WO2020201613A1

WO2020201613A1 - A method of testing cognitive effect of a medical substance

Info

Publication number: WO2020201613A1
Application number: PCT/FI2019/050351
Authority: WO
Inventors: Markus Forsberg; Jouni IHALAINEN; Soili LEHTO
Original assignee: Revised Methods Oy
Priority date: 2019-03-30
Filing date: 2019-05-06
Publication date: 2020-10-08

Abstract

Disclosed is a method for estimating an impact of a medical substance on cognitive performance, comprising selecting a group of persons; obtaining a pre-information of the group of persons and selecting a first test pattern of cognitive performance, a second test pattern of cognitive performance, a first dose of a simulation drug and a second dose of a placebo drug. Furthermore, the method comprises dividing the group of persons to a first sub-group and a second sub-group; providing the first test pattern to the first sub-group and to the second sub-group and collecting first results; administering the second dose of the placebo drug to the first sub-group and the first dose of the simulation drug to the second sub-group; providing the second test pattern to the first sub-group and to the second sub-group and collecting second results; and comparing the first results and the second results to determine a relative impact of the simulation drug to the second sub-group in relation to the first sub-group. Finally, the determined relative impact is used to estimate an impact of the medical substance on cognitive performance.

Description

A METHOD OF TESTING COGNITIVE EFFECT OF A MEDICAL SUBSTANCE

TECHNICAL FIELD

The present disclosure relates generally to a method for estimating an impact of a dose of a medical substance on cognitive performance.

BACKGROUND

When testing a drug related to cognitive performance (or skill), normal testing comprises providing a standardized cognitive test before and after drug administration. Typically, such tests are conducted using double blind testing procedure. In such tests some of the test subjects are given placebo drug and some are given a drug with an medical effect (drug). The group which received the placebo and the group which received the drug are compared to find any effect the drug may have on cognitive performance. Said tests can be conducted with persons having a diagnosed illness or symptom. In some tests, a mixture of medical substances may be tested.

A problem is that setting up a cognitive test protocol for testing of drug effects on cognition is difficult. Further, implementing the test protocol takes long time. This limits the possibilities of testing drug effects on cognition in a large group of people. Further, the analysis of the test results might also take a long time and be complex. Still further, to find an impact of a medical substance in a drug, a set of different doses must be tested to find the impact of the medical substance to cognitive performance. For example, a small dose of the medical substance may not cause any effect for certain group of persons but the same dose may cause a severe effect to another group of persons. Further, it is important to find out what is the dose of the medical substance which may have a negative impact to cognitive performance in a such a way that for example activities of daily living are declined.

A further problem of present estimation methods for cognitive performance is a need of diagnosed persons with illness or symptom for the tests. This limits the possibilities to run comprehensive tests. It also leads to several confounding factors and biases testing of a drug effect. Healthy persons and simulation of disease-like state provides less variation.

Therefore, considering the foregoing discussion, there exists a need for a simplified and effective method of testing and estimating cognitive effect of a medical substance in healthy persons.

SUMMARY

The present disclosure discloses a method for estimating an impact of a dose of a medical substance on cognitive performance, comprising:

- selecting a group of persons;

- obtaining a pre-information of the group of persons;

- selecting a first test pattern of cognitive performance, a second test pattern of cognitive performance, a third test pattern of cognitive performance, a first dose of a simulation drug and a second dose of a placebo drug;

- dividing the group of persons to a first sub-group and a second sub group;

- providing the first test pattern to the first sub-group and to the second sub-group and collecting first results;

- administering for a first time the second dose of the placebo drug to the first sub-group and the first dose of the simulation drug to the second sub-group;

- providing the second test pattern to the first sub-group and to the second sub-group and collecting second results; - administering the dose of the medical substance to the first sub-group and to the second sub-group;

- administering for a second time the second dose of the placebo drug to the first sub-group and the first dose of the simulation drug to the second sub-group;

- providing the third test pattern to the first sub-group and to the second sub-group and collecting third results;

- comparing the first results, the second results and the third results to estimate an impact of the medical substance on cognitive performance.

