SAFETY-CRITICAL DRUG DELIVERY PARAMETER DETERMINATION

FIELD OF THE INVENTION

The present invention relates to drug delivery systems for delivering, administering, injecting, infusing and/or dispensing liquids comprising a medicament or active ingredient. It departs from drug delivery systems involving the use of smartphones for calculating safety critical delivery parameters.

BACKGROUND OF THE INVENTION

A variety of diseases exist that require regular treatment by subcutaneous administration of a medicament. By way of example, diabetes may be treated by administration of insulin with the help of delivery devices that may be handled by the patients themselves. Accordingly, devices that are capable of accurately and controllably delivering fluids are particularly useful in the medical field for administration or dispense of a known amount of drug at predetermined intervals. One category of delivery devices includes infusion pumps that have been developed for the continual subcutaneous administration of insulin or other medicaments for patients suffering from type I or type II diabetes. An insulin pump delivers fast-acting insulin via an infusion line to a small infusion set attached to the skin. The infusion set includes either a Teflon cannula or a small metal needle inserted through the skin for gradual absorption into the blood stream. On the other hand, tubeless patch pumps are directly applied to the skin and continuously deliver insulin through a short cannula on the bottom of the pump. Alternatively, the delivery device may be a variable-dose, generally elongate or pen-shaped injection device that is removed from the injection site after drug delivery, with a control module integrated in the injection device, or as part of an add-on or supplemental device detachably attached to the injection device. Insulin pumps configured as portable infusion devices are often discretely located on or around a patient, such as beneath clothing or in a carrying pouch. Some infusion pumps are therefore adapted to be programmed by means of remote control devices without directly interacting with a user interface of the pump. The pump can be programmed or remote commanded to deliver basal insulin and give a bolus of insulin for a meal or high blood sugar. With the proliferation of handheld consumer electronic devices, such as smartphones, there is a desire to be able to utilize such devices as the remote control device for remotely operating a delivery device. However, medical devices and consumer electronics have vastly different safety and reliability profiles, such that use of consumer electronic devices to program medical devices such as infusion pumps could present safety issues for the patient. In safety critical systems, a safety critical value such as a proposed bolus amount and/or duration, may be computed in a redundant manner via two independent channels, requiring at least approximatively identical output by both channels and thus allowing at least to detect erroneous operation of a single channel. Known redundancy methods include hardware- redundant computation, including complete duplication and execution of a task or algorithm on different microprocessors, or in different cores of a single processor. On the other hand, diverse redundancy is reverting to different number formats to enforce independent calculations on a single microprocessor, and may include integers being processed in an Arithmetic Logic Unit (ALU), and floating point numbers being processed in a Floating Point Unit (FPU). Alternatively, ALU operators may be tested for fault free operation by means of test vectors with known outcome, which allows to detect erroneous behavior due to hardware malfunctioning.

With common consumer electronic devices including smartphones and handheld tablet devices, the above methods may not always be available. Duplication of processors is generally out of scope, and redundant calculations on two different cores of a multi-core processor may not be guaranteed. Furthermore, diverse redundancy calculations are not ensured either, as floating point operations may be executed by virtue of the ALU. Ultimately, test vector evaluation and subsequent calculations may be executed on different cores. Testing of ALU operators in common consumer electronic devices is further complicated by missing assembler instructions or processor specific commands, and by the fact that a same operating system may be used with distinct processors.

WO 16041863 Al discloses a supervising entity or safety module as part of, or separate from, a mobile device, for testing whether the mobile device is functional and free of errors as e.g. introduced by viruses or updates of the operating system. Correct solution of a validation problem in the form of a simple mathematical operation with given starting values as solved by the mobile device is checked by the testing module. WO 2015/100340 discloses a system for enhanced reliability and safety of programming and/or operating an infusion pump, including a remote control device such as a mobile phone. A safety processor acts as an intermediary device between the mobile phone and the infusion pump to review transmissions from the mobile phone prior to the transmissions being delivered to the infusion pump. Specifically, a programming operation for the infusion pump, performed by the smartphone, is transmitted to the safety processor as a request for an operation on the infusion pump. The safety processor reviews the request and determines if it is acceptable or plausible, based on the parameters related to operation of the medical device stored in the memory. The safety processor may receive information from a Continuous Glucose Monitor (CGM), and determine whether it is permissible to execute the operating command on the medical device by utilizing the information from the CGM.

