U.S. patent application number 14/254559 was filed with the patent office on 2014-08-14 for distributed randomization and supply management in clinical trials.
This patent application is currently assigned to Medidata Solutions, Inc.. The applicant listed for this patent is Medidata Solutions, Inc.. Invention is credited to Glen deVries, David Fenster, Jonathan Lebowitsch, Benjamin Young.
Application Number | 20140229197 14/254559 |
Document ID | / |
Family ID | 45096939 |
Filed Date | 2014-08-14 |
United States Patent
Application |
20140229197 |
Kind Code |
A1 |
Young; Benjamin ; et
al. |
August 14, 2014 |
DISTRIBUTED RANDOMIZATION AND SUPPLY MANAGEMENT IN CLINICAL
TRIALS
Abstract
A distributed clinical trial system that provides
configurability, reusability and integration of randomization and
inventory configurations for different clinical trials with various
electronic data capture (EDC) systems. The distributed clinical
trial system includes a method of dispensing medication in a
multi-arm clinical trial. In accordance with the method a subject
identifier and a trial identifier are received from an electronic
data capture system. The trial identifier indicates the multi-arm
clinical trial, and the subject identifier indicates a subject
enrolled in the multi-arm clinical trial. An arm identifier is
retrieved from a database based on the received subject identifier.
The arm identifier indicates an arm in the multi-arm clinical trial
to which the subject is assigned. Thereafter, treatment is
determined for the arm identifier based on a treatment design
previously configured for the multi-arm clinical trial. The
treatment includes a set of one or more units of at least one
article type.
Inventors: |
Young; Benjamin; (Manlius,
NY) ; deVries; Glen; (New York, NY) ; Fenster;
David; (New York, NY) ; Lebowitsch; Jonathan;
(Brooklyn, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Medidata Solutions, Inc. |
New York |
NY |
US |
|
|
Assignee: |
Medidata Solutions, Inc.
New York
NY
|
Family ID: |
45096939 |
Appl. No.: |
14/254559 |
Filed: |
April 16, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13157875 |
Jun 10, 2011 |
8738397 |
|
|
14254559 |
|
|
|
|
61354200 |
Jun 12, 2010 |
|
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Current U.S.
Class: |
705/2 |
Current CPC
Class: |
G16H 10/20 20180101;
G06Q 10/083 20130101; G16H 20/13 20180101; G16H 70/40 20180101 |
Class at
Publication: |
705/2 |
International
Class: |
G06Q 50/22 20060101
G06Q050/22 |
Claims
1. A method of dispensing medication in a multi-arm clinical trial,
the method comprising: receiving a subject identifier and a trial
identifier from an electronic data capture system, the trial
identifier indicating the multi-arm clinical trial, the subject
identifier indicating a subject enrolled in the multi-arm clinical
trial; retrieving an arm identifier from a database based on the
received subject identifier, the arm identifier indicating an arm
in the multi-arm clinical trial to which the subject is assigned;
and determining treatment for the arm identifier based on a
treatment design previously configured for the multi-arm clinical
trial, the treatment including a set of one or more units of at
least one article type.
2. The method of claim 1, further comprising transmitting the set
of one or more units to the electronic data capture system.
3. The method of claim 1, further comprising: uploading a batch of
units of article types, the batch indicating units of article types
available for shipment; and receiving an indication that one or
more units of the at least one article type have been received and
are available at a trial site associated with the subject
identifier.
4. The method of claim 3, further comprising determining whether
there are sufficient units of the at least one article type for the
treatment at the trial site for the subject identifier that comply
with dispensation metrics in the treatment design.
5. The method of claim 1, wherein the subject identifier and the
trial identifier are received from a dispense custom function of
the electronic data capture system.
6. A system to dispense medication in a multi-arm clinical trial,
the system comprising: a computing device; and a machine-readable
medium comprising instructions that, when executed by the computing
device, cause the computing device to perform operations
comprising: receiving a subject identifier and a trial identifier
from an electronic data capture system, the trial identifier
indicating the multi-arm clinical trial, the subject identifier
indicating a subject enrolled in the multi-arm clinical trial;
retrieving an arm identifier from a database based on the received
subject identifier, the arm identifier indicating an arm in the
multi-arm clinical trial to which the subject is assigned; and
determining treatment for the arm identifier based on a treatment
design previously configured for the multi-arm clinical trial, the
treatment including a set of one or more units of at least one
article type.
7. The system of claim 6, wherein the operations further comprise
transmitting the set of one or more units to the electronic data
capture system.
8. The system of claim 6, wherein the operations further comprise:
uploading a batch of units of article types, the batch indicating
units of article types available for shipment; receiving an
indication that one or more units of the at least one article type
have been shipped and are available at a trial site associated with
the subject identifier.
9. The system of claim 8, wherein the operations further comprise
determining whether there are sufficient units of the at least one
article type for the treatment at the trial site for the subject
identifier that comply with dispensation metrics in the treatment
design.
10. The system of claim 6, wherein the subject identifier and the
trial identifier are received from a dispense custom function of
the electronic data capture system.
11. A machine-readable storage medium comprising operational
instructions that, when executed by a processor, cause the
processor to perform operations comprising: receiving a subject
identifier and a trial identifier from an electronic data capture
system, the trial identifier indicating a multi-arm clinical trial,
the subject identifier indicating a subject enrolled in the
multi-arm clinical trial; retrieving an arm identifier from a
database based on the received subject identifier, the arm
identifier indicating an arm in the multi-arm clinical trial to
which the subject is assigned; and determining treatment for the
arm identifier based on a treatment design previously configured
for the multi-arm clinical trial, the treatment including a set of
one or more units of at least one article type.
12. The machine-readable storage medium of claim 11, wherein the
operations further comprise transmitting the set of one or more
units to the electronic data capture system.
13. The machine-readable storage medium of claim 11, wherein the
operations further comprise: uploading a batch of units of article
types, the batch indicating units of article types available for
shipment; and receiving an indication that one or more units of the
at least one article type have been received and are available at a
trial site associated with the subject identifier.
14. The machine-readable storage medium of claim 13, wherein the
operations further comprise determining whether there are
sufficient units of the at least one article type for the treatment
at the trial site for the subject identifier that comply with
dispensation metrics in the treatment design.
15. The machine-readable storage medium of claim 11, wherein the
subject identifier and the trial identifier are received from a
dispense custom function of the electronic data capture system.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/157,875 filed on Jun. 10, 2011, which claims priority
to U.S. Provisional Application No. 61/354,200 filed on Jun. 12,
2010, which are incorporated herein by reference in their
entireties.
BACKGROUND
[0002] 1. Field of Technology
[0003] The present application relates generally to clinical trial
systems. More specifically, the present application is directed to
a distributed clinical trial system that provides configurability,
reusability and integration of randomization and inventory
management configurations for different clinical trials with
various electronic data capture (EDC) systems.
[0004] 2. Brief Description of Related Art
[0005] A clinical trial is performed to, among other things, test
the safety and efficacy of a new drug or treatment (e.g., therapy),
and ultimately, to ascertain whether or not a therapy is
appropriate for widespread human consumption.
[0006] There are generally four phases in the clinical trial. In
Phase I, a few subjects (approximately 20 to 100) are used to
determine toxicity of the therapy. In Phase II, more subjects
(approximately 20-300) are used to determine efficacy and further
ascertain safety of the therapy. In Phase III, hundreds to
thousands of subjects are used to obtain meaningful statistical
analysis of the therapy's efficacy. The treatment may be compared
to either a placebo or another existing therapy. In Phase IV
(post-approval of clinical trial), more testing is performed to
evaluate long-term effects and to evaluate other indications of the
therapy.
[0007] In a comparative clinical trial, subjects are assigned to
multiple arms in order to facilitate analysis in a comparative
fashion. For example, subjects assigned to one arm (e.g.,
"control") can receive a placebo, while subjects assigned to
another arm can receive the medication being tested. Comparing the
results of the therapy in each arm of a multi-arm clinical trial
provides a measure of the efficacy of the medication in testing the
effectiveness of the medication. In another example, arms can also
receive various dosages of the medication being tested to evaluate
the safety and efficacy of the dosages. Still in other examples,
some arms can receive another medication against which the safety
and efficacy of the medication being tested can be evaluated.
[0008] The subjects of the multi-arm clinical trial are generally
randomized (e.g., assigned to the arms of the multi-arm clinical
trial in a random fashion) to avoid biases that may occur in the
selection of subjects for the clinical trial. A bias can be
introduced if a subject who is a particularly well-suited to
respond to a new medication--based on certain prognostic factors
(e.g., sex, age, prior condition or other factor)--is intentionally
assigned to an arm that receives the medication being tested and
not an arm that receives a placebo. This could skew the statistical
analysis and the outcome of the clinical trial to favor the
medication being tested.
[0009] A bias can further be introduced unintentionally if more
subjects having certain prognostic factors are randomly, but
unevenly, assigned to one arm versus another arm of the clinical
trial. Some clinical trials have attempted to mitigate this bias by
attempting to balance certain factors across the arms of the
clinical trial.
[0010] To further mitigate the risk of bias, the multi-arm clinical
trials are generally single-blinded or double-blinded. The
single-blinded clinical trial does not reveal the arm assignment to
the subject, while the double-blinded clinical trial does not
reveal the arm assignment to the subject and to the investigator.
Most randomized clinical trials are blinded.
[0011] There are currently a number of categories of computerized
clinical trial management systems that facilitate different aspects
of the clinical trial. A first category includes an interactive
voice-response (IVR) system or interactive-web-response (IWR)
system. Systems in this category typically facilitate enrolment of
multiple subjects into a clinical trial and the dispensing of
medication during the clinical trial. A second category includes an
electronic data capture (EDC). Systems in this category typically
capture clinical information concerning the subjects during the
clinical trial.
