Patent Application
20150112695
A clinical trial is often performed before the introduction of a new drug or treatment (i.e., therapy), to test the safety and efficacy of the therapy for human consumption. Clinical trials are usually classified into four phases: Phase I generally comprises safety screening on a small group of people, Phase II comprises efficacy screening, Phase III comprises safety screening on a larger group of people, and Phase IV comprises additional studies during an initial sales period.
The guidelines and procedural methods for administration of a clinical trial are known as clinical trial protocols. Clinical trial protocols often determine how subjects will be selected for a trial, how many geographic locations will participate in the trial, and standardized laboratory methods for how test results will be studied during the trial, among other things. In some cases, clinical trial protocols are comparative, i.e., they are set to compare the outcomes of different therapies, and include randomization, the random allocation of subjects to various study arms, where each arm corresponds to one of the therapies being compared. Such randomization is often designed to minimize a clinical trial administrator's bias while enrolling subjects or while allocating therapy to specific subjects or patients.
Often the study design allows or even mandates variability in the doses within an arm. The variability can be of two types: (i) variability across different subjects belonging to the same study arm, for example when dosing is based on weight, and/or (ii) variability across different visits of the same subject during the trial, based on some clinical finding (such as a change in tolerability) or on a scheduled dose titration. If a clinical trial designer or physician desires to change dosages throughout the study, or if the desired dosing for a therapy changes during a clinical trial, these desired changes can be extremely difficult to capture and implement globally for all, or individual, subjects across the study, as implementation of such changes may be time consuming and possess a high error rate. Furthermore, a clinical trial protocol may include complex rules for whether specific dosing changes are allowed. These rules can be difficult to implement globally and often require complex recordkeeping.
Where considered appropriate, reference numerals may be repeated among the drawings to indicate corresponding or analogous elements. Moreover, some of the blocks depicted in the drawings may be combined into a single function.
In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the invention. However, it will be understood by those of ordinary skill in the art that the embodiments of the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to obscure the present invention.
Embodiments of a computerized clinical treatment system have been developed that may configure, integrate, and store numerous variables and components for use in clinical trials and other clinical treatment settings. Such systems may streamline the design and overall management of clinical treatment dispensation. Embodiments may also integrate features and systems for randomization, inventory management, dose scheduling, and electronic data capture, for example. The clinical treatment system may be implemented as a standalone program or may be implemented on a network, for example, over the Internet as a cloud-based service or hosted service, which may be accessed through a standard web service API (application programming interface).
An example of a clinical treatment system is a system that helps design and administer clinical trials. A sponsor (e.g., a drug manufacturer whose drug is being tested) or a contract research organization (CRO), which may execute clinical trials on behalf of a sponsor, may develop a protocol for a clinical trial. The clinical trial protocol may include a dosing schedule to specify when, and how much of, a therapy is to be administered to clinical trial subjects as well as dosing factors that influence what dosage a subject may receive. In some cases, clinical trials may include graduated or conditional dosing schedules that alter the prescribed therapy dose as the clinical trial progresses, a process known as titration. Titration may be based on scheduled or unscheduled physician visits or on specific conditional rules or both. Dosing information from the clinical trial protocol may be used to develop a detailed visit schedule, which often includes a schedule of every combination of every treatment arm according to each dosing factor and titration level detailed in the clinical trial protocol. Such a schedule may comprise tens of thousands of combinations that require hours of labor to create corresponding rows and columns in visit schedule spreadsheets. Upon completion of such a visit schedule spreadsheet, a clinical trial sponsor or CRO may spend several hours on quality control to validate the visit schedule for accuracy. A developer with computer programming skills then must hard code the details of the visit schedule into a computerized clinical trial system for clinical trial site personnel to use. Such complexities lead to error-prone designs and can extend the clinical trial development time by several weeks or longer, resulting in substantially increased costs. Additionally, severe risks to patients may be involved when errors occur in the subject treatment assignment, compromising study integrity.
In order to decrease clinical trial design error rates and corresponding patient risk, decrease time spent on coding and development, and decrease overall cost of clinical trial design, a system has been developed that implements dosing, schedule, and titration rules globally and individually within a clinical trial (or other clinical treatment) protocol, and may modify and customize a clinical trial's dosing, schedule, and titration settings in real-time, without requiring additional hours of custom coding and development. With the system as described herein, clinical trial and treatment designers may capture, implement, and manage complex dispensation requirements for clinical trials and treatments.
Embodiments of the invention enable a designer to enter, manipulate, and implement dosing, schedule, and titration parameters including treatment arms, dosing factors, dosing levels, scheduled and unscheduled titrations, titration limiting rules, and treatment assignment rules, among others. Embodiments of the invention also include a rules engine that automatically computes clinical trial protocol information for use in a treatment assignment subsystem that may generate every combination of every treatment arm according to each dosing factor, dosing level, schedule, and titration. A runtime system may also be included that clinical trial site personnel may use to store and obtain dispensation information and input dispensation requests and patients' responses to treatment.