So called closed loop or artificial pancreas algorithms as disclosed for instance in WO 2017/132577 may be used to track the blood sugar or glucose level of a person and the insulin doses delivered in order to determine when the person needs additional administration of insulin. The system does prompt the person to administer a certain dose of insulin upon determination that the latter is required to control his/her blood sugar, based on current and/or forecast uncontrolled blood sugar level. The amount of insulin may be determined involving a correction factor or insulin sensitivity factor of the user which governs how much insulin is needed to lower the blood sugar level of the user by one unit. Accordingly, in a simple implementation the following relationship is used to determine an amount of insulin needed:

Insulin needed = current blood sugar / correction factor - insulin on board

Here, the insulin on board is reminiscent of any previously administered insulin doses not yet completely absorbed into the blood stream. Alternatively or in addition, a so-called bolus calculator may determine an insulin bolus dose amount based on glucose information including the most recent glucose level reading and historical glucose trend information, patient weight, and an exercise factor of the patient, in order to cover the amount of carbohydrate of a planned or ingested meal according to the following relationship:

Insulin bolus = grams of carbohydrate / carbfactor.

Here, the carbfactor or insulin-to-carbohydrate ratio of the patient indicates the number of grams of carbohydrate that one unit of fast acting insulin may cover. SUMMARY OF THE INVENTION

It is an objective of the invention to increase safety and reliability of adaptable drug delivery systems involving the use of common consumer electronic devices for calculating safety critical delivery parameters. This objective is achieved by a method of confirming a drug delivery operation, a drug delivery system, and a computer program according to the independent claims. Preferred embodiments are evident from the dependent patent claims.

According to the invention, a safety-critical drug delivery operation or task to be performed or executed by means of a drug delivery device is based on a drug delivery command or instruction received via a communication interface of the delivery device. The drug delivery command may include a delivery parameter such as a bolus amount and/or duration, a basal rate, a delivery time or interval, or a mere binary signal triggering instantaneous delivery of a predefined dose. Therefore, the drug delivery command received by the delivery device and/or the resulting drug delivery operation are safety- or health- critical in the sense that any command deviating significantly from the intended command, for instance by specifying an erroneous bolus amount and/or duration or a delayed delivery time, may have severe consequences for the health of the patient. The drug delivery operation and/or the drug delivery command are confirmed or validated according to the following steps:

- Determining, or computing, by a remote control device different from the delivery device and devoid of proven computation redundancy, an unconfirmed drug delivery command by applying a basic arithmetic operation, or the corresponding operator, to control device input data. The basic arithmetic operation may include any of adding, subtracting, multiplying, or dividing two input data values. The control device input data may include first input data indicative of a most recently consumed, or of an imminent, amount of carbon hydrate, input manually into the control device by the patient. The input data may include first input data indicative of a blood glucose level of the patient as determined and transmitted by a Blood Glucose Monitoring (BGM) device. The control device input data may also include second input data including stored medical data of the patient, including patient weight, insulin to carbohydrate ratio, correction factor, and exercise factor of the patient, and historical data indicative of a drug delivery history previously input into, or read by, the control device. The control device is a common consumer electronic device, which excludes approved dedicated medical control devices but includes stationary and, preferably, mobile devices not responding to medical safety standards, such as smartphones, handheld tablet devices, or any other portable or wearable smart gadgets with Human Machine Interfacing capabilities.

- Communicating, by the control device and by wireless transmission, the basic arithmetic operation and the control device input data to a redundancy or safety co- processing module or confirmatory unit implemented on, or hosted by, a redundancy device different from the control device and including a communication interface adapted for receiving the communication from the control device.

- Determining, by the redundancy module, a redundant drug delivery command based on the basic arithmetic operation and the control device input data as received from the control device. To this purpose, the redundancy module may provide for an at least rudimentary and preferably standardized mathematical or calculus service.