[0012] In most clinical trials, the foregoing systems in these two
categories are separate and not integrated. In some cases, where
integration has been effected, the EDC receives information
concerning the enrolled subjects from the IVR/IWR and randomizes
the subjects into arms of the clinical trial. The EDC may also
receive information from the IVR/IWR concerning medication that is
administered to the subjects during visits of the clinical trial.
The second system maintains the received information and other
information concerning the clinical trial in a runtime database.
Upon completion of the clinical trial, the maintained information
is closed out and used to evaluate the medication tested in the
clinical trial.
[0013] Typically, a designer writes a specification for the IVR or
IWR according to the requirements of a particular clinical trial.
Thereafter, a developer generally hard-codes or programs the
IVR/IWR for the clinical trial in accordance with the
specification. Subsequent revisions to the specification of the
clinical trial require recoding of the IVR/IWR. While there has
been some integration in clinical trial management, a clinical
trial management system that enables configurability, reusability
and integration of randomization and dispensing of medication
across different trials and various EDCs has remained illusive.
SUMMARY
[0014] In accordance with an embodiment, a method of randomizing
subjects in a multi-arm clinical trial is disclosed. In the method,
a subject identifier and a trial identifier are received from an
electronic data capture (EDC) system. The trial identifier
indicates the multi-arm clinical trial and the subject identifier
indicates a subject enrolled in the multi-arm clinical trial. A
randomization design previously configured for the multi-arm
clinical trial is retrieved from a database based on the received
trial identifier. The subject identifier is assigned to an arm
identifier of the multi-arm clinical trial based on the
randomization design. The arm identifier indicates an arm of the
multi-arm clinical trial to which the subject has been
assigned.
[0015] In accordance with an embodiment, a method of dispensing
medication in a multi-arm clinical trial is disclosed. In the
method a subject identifier and a trial identifier are received
from an electronic data capture (EDC) system. The trial identifier
indicates the multi-arm clinical trial and the subject identifier
indicates a subject enrolled in the multi-arm clinical trial. An
arm identifier is retrieved from a database based on the received
subject identifier. The arm identifier indicates an arm in the
multi-arm clinical trial to which the subject is assigned. A
treatment for the arm identifier is determined based on a treatment
design previously configured for the multi-arm clinical trial. The
treatment includes a set of one or more units of at least one
article type.
[0016] In accordance with yet another embodiment, a system to
randomize subjects in a multi-arm clinical trial is disclosed. The
system includes a randomizer configured to receive a subject
identifier and a trial identifier from an electronic data capture
(EDC) system, the trial identifier indicating the multi-arm
clinical trial. The subject identifier indicates a subject enrolled
in the multi-arm clinical trial. The randomizer is further
configured to retrieve randomization design previously configured
for the multi-arm clinical trial from a database based on the
received trial identifier. The randomizer is also configured to
assign the subject identifier to an arm identifier of the multi-arm
clinical trial based on the randomization design. The arm
identifier indicates an arm of the multi-arm clinical trial to
which the subject has been assigned.
[0017] In accordance with a further embodiment, a system to
dispense medication in a multi-arm clinical trial is disclosed. The
system includes an article dispenser configured to receive a
subject identifier and a trial identifier from an electronic data
capture (EDC) system, the trial identifier indicating the multi-arm
clinical trial. The subject identifier indicates a subject enrolled
in the multi-arm clinical trial. The article dispenser is further
configured to retrieve an arm identifier from a database based on
the received subject identifier. The arm identifier indicates an
arm in the multi-arm clinical trial to which the subject is
assigned. The article dispenser is also configured to determine
treatment for the arm identifier based on a treatment design
previously configured for the multi-arm clinical trial. The
treatment includes a set of one or more units of at least one
article type.
[0018] In accordance with another embodiment, a machine-readable
storage medium is disclosed. The machine-readable storage medium
includes operational instructions that, when executed by a
processor, cause the processor to receive a subject identifier and
a trial identifier from an electronic data capture (EDC) system.
The trial identifier indicates a multi-arm clinical trial and the
subject identifier indicates a subject enrolled in the multi-arm
clinical trial. The machine-readable storage medium further
includes operational instructions that cause the processor to
retrieve a randomization design previously configured for the
multi-arm clinical trial from a database based on the received
trial identifier. The machine-readable storage medium also includes
operational instructions that cause the processor to assign the
subject identifier to an arm identifier of the multi-arm clinical
trial based on the randomization design. The arm identifier
indicates an arm of the multi-arm clinical trial to which the
subject has been assigned.
[0019] In accordance with still another embodiment, a
machine-readable storage medium. The machine-readable storage
medium includes operational instructions that, when executed by a
processor, cause the processor to receive a subject identifier and
a trial identifier from an electronic data capture (EDC) system.
The trial identifier indicatives a multi-arm clinical trial and the
subject identifier indicates a subject enrolled in the multi-arm
clinical trial. The machine-readable storage medium further
includes operational instructions that cause the processor to
retrieve an arm identifier from a database based on the received
subject identifier. The arm identifier indicates an arm in the
multi-arm clinical trial to which the subject is assigned. The
machine-readable storage medium also includes operational
instructions that cause the processor to determine treatment for
the arm identifier based on a treatment design previously
configured for the multi-arm clinical trial. The treatment includes
a set of one or more units of at least one article type.
[0020] These and other purposes, goals and advantages of the
present application will become apparent from the following
detailed description of example embodiments read in connection with
the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Some embodiments are illustrated by way of example and not
limitation in the figures of the accompanying drawings in
which:
[0022] FIG. 1 illustrates a block diagram of an example clinical
trial system configured to design, simulate and run at least one
clinical trial;
[0023] FIG. 2 illustrates a flowchart of an example method of
configuring a randomization design for a clinical trial;
[0024] FIG. 3 illustrates a flowchart of an example method of
performing a randomization simulation of a randomization design
generated in accordance with FIG. 2;
[0025] FIG. 4 illustrates a flowchart of an example method of
configuring a treatment design for a clinical trial;
[0026] FIG. 5 illustrates a flowchart of an example method for
setting up a clinical trial via a trial administration interface of
an RTSM system of FIG. 1;
[0027] FIG. 6 illustrates a flowchart of an example method of
randomizing a subject via a randomizer illustrated in FIG. 1;
[0028] FIG. 7 illustrates a flowchart of an example method of
assigning a subject to an arm of a clinical trial;
[0029] FIG. 8 illustrates a flowchart of an example method of
dispensing medication via article dispenser 164 illustrated in FIG.
1;
[0030] FIG. 9 illustrates a flowchart of an example method of
randomizing a subject via a trial EDC system illustrated in FIG.
1;
[0031] FIG. 10 illustrates a flowchart of an example method of
dispensing medication to a subject via a trial EDC illustrated in
FIG. 1;
[0032] FIG. 11 illustrates an example webpage to configure a
randomization design for a clinical trial;
[0033] FIG. 12 illustrates an example webpage to setup and simulate
a randomization design for a clinical trial;
[0034] FIG. 13 illustrates an example webpage to display simulation
results of one or more simulations executed in FIG. 12;
[0035] FIG. 14A illustrates an example webpage to display overall
clinical trial balance of subject assignments and balance of
subject assignment in trial sites for a simulation;
[0036] FIG. 14B illustrates an example webpage to display aggregate
statistical results across runs of a randomization simulation;
[0037] FIG. 15 illustrates an example webpage to configure a
treatment design for a clinical trial;
[0038] FIG. 16 illustrates an example webpage to manage article
types illustrated in FIG. 15;
[0039] FIG. 17A illustrates an example webpage generated for trial
sites in a clinical trial to manage or more trial sites;
[0040] FIG. 17B illustrates an example webpage to assign a supply
plan to one or more selected trial sites of the clinical trial;
[0041] FIG. 17C illustrates an example webpage to assign a depot to
one or more selected trial sites of the clinical trial;
[0042] FIG. 18 illustrates an example webpage generated for
management of subjects in a clinical trial;
[0043] FIG. 19 illustrates an example webpage for management of
article shipments in a clinical trial;
[0044] FIG. 20 illustrates an example webpage for managing items of
inventory in a clinical trial;
[0045] FIG. 21 illustrates an example webpage for managing an
inventory batch list in a clinical trial;
[0046] FIG. 22 illustrates an example webpage for managing
logistics supply plan list; and
[0047] FIG. 23 is a block diagram of a general computer system.
DETAILED DESCRIPTION
[0048] A distributed clinical trial system and methods are
disclosed herein. In the following description, for the purposes of
explanation, numerous specific details are set forth in order to
provide a thorough understanding of example embodiments. It will be
evident, however, to one skilled in the art, that an example
embodiment may be practiced without all of the disclosed specific
details.
[0049] FIG. 1 illustrates a block diagram of an example clinical
trial system 100 configured to design, simulate and run at least
one clinical trial. For brevity and conciseness, the following
description will describe the design, simulation and execution of
an example clinical trial. It should be noted that multiple
clinical trials can be designed, simulated and executed, whether
contemporaneously or sequentially, in a similar fashion described
hereinafter.
[0050] The clinical trial system 100 includes a trial
administration system 104, randomization and trial supply
management (RTSM) system 120, and at least one electronic data
capture system (EDC) 176, 190. The clinical trial system can also
include a trial planner 110, study manager 111, supply manager 112,
at least one shipper manager 113, and a plurality of trial sites
114, 116, 118. The trial planner 110, study manager 111, supply
manager 112, shipper manager 113, and trial sites 114, 118, 118 can
be implemented or operated with respective computing devices. A
communication network 102 interconnects the foregoing systems 104,
120, 176 and computing devices 110-118 in the clinical trial system
100.
