order to match the requirements of the drug delivery with the pump’s delivery capabilities.
4 Are there any other factors to consider when choosing between a syringe and a volumetric pump?
Other parameters that differ significantly for volumetric and syringe pumps are the smoothness of delivery (expressed in terms of the constancy index) and the time taken to start the delivery of the set flow rate (start-up time):
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Constancy index: Delivery of volumetric pumps, which are typically peristaltic pumps, is cyclic and may exhibit high fluctuations in flow rate over short time intervals (although over an hourly period accuracy can still be within ±5%). Constancy index is a measure of delivery smoothness, and has an association with a drug’s half-life. In general, drugs with a half-life shorter than a pump’s constancy index would not be recommended for delivery by this infusion pump at rates of 1mL/h and lower. The constancy index for ward-based syringe pumps is typically in the range of 0.5-5 minutes, whereas for volumetric pumps it is 5-15 minutes.
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Start-up time is the time delay before accurate drug delivery is initiated. Syringe pumps have known delays with the start of infusion. These are affected by the disposables used (type of a syringe and its volume) and the procedure followed before the start of infusion, and can be up to 20 minutes. Volumetric pumps, on the other hand, typically start delivering accurately almost immediately.
Careful assessment of infusion pumps’ performance parameters and local clinical procedures would have to be undertaken at site qualification visits to make sure that these can accommodate the study protocol procedures for study drug delivery.
5 Why cannot a universal infusion set be used with all infusion pumps?
For a syringe pump, most of the infusion sets with a standard Luer-lock can be used. Using a universal infusion set in a clinical trial of a new drug is advantageous, as the data related to its material compatibility with the study drug will only need to be gathered for one infusion set. The same set can afterwards be recommended to the clinical trial centres. Almost all modern syringe pumps accept most common brands of syringes of different volumes, and selecting one particular brand and volume for all sites is also possible. In this case, the clinical trial coordinators would have to ensure that the centres are using only the recommended infusion set and syringe.
Infusion sets used for volumetric pumps are different and, unlike infusion sets for syringe pumps, have different parts made of different types of plastic (eg, silicone, PVC, PE etc.). Only the dedicated infusion sets recommended by a pump manufacturer can be used with a volumetric pump, as delivery accuracy and pump performance can be affected adversely if a non-recommended infusion set is used. This is because the infusion set parameters (eg, its internal diameter and material of the tubing used in the pumping segment) need to be known by the pump’s control software, in order to determine the correct flow rate. These parameters vary for infusion sets available from different manufacturers, and using a non-recommended infusion set can result in a pump delivering non-accurately.
There is no universal infusion set which can be used with any volumetric pump. If different volumetric pumps from different manufacturers are used in a clinical trial, this will inevitably require using different infusion sets together with data on the study drug stability and compatibility for each of them.
6 What kind of data on the drug stability and compatibility with fluid-contacting parts of the drug delivery system is normally required?
In general, good compatibility and stability data is based on analysis of the drug concentration over a period of storage, analysis of the concentration of the plasticizer and degradation products, measurement of the drug pH change and the change in weight/water loss over the period of storage, as well as visual examination to assess any colour change or precipitation.
It is important that these analyses are done for clinically relevant concentrations and under appropriate temperature conditions. When using an infusion pump, it is possible to vary the contact time between the drug and the infusion set by varying the drug concentration and thus the flow rates. If the drug is diluted, then it will need to be delivered at higher flow rates to achieve the same dosage. The higher the flow rate, the shorter the drug’s contact time with the elements of an infusion set. Dilution can also be used to improve delivery accuracy because accuracy is improved if delivery rates are high. So, to avoid inaccuracies at low flow rates, it is recommended to dilute solutions further. This information can be utilized when preparing a drug dose delivery protocol.
7 Are there any limitations on the duration of delivery?
Drug stability may dictate the maximum duration of continuous infusion. Infusion may be needed to be interrupted to continue with a new fluid bag/syringe containing a freshly-prepared solution. The duration of continuous infusion via a volumetric pump is also limited by the compliance of an infusion set. The set’s compliance can be affected by prolonged delivery and this can reduce the delivery accuracy. Typically, volumetric pumps’ infusion sets can only be used continuously for 24 hours. However, some pumps offer infusion sets capable of maintaining accurate delivery at maximum flow rate for 96 hours. Information on recommended maximum duration of infusion when delivering at maximum possible flow rate is provided by the pump manufacturer. There are no particular limitations for infusion sets used with the syringe pumps. Luer-lock sets can be used for as long as it is allowed by the local hospital clinical guidance.
8 How reliable are infusion pumps?
Infusion pumps are required to comply with a range of standards in order to ensure their safe and reliable operation. Modern infusion pumps also offer a range of alarms to alert a user to situations that can compromise the therapy provision or its safety. However, some user errors, such as programming the wrong parameters of infusion or a wrongly performed set up of the pump, cannot be prevented by the in-built safety system. An electronic event log is typically present in all modern electrically powered pumps, which stores the history of any keypresses in the pump’s memory. This enables the pump’s operation or any unauthorised interference with its performance to be traced. Regular monitoring of infusion would be advisable, particularly in a clinical trial, and keeping a detailed record of observations might also be helpful for further data analyses.
9 Can a selected infusion pump and its dedicated disposables be provided to clinics where a phase 2 or 3 trial is going to take place?
Unfortunately, it is not practical and in reality will probably never happen. Introduction of new equipment into a clinical environment is associated with increased level of user errors and is one of the known safety hazards. All staff involved with operating a new device would have to undergo training and become competent. This requires extra time and resources to implement. Moreover, clinical regulations in some countries may limit the variety of pumps that can be used in a clinic to reduce the likelihood of user errors, when confusion between different machines may occur. In such cases, introducing a new pump for clinical trial purposes may not be possible. It is very likely that the phase 2 or 3 clinical trial coordinators would have to adopt the pumps already in use in clinics for their study, and ensure their own familiarity with the pumps’ technical characteristics, as well as obtain necessary data related to their disposables.
10 Where can information about infusion pumps be found?
Infusion pump manufacturers have information related to the pump specification, performance and maintenance. They also have information related to their dedicated disposables, such as the material they are made from, conditions for use, etc.
Bath Institute of Medical Engineering (BIME), University of Bath has evaluated independently a large number of infusion pumps over the past 30 years; the reports of the projects undertaken from 2002 can be downloaded from the BIME website (www.bath.ac.uk/bime/evalcentre/pumps.html). Earlier reports are available as hard copies only, and can also be requested from BIME. BIME welcomes any enquiries related to infusion pumps, and offers services such as technical performance verification of the selected infusion pumps and preparation of the study drug delivery protocols, taking into account particular features of the selected pumps.