- Comparing, by a comparator module or unit preferably incorporated in the redundancy device and/or in the control device, the unconfirmed drug delivery command and the redundant drug delivery command, and preventing, in case of diverting commands, transmission, reception, and/or execution of the safety-critical delivery operation by the delivery device. On the other hand, at least approximately matching unconfirmed and redundant drug delivery commands are considered safe, and the drug delivery operation is executed by the delivery device, preferably without any further confirmation on the correctness of the delivery command. By way of example, the control device input data and the basic arithmetic operator may be provided to the redundancy device in Reverse Polish Notation (RPN). The result of a first basic arithmetic operation may further be operated on by applying or executing another basic arithmetic operation. A sequence of suitably prioritized, or bracketed, basic arithmetic operations may thus represent any analytical formulae. Communication from the control device to the redundancy module in this case may include a plurality of basic operators, and more than two control device input data values. On the other hand, the basic arithmetic operators of the basic calculus service may be complemented by logical, comparative, control flow and/or Boolean operators. The aforementioned basic arithmetic operators may thus be combined into more complex algorithms and control flows. Accordingly, an extended service interface of the redundancy module may include a set of operators or instructions supportive of a variety of data types and enabling more flexible computations beyond analytical formulae and including algorithms and control flows. The redundancy device may be providing the above calculus service on behalf of more than one client. In particular, in addition to the control device, a Continuous Glucose Monitor CGM may likewise be requesting a mathematical computation, not necessarily redundant, to be executed on its behalf, such as a statistical function, including a mean value, of several consecutive CGM readings.

Upon availability of a confirmed delivery command at the drug delivery device the latter may be operated manually by the patient activating a trigger button to start delivery, or even providing mechanical power to drive delivery of a dose set automatically based on the drug delivery command. However, the drug delivery device may be a subcutaneous infusion device such as an insulin pump including a power source for automated delivery not requiring further human intervention.

The wireless communication between the control device and the redundancy module may require suitable transceiver units for short or near range wireless communication at both devices. Preferably, such communication is established according to the Bluetooth Low Energy (LE) Core Specification, or any equivalent near range communication technology with application level security including RFID, NFC, Ant, Zigbee, WAN, WLAN, LORA or the like, which in turn may cover the encryption, trust, data integrity and privacy of the communication. Corresponding features include advanced out-of-band pairing where the control device and the redundancy device involved in the communication exchange their identity information to set up trust and get the encryption keys ready for the future data exchange, or the ability to send authenticated data over an unencrypted transport between two devices with a trusted relationship. The near range wireless communication from the control device may be directed to a medical gateway device and complemented by an internet connection from the gateway device to a redundancy module on a remote service provider. The redundancy module may be implemented on a redundancy device, such as a second mobile device, with similar computational shortcomings as the remote control device, or on a dedicated remote server. However, the redundancy module or the corresponding calculus service is preferably implemented on, or hosted by, the delivery device itself. The delivery device, such as an insulin pump, by its very nature, responds to medical safety standards, and as part of the delivery system is readily available without the need for any further communication link to be established.

In an advantageous embodiment, the redundant drug delivery command is communicated from the redundancy module to the control device. The comparator module implemented on the control device then proceeds to comparing the unconfirmed and redundant drug delivery commands, and finally communicates either of the two matching delivery commands to the delivery device. In an alternative advantageous embodiment, the comparator module is implemented on the redundancy device, to compare the unconfirmed drug delivery command received from the control device and the redundant delivery command calculated by the redundancy module of the redundancy device. The redundancy device finally communicates either of the two matching delivery commands to the drug delivery device in case the two devices are distinct. Mixed or conflated embodiments with comparator modules at both the control device and the redundancy device are also possible. In preferred variants of the invention, a token such as a time-stamp or other sufficiently unique identifier is used to enable identification and subsequent comparison of corresponding unconfirmed and redundant delivery commands in respective command sequences generated independently. As the unconfirmed and redundant delivery commands reach the comparator module via distinct paths, an intended order may not be respected, and the token may help to unambiguously unite the commands pertaining to the same basic arithmetic operation and control device input data.

In an advantageous embodiment of the preferred variant, the token is generated by the control device, and communicated together with, or otherwise linked to, the basic arithmetic operation and the input values to the redundancy module. The redundant delivery command is stored in a result list of a storage module of the redundancy device together with the token. In an alternative advantageous embodiment, the token is generated by the redundancy module, and stored together with the redundant delivery command in a result list of a storage module of the redundancy device. In parallel, the token is communicated to the control device as a response to the communicated basic arithmetic operation and data values. In both embodiments, the token is subsequently communicated together with the unconfirmed command by the control device to the comparator module implemented on the redundancy device, and thus having access to the result list for identifying and retrieving the previously stored redundant delivery command.