[0051] The communication network 102 is configured to transmit one
or more messages associated with clinical trial system 100. The
transmission over the network 106 can be accomplished, for example,
via Transfer Control Protocol/Internet Protocol (TCP/IP), User
Datagram Protocol (UDP)/IP, Hypertext Transfer Protocol (HTTP),
File Transfer Protocol (FTP), as well as any combination of
conventional protocols or protocols deployed in the future.
[0052] The computing devices 110-118 can include personal computers
that are configured to communicate via the communication network
102 in order to transmit and receive information concerning the
clinical trial. The computing devices 102 can include clients
(e.g., Internet Explorer.RTM.), which can execute one or more
applications and display one or more web pages associated with the
clinical trial system 100. The web pages can be displayed via
hypertext markup language (HTML), extensible markup language (XML),
extensible HTML, and/or other markup languages, as well as any
other technology now available or to be deployed in the future.
[0053] The trial administration system 104 is a centralized system
that is configured to enable a trial planner (e.g., contract
research organization) 110 to setup and manage a clinical trial as
well as sites and users associated with the trial sites 114, 116,
118. It should be noted the clinical trial system 100 is configured
to support multiple trial planners 110, as well as the setup and
management of multiple clinical trials and their associated sites
and users.
[0054] The trial administration system 104 includes a site setup
module 105, user setup module 106, trial setup and manage module
107, inventory depot setup module 109, and user database 108. The
trial setup and manage module 107 is configured to enable the trial
planner 110 to create and manage the clinical trial in the clinical
trial system 100 in the RTSM system 120 and/or the EDC system 176,
as will be described in greater detail below with reference to the
RTSM system 120 and the EDC system 176. At setup, the trial setup
and manage module 107 is configured to generate a trial ID
associated with clinical trial and to transmit the trial ID, site
IDs (set up via site setup 105) to the RTSM system 120 and the EDC
system 176.
[0055] The trial administration system 104 is further configured to
authenticate the users to use the clinical trial system 100, to
authorize certain of the users to access certain trials and within
these trials to access certain resources (e.g., systems or
subsystems) in the clinical trial system 100, and to interconnect
the constituent systems and computing devices 120, 176 and 110-118
during setup and runtime of the clinical trial via the
communication network 102.
[0056] The site setup module 105 is configured to enable the trial
planner 110 to setup example trial sites 114, 116, 118 (site IDs)
and associate these trial sites with the clinical trial and one or
more users set up via the user setup module 106.
[0057] The user setup module 106 is configured to enable the trial
planner 110 to setup users who are associated with the trial
planner 110, at least one shipper manager 113, trial sites 114,
116, 118, users of any other role in the clinical trial, as well as
their authorizations in the clinical trial system 100. Usernames,
passwords and authorizations of users in the clinical trial system
100 can be maintained by the trial administration system 104 in the
user database 108.
[0058] The inventory depot setup module 109 is configured to enable
the trial planner 110 to setup one or more depots 115 associated
with trial sites 114-118 and shipper managers 113 in the clinical
trial system 100. Each depot 115 can be associated with one or more
of the trial sites and one or more of the shipper managers 113. For
clarity and brevity, one depot 115 is associated with one shipper
manager 113 and trial sites 114-118.
[0059] The RTSM system 120 is configured to enable the trial
planner 110 to select and design randomization and treatment design
for the clinical trial, as well as simulate the selected
randomization design. The RTSM system 120 includes a trial
administration interface 121, user interface 122, EDC interface
123, design and simulation subsystem 124, and runtime subsystem
156.
[0060] The trial administration interface 121 is configured to
interconnect the trial administration system 104 with the RTSM
system 120 and receives the trial ID and site IDs for the clinical
trial from the trial administration system 104. Further, the user
interface 122 is configured to enable the trial planner 110 to
access the design and simulation subsystem 124 in order to
select/configure a randomization design and treatment design
associated with the clinical trial and to simulate the
randomization design. The design can be simulated and configured to
reduce the number of subjects necessary for the clinical trial.
After the selection/configuration of the randomization design and
treatment design, the user interface 122 is configured to store the
received trial ID and indications of the selected/configured
randomization design and treatment design in a runtime database 158
of the runtime subsystem 156.
[0061] The design and simulation subsystem 124 is configured to
enable the trial planner 110 via the user interface 122 to select
and configure a randomization design and treatment design for the
clinical trial (trial ID) and to simulate the randomization design.
The design and simulation subsystem 124 includes a randomization
designer 126, randomization simulator 138, treatment designer 148,
and randomization and article database 154.
[0062] The randomization designer 126 is configured to allow the
trial planner 110 to configure and save a randomization design
(including a plurality of randomization metrics) for the clinical
trial (trial ID). FIG. 11 illustrates an example webpage generated
by the randomization designer 126 to allow the configuration of a
randomization design for the clinical trial. The randomization
designer 126 includes an arm and arm-subject ratio module 128,
randomization factor module 130, factor weight module 132,
randomization-second-best-probability module 134 and strata module
136.
[0063] The arm and arm-subject ratio module 128 is configured to
allow designation of arms in the clinical trial and ratio of
subjects among the arms of the clinical trial. For example, if
there are two arms with a ratio of 1:2, respectively, the RTSM
system 120 will attempt to assign subjects to these arms such that
1/3 of the subjects are assigned to the first arm and 2/3 of the
subjects are assigned to the second arm.
[0064] The randomization factor module 130 is configured to allow
designation of randomizing/balancing factors for the clinical
trial. For example, randomizing factors such as age, sex, metabolic
rate, and/or other factors associated with the assignment of the
subjects to the arms in clinical trial can be designated.
[0065] The factor weight module 132 is configured to allow
designation of randomization weights for the randomizing factors
designated by the randomization factor module 130.
[0066] The randomization-second-best-probability module 134 is
configured to indicate a probability percentage associated with an
assignment of a subject to a second-best arm, mitigating a
deterministic assignment as will be described below in greater
detail with reference to FIG. 7.
[0067] The strata module 136 is configured to allow designation of
two or more states for each randomization factor. For example, for
a randomizing factor of "sex", two states would be defined, i.e.,
"male" and "female". As another example, for a randomizing factor
of "age", multiple states could be designated, such as, 25-35,
35-45, 45-55, 55-65 and greater than 65.
[0068] Once the randomization design has been configured using
modules 128-136, the trial planner 110 can save a randomization
design for the clinical trial (trial ID) via the randomization
designer 126, such as via a "save" indication, to the randomization
and article database 154.
[0069] The randomization simulator 138 is configured to allow the
trial planner 110 simulate the saved randomization design for the
clinical trial. One or more simulations can be generated, saved and
executed. The simulations and their results can be saved in the
randomization and article database 152. FIG. 12 illustrates an
example webpage generated by the randomization simulator 138 to
setup and simulate the randomization design for the clinical trial.
The simulation can be used to validate that the randomization
design meets the requirements of the clinical trial, including
minimizing the number of subjects that are required to be enrolled
in the clinical trial. The randomization simulator 138 includes a
simulation setup module 140, execution module 142, result module
144, and analysis module 146.
[0070] The simulation setup module 140 is configured to receive
simulation metrics from the trial planner 110 for the randomization
simulations, such as, a number of simulation runs, number of
subjects, number of sites and strata distribution ratios
(collectively indicating a probability that a simulated subject
will be generated as belonging to a stratum).
[0071] The execution module 142 is configured to execute the
simulations according to the received simulation metrics. The
execution module 142 generates simulation runs as indicated by the
received number of simulation runs, and within each generated
simulation run generates simulated subjects as indicated by the
received number of subjects. Each simulated subject is generated as
belonging to a trial site and strata in a probabilistic process
controlled by the remaining received simulation metrics,
respectively. For example, if there are two strata with
distribution ratios 1:2, respectively, the process will accord a
1/3 probability of generating a simulated subject belonging to the
first stratum, and 2/3 probability of generating the simulated
subject as belonging to the second stratum.
[0072] Once the simulated subject is generated, the execution
module 142 communicates with a randomizer 162 of FIG. 1, using
algorithmic interface 160, to randomize the simulated subject to an
arm in accordance with the randomization metrics of the
randomization design that was configured via the randomization
designer 126 described hereinabove.
[0073] The result module 144 is configured to display the results
of the executed simulations. The displayed results can include for
each simulation executed, its simulation metrics, start time and
end time, total execution time. An example simulation results
webpage is shown in FIG. 13. The displayed simulation results can
show for each of the runs of the simulation the distribution of the
subjects across the trial arms within each of the following subject
groups: (i) all the subjects in the particular run; (ii) for each
site, the subjects that belong to that site; (iii) for each state
of each factor, the subjects that belong to that state of that
factor; (iv) for each stratum, the subjects that belong to that
stratum.
[0074] The analysis module 146 is configured to aggregate and
analyze the results produced by the execution module 142 for each
run, and present statistically significant quantities, such as a
mean, standard deviation, minimum number of subjects, and a number
of times that a particular group of simulated subjects was out of
balance.
[0075] The design selector 147 is configured to allow the trial
planner (designer) 110 to import the design of an existing study
into a new study or to link the new study to an existing study's
design. The design selector 147 includes a copy design module 151
and share design module 153. The copy design module 151 provides
the ability to import the design of an existing study into a new
study. Changes to the design of the new study do not affect the
existing study, and visa versa. The share design module 153
provides the ability to link the new study to an existing study's
design so that any changes in the existing study design will affect
the design of the new study, and visa versa.