Further, the present disclosure provides a system for estimating an impact of a medical substance on cognitive performance, the system comprising:

- a first computer sub-system having a user interface configured to provide means to

- select a group of persons;

- obtain a pre-information of the group of persons;

- a second computer sub-system arranged to host a testing environment and configured to provide a plurality of test patterns to the first computer sub-system,

wherein the first computer sub-system is further configured to:

- select a first test pattern of cognitive performance, a second test pattern of cognitive performance, a third test pattern of cognitive performance, a first dose of a simulation drug and a second dose of a placebo drug;

- divide the group of persons to a first sub-group and a second sub group;

- provide the first test pattern to the first sub-group and to the second sub-group and collect first results via a communication interface; - provide the second test pattern to the first sub-group and to the second sub-group and collect second results via the communication interface;

- provide the third test pattern to the first sub-group and to the second sub-group and collecting third results;

- compare the first results, the second results and the third results to estimate the impact of the dose of the medical substance on cognitive performance. Embodiments of the present disclosure substantially eliminate, or at least partially address, the aforementioned problems. The method of the present disclosure can therefore help to provide estimation of an impact of a dose of a medical substance on cognitive performance in a simple, fast and reliable manner in healthy persons. Additional aspects, advantages, features and objects of the present disclosure would be made apparent from the drawings and the detailed description of the illustrative embodiments construed in conjunction with the appended claims that follow.

It will be appreciated that features of the present disclosure are susceptible to being combined in various combinations without departing from the scope of the present disclosure as defined by the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the present disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those skilled in the art will understand that the drawings are not to scale. Wherever possible, like elements have been indicated by identical numbers.

Embodiments of the present disclosure will now be described, by way of example only, with reference to the following diagrams wherein: FIG. 1 is an illustration of steps according to embodiments of the disclosure and

FIG. 2 is an illustration of a system according to embodiments of the disclosure.

In the accompanying drawings, an underlined number is employed to represent an item over which the underlined number is positioned or an item to which the underlined number is adjacent. A non-underlined number relates to an item identified by a line linking the non-underlined number to the item. When a number is non-underlined and accompanied by an associated arrow, the non-underlined number is used to identify a general item at which the arrow is pointing.

DETAILED DESCRIPTION OF EMBODIMENTS

The following detailed description illustrates embodiments of the present disclosure and ways in which they can be implemented. Although some modes of carrying out the present disclosure have been disclosed, those skilled in the art would recognize that other embodiments for carrying out or practising the present disclosure are also possible.

The present disclosure provides a method for estimating an impact of a dose of a medical substance on cognitive performance (term performance can refer to how a person performs certain task or tasks associated with various cognitive domains). A "medical substance" refers to a chemical or mixture of chemicals or molecules which may have a medical impact on a person diagnosed with a given illness or symptom. The "cognitive" refer to various cognitive domains such as sensorimotor functions, attention, executive functions, working memory, visual learning and memory, processing speed, social cognition. Some medical substances used for treatment of illness or symptom such as antiepileptic drugs can cause undesired effects/impacts on cognitive performance. Furthermore, some medical substances can have a positive effect/impact on cognitive performance.

The present method provides an estimate of the impact as in the method a chemical substance different from the medical substance is administered. The said chemical substance is referred as a simulation drug. The method thus comprises administering a placebo to one group of persons, and a simulation drug to another group of persons. The simulation drug has a similar effect on cognitive performance as illness or symptom would have to the person, but without disease-related confounding factors. The simulation drug can also have positive effect on cognition.

The method comprises

- selecting a group of persons;

- obtaining a pre-information of the group of persons;

- dividing the group of persons to a first sub-group and a second sub group;

- administering for a first time the second dose of the placebo drug to the first sub-group and the first dose of the simulation drug to the second sub-group; - providing the second test pattern to the first sub-group and to the second sub-group and collecting second results;

- administering the dose of the medical substance to the first sub-group and to the second sub-group;

- comparing the first results, the second results and the third results to estimate the impact of the dose of the medical substance on cognitive performance.

The group of persons is selected preferably from healthy persons. A "healthy person" refers to a person who is not diagnosed with the illness or symptom under study, or a similar illness or symptom. The benefit of selecting healthy persons is that by this means a larger test group can be used, as in general there are more non-diagnosed persons than diagnosed persons. Further, it is easier to form a homogenous test group using present selection method.

Further, a pre-information of the group of persons is obtained. According to an optional embodiment, the pre-information comprises at least one of: demographics such as age and gender; education; medical history; laboratory assessment; and vital signs such as weight and height of each of the persons in the group of persons.