The invention also relates to a drug delivery system with a delivery device adapted to execute a safety-critical task based on an unconfirmed result determined at a remote control device by applying an operator to control device input data. The drug delivery device comprises a communication module to receive, from the control device, the operator and the control device input data, and a redundancy module to determine a redundant result by applying the operator to the control device input data received from the control device. The drug delivery device is adapted to prevent execution of the safety-critical task if the unconfirmed result and the redundant result are found, by a comparator module, to divert. The operator is one of an arithmetic, logical, comparative, control flow and/or Boolean operator, and the result is preferably determined by suitably processing or combining two or more input data values according to the operator. Alternatively, the result may also be obtained from a single input data value, such as by applying a rounding rule. The control device input data and the result may include a system state such as an alarm state or an activated state of the delivery device. Preferably, the operator is a basic arithmetic operator for any of adding, subtracting, multiplying, or dividing two input data values. The control device input data may include first input data indicative of a most recently consumed, or of an imminent, amount of carbon hydrate, input manually into the control device by the patient. The input data may include first input data indicative of a blood glucose level of the patient as determined and transmitted by a Blood Glucose Monitoring (BGM) device. The control device input data may also include second input data including stored medical data of the patient, including patient weight, insulin to carbohydrate ratio, correction factor, and exercise factor of the patient, and historical data indicative of a drug delivery history previously input into, or read by, the control device. The invention ultimately relates to a computer program in the form of a application program stored on a computer-readable medium to be installed and run on a control device for controlling a drug delivery operation performed by means of a drug delivery device. The computer-readable medium may be a floppy disk, a hard disk, an USB (Universal Serial Bus) storage device, a RAM (Random Access Memory), a ROM (Read Only Memory), an EPROM (Erasable Programmable Read Only Memory), or a data communication network, e.g. the Internet, which allows downloading program code. The computer program causes, when being executed by a processor unit of the mobile control device, the processing unit to execute the steps of

- Determining an unconfirmed drug delivery command by applying a basic arithmetic operation to control device input data;.

- Communicating the basic arithmetic operation and the control device input data to a redundancy device;

- Receiving, from the redundancy device, a redundant drug delivery command determined by a redundancy module of the redundancy device by applying the basic arithmetic operation to the control device input data, and

- Comparing the unconfirmed drug delivery command and the redundant drug delivery command, and preventing, in case of diverting commands, execution of the drug delivery operation by the drug delivery device. In the present context, the terms "substance", "drug", "medicament" and "medication" are to be understood to include any flowable medical formulation suitable for controlled administration through a means such as, for example, a cannula or a hollow needle, and comprises a liquid, a solution, a gel or a fine suspension containing one or more medical active ingredients. A medicament can be a composition comprising a single active ingredient or a pre-mixed or co-formulated composition with more than one active ingredient present in a single container. Medication includes drugs such as peptides (e.g., insulin, insulin- containing drugs, GLP-1 containing drugs or derived or analogous preparations), proteins and hormones, active ingredients derived from, or harvested by, biological sources, active ingredients based on hormones or genes, nutritional formulations, enzymes and other substances in both solid (suspended) or liquid form but also polysaccharides, vaccines, DNA, RNA, oligonucleotides, antibodies or parts of antibodies but also appropriate basic, auxiliary and carrier substances.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject-matter of the invention will be explained in more detail in the following text with reference to preferred exemplary embodiments as illustrated in the attached drawings, of which

Fig.1 depicts an exemplary medical drug delivery and patient support system;

Fig.2 illustrates a first variant of the method of confirming a drug delivery command;

Fig.3 illustrates a second variant of the method of confirming a drug delivery command; and Fig.4 illustrates the second variant complemented by the use of a token.

For consistency, the same reference numerals are used to denote similar elements illustrated throughout the drawings. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Fig. l depicts an exemplary medical drug delivery and patient support system, with a patient receiving doses of medication on a regular basis from a drug delivery device 10 through a flexible tube or a cannula 11. A remote mobile control device 20 such as a smartphone or tablet device running a dedicated application program is provided with control device input data 21. The control device 20 determines an unconfirmed drug delivery command intended to control a safety critical operation of the delivery device 10. In order to increase confidence in the drug delivery command, the control device is adapted to communicate with a communication module 30 which in turn serves as an interface to a redundancy, or redundant computation, module 31, a comparator module 32, and/or a storage module 33. In Fig.l, the latter modules are all assigned to, or implemented on, the drug delivery device 10, but nevertheless may be allocated to, and hosted by, distinct devices of the system as will be apparent from the following paragraphs.