[0076] The treatment designer 148 is configured to allow the trial
planner 110 to configure and save a treatment design for the
clinical trial (trial ID). FIGS. 15 and 16 illustrate example web
pages generated by the treatment designer 148 to configure the
treatment design for the clinical trial. The treatment designer 148
includes an article module 150 and arm treatment module 152.
[0077] The design reporting module 149 is configured to deliver to
trial planners 110 or study managers 111 a detailed report
concerning the current study design. The report enumerates and
explains study arms and ratios, randomization factors and strata,
randomization weights, randomization probabilities and article
types and treatments. Other factors, features or aspects associated
with the study design as described herein can be included in the
report.
[0078] The article module 150 is configured to receive from the
trial planner 110 a definition or indication of one or more article
types and associated dispensation metrics for those article types.
For example, "article type 1" can be defined as "Aspirin.times.325
mg.times.1 pill". As another example, "article type 2" can be
"Aspirin.times.81 mg.times.1 pill". The dispensation metrics for
trial sites associated with defined articles can include also
indications of the minimal number of days between dispensation and
expiration of the article. Additional dispensation metrics
associated with the article types can be provided.
[0079] The arm treatment module 152 is configured to receive from
the trial planner 110 a treatment associated with of each arm of
the clinical trial. The treatment is composed by the indication of
an "article type" and a "number of units" for the article type. For
example, arm 1 can receive a treatment composed of 1 unit of
"article type 1", arm 2 can receive 1 unit of "article type 2",
while arm 3 can receive 1 unit of "article type 1" and 2 units of
"article type 2".
[0080] While the foregoing examples are intended to illustrate the
article module 150 and the arm treatment module 152, it should be
understood that the trial planner 110 can configure various
articles (different medications and dosages), as well as treatments
composed of different units of these articles, via the treatment
designer 148.
[0081] The randomization and article database 154 maintains the
randomization design configured via the randomization designer 126,
the results of the simulations generated by the randomization
simulator 138, as well as the treatment design configured via the
treatment designer 148.
[0082] The runtime subsystem 156 is configured to provide trial
management, as well as randomization and article dispensing for
subjects of the clinical trial. The runtime subsystem includes a
runtime database 156, an algorithm interface 160, and a trial
manager 166. The runtime database 156 maintains data for the
clinical trial, including its trial ID, site IDs, randomization
design, treatment design, as well as live data including subject
records, inventory item and batch records, and shipment records for
the clinical trial.
[0083] The EDC interface 123 is configured to interface with one or
more different trial EDCs to receive requests to assign (randomize)
subjects to the arms of the clinical trial and to indicate a set of
units of articles types to dispense to the subjects. The EDC
interface 123 interfaces with an algorithm interface 160 that
includes a randomizer 162 and an article dispenser 164, which
assign the subjects to the arms of the clinical trial and identify
the units if article types, respectively. The algorithm interface
160 also includes a shipping (shipper) algorithm 165. The EDC
interface 123 returns the subject assignments and unit
identifications to the requesting trial EDCs.
[0084] The randomizer 162 is configured to receive randomization
data (e.g., trial ID, site ID, subject ID, and state of the subject
ID in each of the factors defined in the randomization design) from
a randomization custom function (CF) 186 of the trial EDC 176, as
will be described greater detail below with reference to the trial
EDC 176. As described hereinabove, the randomizer 162 is also
configured to receive simulated randomization data (e.g., simulated
trial ID, site ID, subject ID, and state of the subject ID in each
of the factors defined in the randomization design) from the
randomization simulator 138.
[0085] The randomizer 162 is further configured to retrieve the
randomization design for the trial ID. In one embodiment, the
randomizer 162 retrieves an indication of the randomization design
associated with the trial ID from the runtime database 158 and
further retrieves the randomization design from the randomization
and article database 154 based on the indication. In another
embodiment, the randomizer 162 is configured to retrieve the
randomization design for the simulated trial ID from the
randomization and article database 154.
[0086] The randomizer 162 is also configured to assign (randomize)
the subject (subject ID) to an arm (arm ID) of the clinical trial
(trial ID) based on the randomization design, as well as to store
the trial ID, site ID, subject ID, states of the factors, and arm
ID assignment to the runtime database 158. Subject assignment to
the arm of the clinical trial is described in greater detail below
with reference to FIG. 7. The randomizer 162 is further configured
to transmit a randomization indicator to the randomization CF 186
of the trial EDC 176, which indicates that the subject has been
assigned (randomized) in the clinical trial. For simulations, the
randomizer 162 is similarly configured to store simulated data and
assignments to the randomization and article database 154 and to
return a randomization indicator to the randomization simulator
138.
[0087] The article dispenser 164 is configured to receive article
dispense data (e.g., trial ID, site ID, subject ID, and visit ID)
from a dispense CF 188 of the trial EDC 176, as will be described
greater detail below with reference to the trial EDC 176. The
article dispenser 164 is further configured to retrieve an arm ID
for the subject ID from the runtime database 158, which indicates
to which arm the subject ID is assigned. The article dispenser 164
is further configured to determine a treatment (e.g., set of one or
more units of articles) for the arm ID from the treatment design
associated with the clinical trial ID in the randomization and
article database 154. Further, the article dispenser 164 is
configured to determine whether there are sufficient units of
articles in the inventory associated with the trial ID that comply
with dispensation metrics for the site ID. If so, the article
dispenser 164 transmits a set of units of the articles to the
dispense CF 188 of the trial EDC 176 for dispensing to the subject
ID. The article dispenser 164 is also configured to adjust the
inventory for the trial ID based on the dispensed set of units to
the subject ID.
[0088] The logistics interface 125 interfaces the study managers
111 and supply managers 112 with algorithm interface 160. More
specifically, the logistics interface 125 allows study managers 111
and supply managers 112 to set "supply plans" for trial sites
114-118.
[0089] A supply plan determines the triggers and supply levels that
the shipper algorithm 165 will aim to maintain for the trial sites
(e.g., trial sites 114-118) that are assigned that supply plan.
Different supply plans can be defined for different trial sites. A
supply plan defines how trial sites associated with that supply
plan will be supplied. Each supply plan defines: (i) a unique name;
(ii) four parameters for each article type, (a) minimal number of
days between shipping and expiration, (b) initial site stocking
level, (c) resupply threshold level, and (d) resupply stocking
level; and (iii) a parameter that sets the supply plan as the
default for the study.
[0090] As will be described in greater detail with reference to
FIG. 22, the logistics interface 125 provides several user
interface screens to manage supply plans: (i) the supply plan list
interface; and (2) the supply plan manage interface. The supply
plan manage interface illustrates the details of a specific supply
plan and is used for adding, changing and deleting supply plans.
The supply plan list interface shows the list of supply plans.
[0091] The shipping algorithm 165 is executed periodically or upon
request. In some embodiments, the shipment module 172 via algorithm
interface 160 can periodically (e.g., every night) execute the
shipping algorithm 165. Alternatively or in addition, shipper
managers 113, study managers 111 and supply managers 112 can also
manually execute the shipping algorithm 165 from the shipments user
interface (e.g., FIG. 19), such as via the logistics interface
125.
[0092] When the shipping algorithm 165 is executed, for every trial
site and every article type, it compares the number of items of
that article type that are either available at trial site (let a1
be the number of such items), or are currently being shipped to
that site (let a2 be the number of such items) or allocated to be
shipped to that trial site (let a3 be the number of such items),
with the threshold number for that article type (let t be the
number of such items) as defined in the trial site's supply
plan.
[0093] Accordingly, if a1+a2+a3.ltoreq.t, the shipping algorithm
165 will allocate new items of that article type that are available
for shipping at the trial site's associated depot 115 to a new
shipment. Where r is the resupply target set for that article type
in the trial site's supply plan, the shipping algorithm 165 will
allocate r-(a1+a2+a3) items for shipment. It should be noted that
the shipping algorithm 165 will only allocate to a trial site items
that have an expiry date later than the "minimal number of days
between shipping and expiry" value set in that trial site's supply
plan. The shipping algorithm 165 will also prefer to ship items
with sooner expiry days rather than later ones, as long as the
items satisfy the restrictions above.
[0094] The shipping algorithm 165 will traverse through all the
article types, and once done, all the items allocated for shipment
for the specific trial site will be collected into a new shipment
record. The shipping algorithm 165 can then issue (and transmit) an
email to the supply managers 112, as well as any shipper manager
113 associated with a depot 115 (associated with the trial site),
alerting them to the existence of a new pending shipment (shipment
record).
[0095] By following a link provided in such email, a shipper
manager 113 associated with the depot 115 can access the shipment
record, review the list of items requested for shipping, ship those
items, and then confirm the shipment. The shipper manager 113 can
also dissolve the shipment, resetting the status of the items in
the shipment to "available for shipment" once again. It should be
noted that dissolving a shipment assigns the inventory items in
that shipment to an "available for shipment" status at the depot
115 with which their batch is currently associated. For example, if
a request for shipment s is created for depot d1, inventory item i
is included in this shipment and item i belongs to batch b (this
can only happen if b is assigned to depot d1 as well). In this
example, assume that after the shipment request s is created, batch
b is reassigned to depot d2 Thus, if shipment s is dissolved, item
i is marked as "available for shipping" at depot d2.
[0096] Moreover, the shipping algorithm 165 is also configured to
issue email notifications for shipments that have been requested as
well as when depots 115 run out of stock.