Furthermore, a first test pattern of cognitive performance, a second test pattern of cognitive performance, a third test pattern of cognitive performance, a first dose of a simulation drug and a second dose of a placebo drug is selected. Test pattern refers to a set of cognitive tests (measuring sensorimotor functions, attention, executive functions, working memory, visual and learning and memory, processing speed, social cognition etc.) which can be used to obtain a number value representing the cognitive performance level of the test subject (i.e. a person part of the group of persons selected). The first test pattern can be different or same as the second test pattern which can be same or different from the third pattern. The test patterns can be selected from a larger set of tests, i.e. the test pattern can be a sub set of another test pattern. The larger set of tests can comprise tests 1 through 100. First test pattern can be selected as tests 1-10, a second test pattern as tests 11-20 and a third test pattern as tests 21-30. In addition, the test patterns can be partly or entirely overlapping. Further, the larger test pattern can contain tests at different degree of difficulty. For example, tests 1-50 can be easy and tests 51-100 difficult. The test patterns can be selected based on pre-selection, which can be for example based on background information or on a preliminary testing (which then defines the reference level). The placebo drug refers to a chemical substance which has no medical effect or, in context of cognitive tests, is a substance which is not known to have any negative or positive effect on cognitive performance. The simulation drug is a chemical substance which is known to have a negative or positive effect on cognitive performance, as mentioned above. Most typically, the simulation drug is a chemical substance having a negative effect on cognitive performance. The dose refers to an amount of a given drug, i.e. of the placebo, the simulation drug or the medical substance. The dose can refer to mg of active chemical compound in simulation drug or medical substance. It can further refer to amount of placebo.

The step of comparing the first results, the second results and the third results to estimate an impact of the medical substance on cognitive performance may comprise comparing the results within a given sub- group (or within all sub-groups) and between the sub-groups. According to an optional embodiment, the first, second and third test patterns of cognitive performance are selected based on the pre information of the group of persons. As an example, a more difficult test can be selected for young adults than elderly adults. Furthermore, the test pattern and cognitive tests included in the pattern can be selected based on for example the educational background of the persons. Furthermore, the first test pattern of cognitive performance can be referred as a reference level test to determine cognitive performance level of the group of persons at the beginning of estimation process. According to another optional embodiment, the first dose and the second dose are selected based on the selected first, second and third test patterns and the pre-information. As an example, if the selected first test pattern, the selected second test pattern and the selected third test pattern are very difficult, then the selected first dose and the selected second dose can be set to a low level. A further example is that if, based on the pre-information, the test group has high cognitive performance, the dose (of the simulation drug or the medical substance) can be set to be at a high level to ensure an effect on cognitive performance.

Furthermore, the group of persons is divided to a first sub-group and a second sub-group. According to an optional embodiment, the group of persons is divided to sub-groups using randomization. Further, the number of sub-groups can be arbitrary as long as it is at least two.

After forming the sub-groups, tests are performed with the first and the second sub-groups. The first test pattern is provided to the first sub- group and to the second sub-group and first results are collected. The first results refer to tests results of the first test pattern, which was provided before administering of the placebo and simulation drugs.

According to yet another optional embodiment, the method comprises further updating the first test pattern to comprise a first additional test based on the collected first results, if the collected first results provide an average score above a first predetermined limit. This way the test procedure can be altered during the procedure or progress. Adding the first additional test might be needed for example if, based on the collected first results, all test subjects received full score or no score. This is needed to ensure that effects of the simulation drug on cognitive performance can be measured. In some of the conducted experiments it was found that if the test group was very skilful to start with, then more difficult cognitive tests were needed to obtain meaningful results. Indeed, by this means a degree of difficulty of certain tests may be adjusted to obtain relevant results.

The second dose of the placebo drug is administered for a first time (during test procedure) to the first sub-group and the first dose of the simulation drug is administered to the second sub-group. According to an optional or alternative embodiment there can be several administering steps. For example, the drugs can be administered over several days or weeks.

According to an optional embodiment, the simulation drug is ketamine, and the first dose is selected based on a pre-estimated impact of the dose of the medical substance on cognitive performance. As an example, benefit of using ketamine as the simulation drug is that it can be administered to healthy persons to induce cognitive deficits. Indeed, if a positive effect (i.e. impact) of a medical substance on cognitive performance is to be studied, ketamine is administered to healthy persons. According to an alternative embodiment the simulation drug may have a positive effect on cognitive performance. This way, the negative effect of a dose of a medical substance, on cognition can be estimated. As an example, the simulation drug can be a wakefulness- increasing drug, such as modafinil, that may have effect on cognitive performance. This way, the negative effect of a dose of a medical substance on cognition can be estimated better.

After administering the drugs, the second test pattern is provided to the first sub-group and to the second sub-group and a second set of results is collected. According to alternative or additional embodiment, test patterns are provided between two sequential administering steps.