The control device 20 has a user interface to receive control device input data 21, either entered manually or input via suitable communication means from another device, and/or memory means from which previously stored control device input data 21 may be retrieved. The input data may include user data such as patient weight, insulin to carbohydrate ratio, correction factor, and exercise factor. The control device is adapted to send commands or instructions to the delivery device 10. The commands include a dose amount and/or a dose timing, determined by taking into account glucose level and trend, and other factors. The control device may be in continuous communication with a glucose monitor and the delivery device to provide for near real-time adjustments in glucose treatment. Glucose data, insulin injection data, and other relevant data may be stored and accessible to interested parties either locally through the user interface of the control device, or globally via remote servers or databases.

Fig.2 illustrates a first variant of the method of confirming a drug delivery command and a corresponding configuration of the devices of the medical drug delivery system. A control device 20 has access to control device input data 21 including two parameter values A, B. The safety critical calculation to be performed being "A plus B", suitable processing capability of the control device determines an unconfirmed delivery command or instruction C. In parallel, the input data A, B as well as the operator "plus" are forwarded to a redundancy module 31 on a redundancy device 10', and a redundant delivery command C is calculated by the redundancy module 31. The redundant delivery command C is returned to the comparator module 32 of the control device 20, and upon successful validation, either of the unconfirmed command C or the redundant command C is forwarded by the control device 20 to the delivery device 10. In the preferred case where the redundancy device 10' and the delivery device 10 are one and the same device, such forwarding may be limited to an indication about the successful validation of the redundant command C, such that the latter may be shared device-internally with a delivery controller of the drug delivery device. Incidentally, either the control device or the redundancy module 31 may proceed to a plausibility check based on the physical units of the input parameters A, B, and for instance abort the process if two input parameter values with distinct units are to be summed. Fig.3 differs from Fig.2 to the extent that the comparator module 32 is arranged on the redundancy device 10', and in that the unconfirmed delivery command C is communicated to the redundancy device 10' for the purpose of comparison. Upon successful validation by the comparator module 32, either of the unconfirmed command C or the redundant command C is forwarded to the delivery device 10. In the preferred case where the redundancy device 10' and the delivery device 10 are one and the same device, such forwarding may be limited to a device internal sharing of the delivery command with a delivery controller of the drug delivery device.

In the variant of Fig.3, the unconfirmed delivery command and the input data values are assigned a command type identifier or functional designation in the form of a simple tag indicative of the command type inherent to, or associated with, the unconfirmed command C, such as "instantaneous bolus". Reverting to such a simple command type identifier is based on the assumption that there is a sufficient pause between successive commands of the same type or designation to prevent mixing of successive commands. The command type identifier then allows the comparator module 32 to proceed to a further plausibility check, and to abort the process in case the command type of the unconfirmed command does not match the command type identifier of the redundant command C

Fig.4 illustrates the variant of Fig.3, complemented by the use of a token in order to unambiguously identify corresponding delivery commands. In this case, a token t is generated by or on behalf of the redundancy module 31 by a token generator 34, and stored together with the redundant delivery command C in a result list of a storage module 33 of the redundancy device 10' . In parallel, the token t is communicated to the control device 20 as a response to the previously communicated basic arithmetic operation and data values, as indicated by the connector pointing from right to left in Fig.4. The token t is ultimately communicated together or in parallel with the unconfirmed delivery command C by the control device to the comparator module 32 likewise implemented on the redundancy device 10' . The comparator module has access to, or is provided with, the result list for identifying and retrieving therefrom the previously stored redundant delivery command C based on the token t. A token may also be employed in connection with other variants, such as the one depicted in Fig.2.

In order to further increase reliability of the process, the token introduced above may be provided with a timeout property, may include a suitably increment to ensure single usage at least during a suitably defined process cycle, and/or may be encrypted or hashed. Furthermore, a token may be indicative of, or linked to, a type of the delivery command, such that e.g. "instantaneous bolus" type commands are incremented separately. Token t and corresponding delivery command C may be eliminated from the result list upon initial identification, but may also be stored for an extended period of time. In the latter configuration, command C may be retrieved at a later time, as input data for a subsequent iterating calculation, which has the potential of saving processing power at both the control device and the redundancy device. To that purpose, a token table maintained by the token generating entity, or any other set of identifiers indicative of previous calculations, may prove helpful.

While the invention has been described in detail in the drawings and foregoing description, such description is to be considered illustrative or exemplary and not restrictive. Variations to the disclosed embodiments can be understood and effected by those skilled in the art and practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain elements or steps are recited in distinct claims shall not preclude the existence of further meaningful combinations of these elements or steps.

LIST OF REFERENCE NUMERALS

10 drug delivery device

10' redundancy device

20 control device

21 control device input data

30 communication module redundancy module comparator module storage module