[0097] The trial manager 166, which can be accessed via user
interface 122, is configured to provide management functionality
for the different users of the clinical trial system 100, such as
of the trial planner 110, study manager 111, supply manager 112 and
shipper manager 113, and personnel from trial sites 114-118. The
trial manager 166 includes a site module 168, subject module 170,
shipment module 172, and inventory module 174.
[0098] While the trial planner 110 generally configures the trial
sites via site setup 105 of the trial administration system 104,
and configures depots 115 via inventory depot setup 109, the site
module 168 is configured to enable the study manager 111 to manage
RTSM parameters associated with each of the trial sites in the
clinical trial. FIG. 17 illustrates an example webpage generated by
the site module 168 for the clinical trial, including one or more
trial sites (e.g., trial sites 1114, 116, 118). For each trial
site, site module 168 is configured to allow setup of a supply plan
and assignment of a depot (e.g., depot 115) for the trial site, as
well as to present a number (site ID), number of subjects
randomized to the trial site, number of shipments to the trial site
and number of inventory items at the trial site. The site module
168 is further configured to enable the study manager 111 to
activate/deactivate drug shipping from the depot (e.g., depot 115)
to each of the trial sites (e.g., trial sites 114-118).
[0099] In addition, supply plans play an important role in the site
module 168. The site module 168 is configured to assign and provide
for each site the supply plan it is associated with and can assign
trial sites to a supply plan "en mass".
[0100] The subject module 170 is configured to enable the study
manager 111 and trial sites 114-118 to manage the subjects in the
clinical trial. FIG. 18 illustrates an example webpage generated by
the subject module 170 for the clinical trial, including one or
more subjects (subject IDs). In one embodiment, for each subject
ID, the subject module 170 is configured to provide stratum, trial
site (site ID), trial arm (arm ID), arm selection method and when
the subject was assigned (randomized) to the trial arm. The actual
data of the clinical trial that is displayed by the subject module
170 to various users depends on their authorizations (or
permissions) provided by the user setup module 106 of the trial
administration system 104.
[0101] Importantly, these permissions determine the scope of the
user access to the subject population in the clinical trial. For
example, the study manager 111 could view a list of subjects
enrolled in multiple trial sites, whereas trial site 114 could only
view subjects belonging to that trial site. Furthermore, different
users can have different display for the same subjects. For
example, the study manager 111 may have access to view arm
assignments of subjects, while other users, such as trial sites
114-118, may not have such access to arm assignments.
[0102] The design update module 171 is configured to enable the
trial planner (designer) 110 to modify or update the study design
at runtime, i.e., after the study has already gone live. The design
update module allows modification the ratios of study arms via the
arm ratios module 128, weights of the randomization factors via the
factor weight module 132, probability percentage via the
randomization probability module 134, and minimal time between
dispensation and expiry via the article module 150.
[0103] The shipment module 172 is configured to enable the supply
manager 112, trial sites 114-118, as well as shipper manager 113 to
manage the article shipments in the clinical trial. FIG. 19
illustrates an example webpage generated by the shipment module 172
for the clinical trial, including one or more shipments. Each of
the one or more shipments can include a name of the shipment, trial
site (site ID), date shipment was shipped from depot by shipper
manger, date the shipment was received at the trial site, a
tracking number associated with the shipment, and units of articles
shipped in the shipment. The shipment module 172 includes "waste
and replace" functionality configured to allow the shipper manager
113 to mark items reserved for the shipment as wasted, and request
replacements for inclusion in the shipment. Permissions of the
users configured via the trial administration system 104 also
affect the data displayed by the shipment module. The permissions
determine the scope of user access to the shipments in the clinical
trial. For example, trial site 114 will be able to see shipments
destined for trial site 114, but will not be able to see shipments
destined for trial site 116. Similarly, the shipper manager 113 can
see just those shipments originating from a depot 115 with which
the shipper manager 113 is associated, and not shipments
originating from others depots (not shown).
[0104] The unblinding module 173 is configured to authorize subject
unblinding or item unblinding for subjects or items, respectively.
In most clinical trials subjects remain "blinded", e.g., without
disclosure to which study arm subject were randomized, and to which
article types inventory items belong. The unblinding module 173
allows authorized users to get access to this information. This
action can be audited by the audit module 169 as described
below.
[0105] The audit module 169 is configured to allows the study
manager 111 to audit or view any changes that were made to the
study design, to the supply plans, to the site's associated depots
or supply plans as well as any changes that happened to any
subject, inventory item, inventory batch or shipment record.
[0106] The inventory module 174 is configured to enable the trial
planner 110, study manager 111, shipper manager 113, and trial
sites 114-118 to manage the inventory associated with the clinical
trial. FIGS. 19 and 20 illustrate example web pages generated by
the inventory module 174 for the clinical trial. For example, FIG.
19 illustrates a general inventory item list, while FIG. 20
illustrates a list of batched items uploaded by the inventory
module 174 via user interface 122, from the trial manager 111 or
shipper manager 113, into the clinical trial inventory in the
runtime database 158. Again, permissions of users determine the
scope over the list of items available and information available
for each item to the users.
[0107] The EDC system 176 is configured to receive and maintain
data associated with a clinical trial from the trial sites 114,
116, 118 and the RTSM 120. The EDC system 176 can be any clinical
trial data capture system that can execute a custom function
described herein to communicate with the RTSM system 120. The EDC
176 includes trial database 178, trial setup subsystem 180 and
trial runtime subsystem 182. These subsystems of the EDC system 176
are not exhaustive, but are meant to illustrate the integration of
the RTSM system 120 and EDC system 176, which is described in this
application. Accordingly, one or more additional subsystems or
components can be included in a particular EDC system 176.
[0108] The trial database 178 maintains data associated with the
clinical trial, such as subjects, trial sites and dispensed units
of articles, as well as clinical information collected for the
subjects during the clinical trial. The trial setup subsystem 180
is configured to receive a trial ID and site ID associated with the
clinical trial from the trial administration system 104, when a
trial site (e.g., trial site 114) logs into the trial
administration system 104. The trial setup subsystem 180 is further
configured to store and maintain the received trial ID, site ID and
associated trial data in the trial database 178.
[0109] The trial runtime subsystem 182 is configured to receive
data of a subject from a trial site (e.g., trial site 114) and to
enroll the subject into the clinical trial. It is to be noted that
multiple subjects can be enrolled from each of the trial sites 114,
116, 118. The trial runtime subsystem 182 is further configured to
randomize the enrolled subjects in the clinical trial and to
dispense appropriate medication to the subjects via the RTSM system
120. The trial runtime subsystem 182 includes a subject data input
module 184, randomization CF 186, and dispense CF 188.
[0110] The subject data input module 184 is configured to receive
data associated with a subject to be enrolled into the clinical
trial, for example, from trial site 114. This data can include the
subject's enrollment consent form and personal data associated with
the subject (e.g., name and contact information). The received data
also includes states of the subject in each of the one or more
factors required for randomization of the subject in the clinical
trial, as described hereinabove with reference to the randomizer
162 of the RTSM 120. It should be noted that the states of the
factors can also be received by the subject data input module 184
via integration of the EDC system 176 with other clinical
information systems that collect subject information at the start
or during the clinical trial. The subject data input module 184 is
further configured to assign the enrolled subject a subject ID and
to add a new subject record for the subject ID to the trial
database, which includes the trial ID, site ID, states of the
factors and any other information received for the subject from the
trial site (e.g., trial site 114).
[0111] The randomization CF 186 is configured to randomize a
subject ID. Specifically, the randomization CF 186 determines
whether randomization of the enrolled subject (subject ID) has been
triggered via input received by the subject data input module 184.
The randomization trigger can be automatically determined based on
whether all required input for randomization has been received for
the subject ID (e.g., from trial site 114) or can be user-initiated
from the trial site (e.g., trial site 114). Once triggered, the
randomization CF 186 is configured to convert the trial ID, site
ID, subject ID and the states of the subject in the factors to RTSM
randomization data. The randomization CF 186 is further configured
to transmit the RTSM randomization data to the EDC interface 123 of
RTSM system 120 and to receive a randomization indicator that
indicates successful assignment (randomization) of the subject ID
to an arm of the clinical trial. The randomization CF 186 stores
the randomization indicator to the record of the subject ID in the
trial database 178.
[0112] The dispense CF 188 is configured to determine the number of
units of articles to dispense to the subject ID at a visit to the
trial site (e.g., trial site 114). The visit can be at the same
time the subject ID is enrolled and randomized in the clinical
trial and/or a later visit, being indicated by a visit ID. The
visit ID can be any alphanumeric string that uniquely identifies
the dispensing (e.g., a date indicator). The dispense CF 188
determines whether dispensing to the subject ID has been triggered
by the trial site (e.g., trial site 114), such as via
user-initiated input. Once triggered, the dispense CF 188 adds a
dispense record for the subject's record associated with the
subject ID, which includes a dispense indication. The dispense CF
188 is configured to convert the trial ID, site ID, subject ID
visit ID to RTSM dispense data. The dispense CF 188 is further
configured to transmit the RTSM dispense data to the EDC interface
123 of RTSM system 120 and to receive a set of one or more units
indicators to be dispensed to the subject ID. The dispense CF 188
stores the dispense unit indicators to the visit record of the
subject ID in the trial database 178.
[0113] FIG. 2 illustrates a flowchart of an example method 200 for
configuring a randomization design for a clinical trial. The method
200 starts at operation 202 where the trial planner 110 invokes or
executes the randomization designer 126 to configure the
randomization design, as illustrated in FIG. 1. At operation 204, a
number of trial arms are received for a clinical trial. Zero or
more randomizing factors, such as age, sex and/or one or more other
factors are received at operation 206. At operation 208, weights
associated with clinical trial, trial site and strata, as well as
with the randomization factors of operation 206 are received. At
operation 210, a second best probability percentage associated with
the randomization of subjects is received. Two or more strata
states are received at operation 212 for each of the randomization
factors received at operation 206. At operation 214, the
randomization design with the received design metrics is saved, for
example, in the randomization and article database 154.