Reference is now made to
Reference is now made to
In
Rules engine 150 may utilize treatment parameters to compute treatment combinations to drive treatment assignment subsystem 160. In turn, treatment assignment subsystem 160 may be used by designer 20 to generate clinical trial design specification (or configuration report) 162, as well as treatment dispensation information 165, which may be used to configure treatment dispensation system 170, which, along with runtime subsystem 180, is part of runtime system 190. Although clinical trial design specification 162 is depicted in
Dosing factor subsystem 105 may be used to allow a designer 20 to set up additional dosing parameters that help determine appropriate treatment for the subject or patient. Dosing factors may comprise clinical factors such as a patient's gender, weight, or body surface area, or may comprise more abstract factors like a patient's dosing level, or a combination of both. In one embodiment, dosing factors may include factors for randomization.
Treatments subsystem 110 may be used to assign types of therapies and combinations of therapies, for example. As shown in
In another embodiment, randomization factors may be provided by randomization design subsystem 120. Titration design subsystem 140 may allow designer 20 to implement titrations and titration rules into the clinical trial design specification.
As shown in
Naming interface 142 may enable specific titration level sets to be identified by name. Embodiments of this feature may allow titration level sets to be implemented into treatment assignment subsystem 160 and identified accordingly. Schedule interface 143 may allow designer 20 to implement a scheduled or unscheduled titration design into treatment assignment subsystem 160. Level set interface 144 may allow designer 20 to implement specific titration levels into the dispensation design system.
For a clinical trial including a scheduled titration design, level set interface 144 may interact with study visit schedules subsystem 130, shown in
For a trial with an unscheduled titration design, level set interface 144 may interact with study visit schedules subsystem 130 to assign a default titration level to an initial patient visit. In this case, dosing may continue to be dispensed according to default titration levels unless the clinical trial implements conditions or requests to titrate to another level. Generally, unscheduled titrations implement a titration level change based on conditions outside of the number of a patient's visits, or the physician's discretion. Unscheduled titration conditions may be pre-defined or designated by the clinical trial designer.
Embodiments of system 100 may incorporate conditional titration rules through limiting rules module 147, which may be used to govern the number of unscheduled titrations for one or more subjects in the clinical trial. For example, these rules may be applicable to visits in which a clinical factor, such as a subject's weight or reaction to the therapy, or physician discretion, dictates unscheduled titrations. Limiting rules module 147 and the rules therein may control unscheduled titrations both in the case of unscheduled titration design, where all the titrations are unscheduled, and in the case of scheduled titration design, where unscheduled titrations—deviations from the titration schedule—may be allowed or mandated.
Level set interface 144 may allow a clinical trial designer to implement titration levels or specific dosing values across the clinical trial visit schedule. Titration level sets often comprise an ordered set of increasing titration levels. Titration level sets may be ordered and numbered, with the first level as the lowest dosing value, and successive levels as incremental steps up from each value. For example, a designer could set three titration levels in a titration level set with three levels where Level 1 may be 3 mg/kg, Level 2 may be 6 mg/kg and Level 3 may be 9 mg/kg.
Limiting rules module 147 may allow system 100 to implement rules that limit dosing from titrating up or down. Titrating up (“up-titration”) increases the subject's titration by one level. Titrating down (“down-titration”) decreases the subject's titration by one level. Other types of conceived rules may include rules to “maintain” or “use default.” A request to “maintain” may continue the subject at the same titration level regardless of any up-titrations or down-titrations scheduled for a visit. A request to “use default” may result in the dosage to be dispensed in accordance with the schedule, if one exists. Examples of titration limiting rules embodied in limiting rules module 147 may include at least the following:
Example Rule 1: The number of times a subject can titrate up outside of a primary treatment design. If a designer activates this rule and enters a number, the designer may prevent subjects from being titrated up off-schedule more times than the number specified. If Example Rule 1 is selected and a request arrives to titrate up a subject after the maximum number of times has already been reached, the system may maintain the current titration level. Optional responses include returning an error message or dispensing a titration according to the current titration level. In one embodiment, Example Rule 1 may allow scheduled or unscheduled down-titrations to occur for subjects that have reached a maximum number of up-titrations.
Example Rule 2: The number of times a subject can titrate down outside of the primary treatment design. If a designer activates this rule and enters a number, the designer may prevent subjects from being titrated down off-schedule more times than the number specified. If Example Rule 2 is selected and a request arrives to titrate down a subject after the maximum number of times has already been reached, the system may maintain the current titration level. Optional responses include returning an error message or dispensing a titration according to the current titration level. In one embodiment, Example Rule 2 may allow scheduled or unscheduled up-titrations to occur for subjects that have reached a maximum number of down-titrations.
Example Rule 3: The number of times a subject can titrate up or down outside of the primary treatment design. If a designer activates this rule and enters a number, the system may prevent subjects from being titrated up or down off-schedule more times than the number specified. If Example Rule 3 is selected and a request arrives to titrate after the maximum number of times has already been reached, the rule may instruct the software to maintain the current titration level. Optional responses include returning an error message or dispensing a titration according to the current titration level. In one embodiment, scheduled titrations are not counted. If a subject has reached the maximum number of unscheduled titrations they may be maintained for the remainder of the study, regardless of future scheduled titrations.