[0114] FIG. 3 illustrates a flowchart of an example method 300 for
performing a randomization simulation of a randomization design
generated in accordance with FIG. 2. The method 300 starts at
operation 302 where the trial planner 110 invokes or executes the
randomization simulator 138 to perform the randomization
simulation, as illustrated in FIG. 1. At operation 304, simulation
metrics for the randomization simulation are received. The
simulation metrics can include number of execution runs, subjects
and trial sites, as well as strata distribution. At operation 306,
the randomization simulation is executed according to the received
simulation metrics based on the randomization design generated in
FIG. 2. At operation 308, the simulation results of the simulation
are saved, such as in the randomization and article database 152
illustrated in FIG. 1.
[0115] At operation 310, a determination is made as to whether the
randomization simulation yielded satisfactory results for the
randomization design. The reasons for determining that the whether
the simulation results are satisfactory can include, but are not
limited to, high frequency of imbalance among runs at one or more
group of subjects (e.g., group of subjects in the entire clinical
trial, groups of subjects at trial sites, groups for states of
subject factors, and groups for subject strata), too few or too
many subjects assigned to at least one arm within one or more of
the groups, or too high variability among the runs.
[0116] If it is determined that the simulation results were
satisfactory at operation 310, the method ends at operation 318.
However, if it is determined that the simulation results were not
satisfactory at operation 310, the method 300 continues at
operation 312, where a determination is made as to whether the
randomization design should be updated. If it is determined that
the randomization design should not be updated at operation 312,
the method continues at operation 304 to receive updated simulation
metrics for the randomization simulation, and the simulation is
executed according to the updated simulation metrics and the
previously saved randomization design at operation 306.
[0117] If it is determined that the randomization design should be
updated at operation 312, the method continues at operation 314 to
invoke method 200 of FIG. 2 for updating the randomization design
(design metrics of the randomization design). At operation 316, a
determination is made whether simulation metrics for the
randomization simulation should be updated.
[0118] If it is determined that simulation metrics should be
updated at operation 316, the method 300 continues at operation 304
to receive simulation metrics for the randomization simulation. At
operation 306, the simulation is executed according to the updated
simulation metrics and the updated randomization design.
[0119] However, if it is determined that simulation metrics should
not be updated at operation 316, the method continues at operation
306 to execute the randomization simulation according to the
previously received simulation metrics and the updated
randomization design.
[0120] FIG. 4 illustrates a flowchart of an example method 400 for
configuring a treatment design for a clinical trial. The method 400
starts at operation 402 where the trial planner 110 invokes or
executes the treatment designer 148 to configure the treatment
design, as illustrated in FIG. 1.
[0121] At operation 404, definitions of one or more article types
and associated dispensation metrics are received for the clinical
trial. For example, "article type 1" can be defined as
"Aspirin.times.325 mg.times.1 pill" and "article type 2" can be
"Aspirin.times.81 mg.times.1 pill". The article type indicates the
medication, dosage, and pill count number. A treatment associated
with each arm of the clinical trial is received at operation 406.
The treatment is composed by the indication of an "article type"
and a "number of units" for the article type. For example, arm 1
can receive a treatment composed of 1 unit of "article type 1", arm
2 can receive 1 unit of "article type 2", while arm 3 can receive 1
unit of "article type 1" and 2 units of "article type 2".
[0122] At operation 408, the treatment design is saved, such as in
the randomization and article database 152 illustrated in FIG. 1.
Thereafter, the method 400 ends at operation 410.
[0123] FIG. 5 illustrates a flowchart of an example method 500 for
setting up a clinical trial via the trial administration interface
122 of the RTSM system 100 of FIG. 1. The method 500 starts at
operation 502 where the trial planner 110 logs into the trial
administration system 104. At operation 504, trial and site
information associated with clinical trial are received from the
trial administration system 104. The received information can
include a trial ID that identifies the clinical trial and site IDs
associated with the trial ID that identify the trial sites of the
clinical trial.
[0124] At operation 506, a randomization design and treatment
design are selected for the clinical trial (trial ID) from one or
more saved randomization designs and treatment designs. The trial
ID and associated selection of the randomization and treatment
design are stored, such as in the runtime database 158 of the
runtime subsystem 158, as operation 508. At operation 510, an
inventory associated with a depot 115 is generated for the trial ID
according to the selected treatment design, such as in the runtime
database 158. An inventory batch that indicates units of articles
(article IDs) that are available to ship by the depot 115 are
received into the inventory of the depot at operation 512.
[0125] At operation 514, a number of units (unit IDs) of articles
(article IDs) for shipment to the site IDs are identified from the
inventory of the depot 115 based on supply plans associated with
the site IDs. A message is generated and transmitted to the shipper
manager 113 of the depot 115 to ship one or more shipments of
identified unit IDs of Article IDs to the site IDs at operation
516. At operation 518, the inventory for the depot 115 is adjusted
to reflect articles available to ship from the depot 115 based on
the identified unit IDs of Article IDs.
[0126] At operation 520, a determination is made as to whether the
shipments have been shipped to the trial sites. Initially, shipment
status of a shipment is "requested". When a shipment is shipped by
the shipper manager 113 from the depot 115, the inventory is
updated to reflect shipment status and unit status to "in transit".
The shipper manager 113 can also "dissolve" the shipment such that
the shipment is marked as "dissolved" and items collected for
shipment are marked as "available at depot". At operation 524, a
further determination is made as to whether the shipment has been
received. If it is determined that the shipment was received, then
the shipment status is updated to "received" and unit status is
updated to "available at site". If it is determined that the
shipment was not received, then the shipment status is updated to
"lost" and unit status is updated to "wasted". Thereafter, the
method 500 ends at operation 532.
[0127] If it is determined that the shipment was not shipped at
operation 520, then at operation 530, the shipment status is
updated to "pending shipment confirm". Thereafter, the method 500
ends at operation 532.
[0128] FIG. 6 illustrates a flowchart of an example method 600 for
randomizing a subject via randomizer 162 illustrated in FIG. 1. The
method 600 starts at operation 602 where the EDC 176 has enrolled a
subject (subject ID) provided by a trial site (site ID), for
example trial site 114, into a clinical trial (trial ID). At
operation 604, randomization data is received for a subject from
the randomization CF 186 of the EDC 176. The randomization data
includes trial ID, site ID, subject ID, and state of the subject
for factors identified in the randomization design. At operation
606, the randomization design associated with the trial ID is
retrieved, such as from the randomization and article database
154.
[0129] At operation 608, the subject (subject ID) is assigned to an
arm (arm ID) of the clinical trial (trial ID) based on the
randomization design. An example method of assigning (randomizing)
the subject to the arm of the clinical trial is described in detail
below with reference to FIG. 7. More specifically, the
randomization design is executed to assign the subject ID to the
arm ID of the trial ID. The trial ID, site ID, subject ID, arm ID,
and states of factors are stored, such as in the runtime database
158, at operation 610. Thereafter, at operation 612, a
randomization indicator that indicates assignment of the subject
(subject ID) is transmitted to the randomization CF 186 of the EDC
176. The method 600 ends at operation 614.
[0130] FIG. 7 illustrates a flowchart of an example method 700 for
assigning a subject to an arm of a clinical trial. The example
method 700 can be performed by the randomizer 162 illustrated in
FIG. 1. The method 700 starts at operation 702 in which trial ID,
site ID and subject ID are provided from operation 608 of FIG.
6.
[0131] At operation 704, an overall trial imbalance in subject
population is determined when the subject ID is treated
hypothetically as if assigned to a selected arm (Arm ID) of the
trial ID. A site imbalance is determined for the site (site ID) in
the subject population when the subject ID is assigned to the
selected arm ID of the trial ID at operation 706. At operation 708,
a state imbalance is determined for each factor in the subject
population of the trial ID that shares that state with the subject
ID. At operation 710, strata imbalance is determined in subject
population that share the strata with subject ID.
[0132] Thereafter, at operation 712, a weighted sum of the
imbalances for the selected arm (arm ID) is generated based on the
randomization design. The weighted sum is saved temporarily for the
selected arm ID. At operation 714, a determination is made as to
whether there are additional arms to process. If it is determined
that there are additional arms, then the method 700 performs
operations 707-714 for the remaining arm IDs, saving temporarily
the weighted sum of the imbalances for every processed arm ID.
[0133] If it is determined that there are no additional arms to
process at operation 714, then the method 700 continues at
operation 716, where a determination is made as to whether there is
a set of two or more arm IDs having the lowest weighted sum. If it
is determined there are multiple arms with the lowest weighted sum
at operation 716, then the subject ID is assigned randomly to an
arm ID among the set of arm ID at operation 718. Thereafter, the
method 700 ends at operation 728.
[0134] However, if it is determined there is one arm with the
lowest weighted sum at operation 716 then the method continues at
operation 720, where a determination is made as to whether a second
best probability percentage has been defined or set in the
randomization design for the clinical trial. If the second best
probability percentage has not been set at operation 720, then the
subject ID is assigned to the arm ID with the lowest weighted
imbalance determined at operation 716.
[0135] Alternatively, if the second best probability percentage has
been set at operation 720, the method 700 continues at operation
724, where a set of one or more arms (arm IDs) having a next lowest
weighted imbalance is selected. At operation 726, the subject ID is
assigned to an arm randomly from the one arm with the lowest
weighted imbalance and the set of arms with the next lowest
weighted imbalance based the second best probability percentage.
For example, if the second best probability percentage is set to
10%, the one arm with the lowest weighted imbalance will be
selected randomly 90% of the time, while an arm in the set with
next lowest weighted imbalance will be selected randomly 10% of the
time.
[0136] FIG. 8 illustrates a flowchart of an example method 800 for
dispensing via article dispenser 164 illustrated in FIG. 1. The
method 800 starts at operation 802 where the EDC 176 has enrolled a
subject (subject ID) provided by a trial site (site ID) into a
clinical trial (trial ID) and has randomized the subject ID into an
arm (arm ID) of the trial ID via randomizer 162 of FIG. 1. At
operation 804, dispense data is received for a subject from the
dispense CF 188 of the EDC 176. The dispense data includes trial
ID, site ID, subject ID, and visit ID associated with the clinical
trial.
[0137] At operation 806, an arm (arm ID) is retrieved for the
subject (subject ID) from the runtime database 158 indicating to
which arm the subject is assigned. At operation 808, a treatment
(set of one or more units of one or more articles) is determined
for the arm ID from the treatment design for the clinical trial
(Trial ID). At operation 810, a determination is made as to whether
there are sufficient units of articles at the site ID for a
treatment that complies with dispensation metrics for the site ID
from the inventory in runtime database 158.
[0138] If it is determined that there are sufficient units, the set
of units to be dispensed to the subject ID is transmitted to the
dispense CF 188 of the EDC 176. The trial site can dispense the
identified units of articles to the subject indicated by the
subject ID. At operation 814, inventory for the site ID is adjusted
based on units dispensed to the subject ID. The method 800 ends at
operation 820.
[0139] However, if it is determined that there are insufficient
units, a message of "insufficient inventory" is transmitted to the
dispense CF 188 of the EDC 176 at operation 818. The trial site can
then notify the trial planner 110 or the shipper manger 113 of a
depot concerning the inventory at the trial site. Other mitigation
procedures may be invoked if there is a determination of inventory
insufficiency at a trial site. The method 800 ends at operation
820.
[0140] FIG. 9 illustrates a flowchart of an example method 900 for
randomizing a subject via the trial EDC 176 illustrated in FIG. 1.
The method 900 starts at operation 602 where a trial site (e.g.,
trial site 114) has logged on via the trial administration system
104. At operation 904, a trial ID and a site ID are received from
the trial administration system 104 for the logged on trial site.
At operation 906, the subject's states for factors required to
randomize the subject in the clinical trial (per randomization
design) are received from the trial site (e.g., trial site 114).
Other information concerning the subject can also be received
(e.g., name, contact information, as well as other information for
the clinical trial).
[0141] At operation 908, the subject is assigned a subject ID. A
new record for the subject ID is added to the trial database 178.
The record can include trial ID, site ID, states of the factors, as
well as any other information associated with the subject (subject
ID).
[0142] At operation 912, it is determined whether randomization of
the subject ID has been triggered, such as programmatically when
certain input requirements for randomization are fulfilled or when
randomization is user-initiated. If not trigged, the method 900
waits until a trigger is received. Once randomization is triggered
at operation 914, the trial ID, site ID, subject ID and states of
the factors are converted via randomization CF 186 to RTSM
randomization data.
[0143] At operation 916, the RTSM randomization data is transmitted
to the randomizer 162 of the RTSM system 120. A randomization
indicator that indicates successful randomization is received from
the randomizer 162 at operation 918. The randomization indicator is
stored to the record for the subject ID at operation 920. The
method 900 ends at operation 922.
[0144] FIG. 10 illustrates a flowchart of an example method 1000
for dispensing medication to a subject via the trial EDC 176
illustrated in FIG. 1. The method 1000 starts at operation 1002
where a trial site (e.g., trial site 114) has logged on via the
trial administration system 104. At operation 1004, a trial ID,
site ID, subject ID and visit ID associated with a clinical are
received for a subject of the logged on trial site.
[0145] At operation 1006, a dispense trigger is received from the
trial site, such as programmatically upon randomization of the
subject via randomization CF 186 for the first visit or via
user-initiated input for subsequent visits. If not trigged, the
method 1000 waits until a dispense trigger is received.
[0146] At operation 1008, a visit record (visit ID) and dispense
indication are added to the trial database 178 for the subject ID.
At operation 1010, the trial ID, site ID, subject ID and visit ID
are converted via a dispense CF 188 to RTSM dispense data. The RTSM
data is transmitted to the article dispenser 164 of RTSM system 120
at operation 1012.
[0147] At operation 1014, a set of one or more unit indicators to
be dispensed to the subject ID is received from the RTSM system
120. Thereafter, at operation 1016, the dispensed set of unit
indicators is stored to the visit record for the subject ID. The
method ends at operation 1018.
[0148] FIG. 11 illustrates an example webpage to configure a
randomization design for a clinical trial. The example webpage can
be generated by the randomization designer 126 of the RTSM system
120. As illustrated in the web page, the trial planner 110 can
configure the number of arms in the clinical trial and ratio of
subjects across the arms. The trial planner 110 can further
configure randomization factors and their weights for the clinical
trial. The trial planner 110 can also configured the second-best
probability for randomization and strata associated with the
randomization factors in the clinical trial.
[0149] FIG. 12 illustrates an example webpage to setup and simulate
the randomization design for a clinical trial. The example webpage
can be generated by the simulation module 140 of the randomization
simulator 138. The simulations can be executed by the execution
module 142. The simulation can be used to minimize the number of
subjects in the clinical trial. Multiple simulations can be setup
and simulated, as illustrated in FIG. 12.
[0150] FIG. 13 illustrates an example webpage to display simulation
results of one or more simulations executed in FIG. 12. The example
webpage can be generated by the results module 144 of the
randomization simulator 138. The displayed results can include for
each simulation executed, its simulation metrics, start time and
end time, total execution time.
[0151] FIG. 14A illustrates an example webpage to display aggregate
subject arm assignment within a particular run of a simulation. The
example webpage can be generated by the analysis module 146 of the
randomization simulator 138. For a particular run shown in FIG. 14,
in each of the subject groups the following information is
provided: i) a number of simulated subjects in that group that were
assigned to each arm; ii) an absolute value of the difference
between that number and the total number of subjects in that group,
multiplied by a ratio of subjects that should be in each arm given
the arm's weights; iii) whenever the absolute value in (ii) is
greater than 1, cells with imbalance are identified.
[0152] As shown, the subject groups are: 1) subject population of
the whole clinical trial; 2) subject population of each trial site;
3) subjects that share a state of a factor (for each factor); and
4) subjects that share a stratum (for each stratum).
[0153] FIG. 14B illustrates an example webpage to display aggregate
statistical results across runs of a randomization simulation. The
aggregate statistical analysis shows for each of the subject groups
and each of the arms the mean and standard deviation as well as the
minimum number of the subjects from that subject group assigned to
that arm. In addition, for each of the subject groups it shows the
number of runs that were out of balance.
[0154] FIG. 15 illustrates an example webpage to configure the
treatment design for a clinical trial. The example web page can be
generated by the treatment designer 148. The webpage enable
definition of article types and treatments for the clinical
trial.
[0155] FIG. 16 illustrates an example webpage to manage article
types illustrated in FIG. 15. For a given article type illustrated
in FIG. 15, dispensation metrics shown can be defined as
illustrated in FIG. 16. The example web page can also be generated
by the treatment designer 148.
[0156] FIG. 17A illustrates an example webpage generated for a
clinical trial to manage one or more trial sites. The example
webpage can be generated by the site module 168. For each trial
site, the webpage displays a study name, trial site number (site
ID), country, depot, supply plan, number of subjects randomized to
the trial site, number of shipments to the trial site, number of
inventory items at the trial site, as well as shipping status. FIG.
17 further illustrates that a supply plan and/or a depot can be
assigned to a trial site. Moreover, shipping can also be
activated/deactivated for the trial site.
[0157] FIG. 17B illustrates an example webpage to assign a supply
plan to one or more selected trial sites of the clinical trial. The
trial sites for which the supply plan is to be updated (or changed)
can be selected in FIG. 17A via check boxes illustrated next to the
names of the trial sites. As illustrated in FIG. 17B, the "medium
enrollers" supply plan is chosen and reflected for the selected
"Balance study site 3" illustrated in FIG. 17A. As further
illustrated in FIG. 17A, the "high enrollers" study plan was
associated with the trial sites "site 1" and "site 2".
[0158] FIG. 17C illustrates an example webpage to assign a depot to
one or more selected trial sites of the clinical trial. The trial
sites for which the depot is to be updated (or changed) can be
selected in FIG. 17A via check boxes illustrated next to the next
to the names of the trial sites. As illustrated in FIG. 17C, the
"EU Depot LTD. United Kingdom" depot is chosen and this depot is
associated with the selected "Balance study site 3" illustrated in
FIG. 17A.
[0159] FIG. 18 illustrates an example webpage generated for
management of subjects in a clinical trial. The example webpage can
be generated by the subject module 170. For each subject ID, the
webpage can include stratus, site, assigned study arm, and
randomization time. Other detail can be displayed for the subjects
in the example webpage illustrated in FIG. 18.
[0160] FIG. 19 illustrates an example webpage for management of one
or more article shipments in a clinical trial. The example webpage
can be generated by generated by the shipment module 172. Each
shipment can include a name of the shipment, status, time status
was changes, trial site, depot, tracking number associated with
shipment (is status is "shipped"), and units of articles (items of
inventory).