Example Rule 4: If a subject maintains a titration level during a scheduled visit, count as an up or down titration. If a designer activates this rule, the system may count any request to maintain the subject's titration level as an up-titration if a down-titration was scheduled. Conversely, the system may maintain the subject's titration level as a down-titration if an up-titration was scheduled.
Example Rule 5: Enforce single step titration. If a designer activates this rule, the system may prevent titration level selections that are more than one level up or down from the previously selected titration level. In some embodiments, the system may ensure subjects are only titrated one level up or down in the direction of the desired titration.
Example Rule 6: Determine system reaction if upper or lower titration level limits are reached. A designer can use this rule to select how the system will react to a request to up-titrate above a maximal level, down-titrate below a minimal level, or titrate in a manner in conflict with Example Rules 1-3. Example Rule 6 may allow the designer to select between maintaining a current titration level or return an error.
After all desired treatment parameters have been entered into the modules described above, rules engine 150 may compute a treatment combination set configurable by treatment assignment subsystem 160, including all combinations of treatment parameters based on treatment arms, dosing levels, titration rules, and scheduled visits, among others. Rules engine 150 may operate by creating rules based on treatment parameters and applying them globally to map every possible combination. As an example, rules engine 150 may create rules by multiplying the number of treatment arms by the numbers of scheduled visits and dosing levels to generate all possible combinations of treatment dispensation during the clinical trial. Rules engine 150 may then translate these combinations into rules that may be selectively assigned in groups across multiple treatment arms and visits by treatment assignment subsystem 160. Such assignment may reduce tens of thousands of applied treatment combinations into a handful of rules that may be assigned globally to automatically generate clinical trial design specification 162 and provide information to runtime system 190 (including treatment dispensation subsystem 170 and runtime subsystem 180).
As discussed above, after rules engine 150 generates treatment combinations based on information from input subsystems and provides the combination to treatment assignment subsystem 160, a designer may configure treatment assignment subsystem 160 according to clinical trial protocol 15. Designer 20 may specifically configure treatment parameters within the treatment combination set by filtering and assigning specific treatments to arms, dosing factors, titration levels, and visits, for example, pursuant to clinical trial protocol 15. Treatment assignment subsystem 160 may include filtering and multi-selection capabilities that may allow designer 20 to isolate specific treatment parameters of the clinical trial and implement rules as desired. Treatment assignment subsystem 160 may be automatically configured by rules engine 150 to capture every treatment parameter combination and may prevent designer 20 from configuring treatment dispensation information contrary to rules implemented in clinical trial protocol 15. For example, designer 20 may designate as invalid specific combinations of segments (arms), visits, and levels of each dosing factor by filtering out such invalid combinations. In another embodiment of the invention, treatment assignment subsystem 160 may automatically invalidate specific conditional combinations that are improper. Once designer 20 completes configuration of treatment assignment subsystem 160, system 100 may generate clinical trial design specification or configuration report 162. Specification 162 may be a paper printout or digital copy of a treatment dispensation schedule, although additional information may also be included. Part of a clinical trial design specification is shown in
As shown in
As shown in
An exemplary interface 200d for treatment assignment subsystem 160 is shown in
Reference is now made to
Besides the operations shown in
The parts and blocks shown in
In sum, described herein is a system for managing clinical treatment dispensation that interacts with a runtime treatment system to provide more efficient treatment design than was available before. More steps are performed automatically and human error may be minimized. Moreover, in prior systems, a software developer was needed to code details of the visit schedule, but this system does away with the need for such coding and the treatment designer is able to complete a design in less time and with decreased possibility for error. And although much of the discussion has been directed to the use of system 10 in designing a clinical trial and assigning treatments to subjects in a clinical trial, the system may be used in other scenarios to design treatments for other clinical settings, such as a doctor's office or clinic or hospital, and where the patient may not be a subject in a clinical trial but is being treated by the doctor or hospital.
Aspects of the present invention may be embodied in the form of a system, a computer program product, or a method. Similarly, aspects of the present invention may be embodied as hardware, software or a combination of both. Aspects of the present invention may be embodied as a computer program product saved on one or more computer-readable media in the form of computer-readable program code embodied thereon.
For example, the computer-readable medium may be a computer-readable signal medium or a computer-readable storage medium. A computer-readable storage medium may be, for example, an electronic, optical, magnetic, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any combination thereof.
A computer-readable signal medium may include a propagated data signal with computer-readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electromagnetic, optical, or any suitable combination thereof. A computer-readable signal medium may be any computer-readable medium that is not a computer-readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.
Computer program code in embodiments of the present invention may be written in any suitable programming language. The program code may execute on a single computer, or on a plurality of computers. The computer may include a processing unit in communication with a computer-usable medium, wherein the computer-usable medium contains a set of instructions, and wherein the processing unit is designed to carry out the set of instructions.
The above discussion is meant to be illustrative of the principles and various embodiments of the present invention. Numerous variations and modifications will become apparent to those skilled in the art once the above disclosure is fully appreciated. It is intended that the following claims be interpreted to embrace all such variations and modifications.