[0161] FIG. 20 illustrates an example webpage for managing one or
more items of inventory in a clinical trial. The example webpage
can be generated by generated by the inventory module 174. Each
item is identified by an item number and can include a status,
trial site, depot, subject, visit, shipment, inventory batch to
which the item belongs, article type associated with the item,
sequence and location.
[0162] FIG. 21 illustrates an example webpage for managing an
inventory batch list for a clinical trial. These inventory batches
are lists of inventory items (e.g., collected in comma separated
value (CSV) format) that a study manager 111 or shipper manager 113
can upload to the RTSM system 120. The inventory batch includes
batch name, article type, expiry date, additional batch identifier,
notes, depot, and number of items in the batch. When a list (or
file) is uploaded RTSM system 120, the inventor module 174
processes the list and enters the articles as well as associated
information into the runtime database 158.
[0163] FIG. 22 illustrates an example webpage for managing
logistics supply plan. The example webpage illustrates the details
of specific supply plans and be used to add, change and delete
supply plans. Two defined supply plans are shown: medium enrollers
and high enrollers. For each plan, there can be defined a supply
plan name, article type, minimal number of days between dispensing
and expiration, minimal number of days between shipping and
expiration, initial trial site stocking level, trial site
restocking threshold, trial site restocking level and number of
trial sites associated with the supply plan.
[0164] FIG. 23 is a block diagram of a general computer system
2300. The computer system 2300 can include a set of instructions
that can be executed to cause the computer system 2300 to perform
any one or more of the methods or computer based functions
disclosed herein with respect to FIGS. 1-22. The computer system
2300 or any portion thereof, may operate as a standalone device or
may be connected (e.g., using a network 2324) to other computer
systems or devices disclosed herein with respect to FIGS. 1-22. For
example, the computer system 2300 can include or be included within
any one or more of the computing devices or system in FIG. 1, or
any other devices or systems disclosed herein with respect to FIGS.
1-22.
[0165] In a networked deployment, the computer system 2300 may
operate in the capacity of a server or a client machine in a
server-client network environment, or a peer machine in a
peer-to-peer (or distributed) network environment. The computer
system 2300 can also be implemented as or incorporated into various
devices, such as a personal computer (PC), a tablet PC, a personal
digital assistant (PDA), a web appliance, a communications device,
a mobile device, a wireless telephone, a server, a client or any
other machine capable of executing a set of instructions
(sequential or otherwise) that specify actions to be taken by that
machine. Further, while a single computer system 2300 is
illustrated, the term "system" shall also be taken to include any
collection of systems or sub-systems that individually or jointly
execute a set, or multiple sets, of instructions to perform one or
more computer functions.
[0166] As illustrated in FIG. 23, the computer system 2300 can
include a processor 2302, e.g., a central processing unit (CPU), a
graphics-processing unit (GPU), or both. Moreover, the computer
system 2300 can include a main memory 2304 and a static memory 2306
that can communicate with each other via a bus 2326. As shown, the
computer system 2300 may further include a video display unit 2310,
such as a liquid crystal display (LCD), an organic light emitting
diode (OLED), a flat panel display, a solid state display, or a
cathode ray tube (CRT). Additionally, the computer system 2300 may
include an input device 2312, such as a keyboard, and a cursor
control device 2214, such as a mouse. The computer system 233300
can also include a disk drive unit 2316, a signal generation device
2322, such as a speaker or remote control, and a network interface
device 2308.
[0167] In a particular embodiment, as depicted in FIG. 23, the disk
drive unit 2316 may include a machine or computer-readable medium
2218 in which one or more sets of instructions 2320 (e.g.,
software) can be embedded. Further, the instructions 2320 may
embody one or more of the methods or logic as described herein with
reference to FIGS. 1-22. In a particular embodiment, the
instructions 2320 may reside completely, or at least partially,
within the main memory 2304, the static memory 2306, and/or within
the processor 2302 during execution by the computer system 2300.
The main memory 2304 and the processor 2302 also may include
computer-readable media.
[0168] In an alternative embodiment, dedicated hardware
implementations, such as application specific integrated circuits,
programmable logic arrays and other hardware devices, can be
constructed to implement one or more of the methods described
herein. Applications that may include the apparatus and systems of
various embodiments can broadly include a variety of electronic and
computer systems. One or more embodiments described herein may
implement functions using two or more specific interconnected
hardware modules or devices with related control and data signals
that can be communicated between and through the modules, or as
portions of an application-specific integrated circuit.
Accordingly, the present system encompasses software, firmware, and
hardware implementations.
[0169] In accordance with the various embodiments, the methods
described herein may be implemented by software programs that are
tangibly embodied in a processor-readable medium and that may be
executed by a processor. Further, in an example, non-limited
embodiment, implementations can include distributed processing,
component/object distributed processing, and parallel processing.
Alternatively, virtual computer system processing can be
constructed to implement one or more of the methods or
functionality as described herein.
[0170] While the computer-readable medium is shown to be a single
medium, the term "computer-readable medium" includes a single
medium or multiple media, such as a centralized or distributed
database, and/or associated caches and servers that store one or
more sets of instructions. The term "computer-readable medium"
shall also include any medium that is capable of storing, encoding
or carrying a set of instructions for execution by a processor or
that cause a computer system to perform any one or more of the
methods or operations disclosed herein.
[0171] In a particular non-limiting, example embodiment, the
computer-readable medium can include a solid-state memory such as a
memory card or other package that houses one or more non-volatile
read-only memories. Further, the computer-readable medium can be a
random access memory or other volatile re-writable memory.
Additionally, the computer-readable medium can include a
magneto-optical or optical medium, such as a disk or tapes or other
storage device to capture carrier wave signals such as a signal
communicated over a transmission medium. A digital file attachment
to an e-mail or other self-contained information archive or set of
archives may be considered a distribution medium that is equivalent
to a tangible storage medium. Accordingly, the disclosure is
considered to include any one or more of a computer-readable medium
or a distribution medium and other equivalents and successor media,
in which data or instructions may be stored.
[0172] In accordance with various embodiments, the methods
described herein may be implemented as one or more software
programs running on a computer processor. Dedicated hardware
implementations including, but not limited to, application specific
integrated circuits, programmable logic arrays and other hardware
devices can likewise be constructed to implement the methods
described herein. Furthermore, alternative software implementations
including, but not limited to, distributed processing or
component/object distributed processing, parallel processing, or
virtual machine processing can also be constructed to implement the
methods described herein.
[0173] It should also be noted that software which implements the
disclosed methods may optionally be stored on a tangible storage
medium, such as: a magnetic medium, such as a disk or tape; a
magneto-optical or optical medium, such as a disk; or a solid state
medium, such as a memory card or other package that houses one or
more read-only (non-volatile) memories, random access memories, or
other re-writable (volatile) memories. A digital file attachment to
e-mail or other self-contained information archive or set of
archives is considered a distribution medium equivalent to a
tangible storage medium. Accordingly, the disclosure is considered
to include a tangible storage medium or distribution medium as
listed herein, and other equivalents and successor media, in which
the software implementations herein may be stored.
[0174] Although the present specification describes components and
functions that may be implemented in particular embodiments with
reference to particular standards and protocols, the invention is
not limited to such standards and protocols. For example, standards
for Internet and other packet switched network transmission (e.g.,
TCP/IP, UDP/IP, HTML, HTTP) represent examples of the state of the
art. Such standards are periodically superseded by faster or more
efficient equivalents having essentially the same functions.
Accordingly, replacement standards and protocols having the same or
similar functions as those disclosed herein are considered
equivalents thereof.
[0175] Thus, a distributed clinical trial system has been
described. Although specific example embodiments have been
described, it will be evident that various modifications and
changes may be made to these embodiments without departing from the
broader scope of the invention. Accordingly, the specification and
drawings are to be regarded in an illustrative rather than a
restrictive sense. The accompanying drawings that form a part
hereof, show by way of illustration, and not of limitation,
specific embodiments in which the subject matter may be practiced.
The embodiments illustrated are described in sufficient detail to
enable those skilled in the art to practice the teachings disclosed
herein. Other embodiments may be utilized and derived therefrom,
such that structural and logical substitutions and changes may be
made without departing from the scope of this disclosure. This
Detailed Description, therefore, is not to be taken in a limiting
sense, and the scope of various embodiments is defined only by the
appended claims, along with the full range of equivalents to which
such claims are entitled.
[0176] Such embodiments of the inventive subject matter may be
referred to herein, individually and/or collectively, by the term
"invention" merely for convenience and without intending to
voluntarily limit the scope of this application to any single
invention or inventive concept if more than one is in fact
disclosed. Thus, although specific embodiments have been
illustrated and described herein, it should be appreciated that any
arrangement calculated to achieve the same purpose may be
substituted for the specific embodiments shown. This disclosure is
intended to cover any and all adaptations or variations of various
embodiments. Combinations of the above embodiments, and other
embodiments not specifically described herein, will be apparent to
those of skill in the art upon reviewing the above description.
[0177] The Abstract is provided to comply with 37 C.F.R.
.sctn.1.72(b) and will allow the reader to quickly ascertain the
nature and gist of the technical disclosure. It is submitted with
the understanding that it will not be used to interpret or limit
the scope or meaning of the claims.
[0178] In the foregoing description of the embodiments, various
features are grouped together in a single embodiment for the
purpose of streamlining the disclosure. This method of disclosure
is not to be interpreted as reflecting that the claimed embodiments
have more features than are expressly recited in each claim.
Rather, as the following claims reflect, inventive subject matter
lies in less than all features of a single disclosed embodiment.
Thus the following claims are hereby incorporated into the
Description of the Embodiments, with each claim standing on its own
as a separate example embodiment.
* * * * *