According to an optional embodiment, the method further comprises updating the second test pattern to comprise a second additional test based on the collected second results, if the collected second results have an average score above a second predetermined limit.

The dose of the medical substance is administered to the first sub-group and to the second sub-group. This way both groups are subjected to possible cognitive performance effects of the medical substance. According to an optional or alternative embodiment there can be several administering steps. For example, the drugs can be administered over several days or weeks. The dose of the medical substance is typically pre set parameter before start of testing procedure. As an example of the dose can be amount in mg / kg (of weight of test person in a group) of the medical substance. After administering (or at the same time) the second dose of the placebo drug is administered for a second time (during test procedure) to the first sub-group and the first dose of the simulation drug is administered to the second sub-group.

The third test pattern is provided to both the first sub-group and the second sub-group. A third set of results are collected based on the tests.

The first, second and third results are compared to estimate an impact of the dose of the medical substance on cognitive performance. Table 1 is a first example of test results. According to the results it appears that the dose of medical substance is able to reverse the effect caused by the dose of the simulation drug.

Table 1

Table 2 is a second example of test results. According to the results it appears that the dose of medical substance is not able to reverse the effect caused by the dose of the simulation drug.

Table 2

Table 3 is a third example of case in which the dose of medical substance causes negative effects on cognition (simulation drug has minor positive effect on cognitive performance) . Table 3

In general, several test runs can be conducted to find a) what is the dose of simulation drug needed to induce negative or positive effects/impact on cognition and b) does a dose of a medical substance have positive or negative impact.

According to example embodiment, the first results, the second and the third results are compared to determine a first relative impact of the simulation drug to the second sub-group. Then the first results and the second results are compared to determine a first relative impact of the simulation drug to the first sub-group. The determined first relative impact and the determined second relative impact are used to estimate an impact of the medical substance on cognitive performance. Relative impact can be determined for example by dividing an average score of the first test pattern or a single cognitive test in a pattern with an average score of the second test pattern or a single cognitive test in a pattern. It is also possible to use only one test pattern, performed twice. Alternatively, relative impact can be determined by comparing the test results collected from the first sub-group to the test results collected from the second sub-group. If, based on alternative or additional embodiment, a larger time scale test of several test pattern runs and rounds of administering is done, said comparisons can be arranged as a time series to determine the relative impact over time. Optionally the determined relative impact is further used to estimate an impact of the medical substance on cognitive performance. The estimation can be done for example by extrapolating the measured effect of the medical substance to the simulation drug. As further example, animal study results and studies of medical substance administered to animals and the simulation drug administrated to animals can be used as an estimation basis.

According to an optional embodiment, the impact is defined as "no effect", if the relative impact is within a first range. The first range is defined as a range where no statistically significant deviation between results as compared between the first test pattern and the second test pattern and the sub-groups is observed (first deviation). Further, the impact is defined as "mild effect", if the relative impact is within a second range. The second range is defined as deviation of two times first deviation. The impact is defined as" moderate effect", if the relative impact is within a third range. The third range is defined as deviation of three times the first deviation. The impact is defined as "severe effect" if the relative impact is within a fourth range. The fourth range is defined four times the first deviation. According to a further additional embodiment, the method further comprises determination of biomarkers from the group of persons before and after the drug administering step. The biomarkers can be used to calibrate the first results and the second results. As an example, biomarkers can be heart rate, blood pressure, EEG, ECG, blood drug level, blood composition.

Further, the present disclosure provides a system for estimating an impact of a medical substance on cognitive performance. The system comprises a first computer sub-system and a second computer sub^¬ system. The first computer sub-system comprises a user interface. The user interface can be for example a web interface for providing access to the first computer system via web browser. Alternatively, the user interface can be a user interface implemented with a touch screen of the first computer sub-system. The first computer sub-system can be for example smart phone, web pad, laptop or a desktop. The first computer sub-system can be a combination where part of the first computer sub system is arranged as a service in a cloud environment (server part) and part as remote user interface (as in case of accessing the server part via web pad, smart phone, laptop or desktop) . The user interface is configured to provide means (such as radio buttons, pull down menus or free text areas) for a user to select a group of persons (i .e. to provide a list of the persons) and the computer system to obtain a pre-information of the group of persons. The pre-information can be provided by the user of the first computer sub-system manually or the user interface can be configured to download the pre-information or part of the pre-information from a 3^rd party service.

The second computer sub-system is arranged to host a testing environment. The testing environment refers to a computer implemented code and databases which are used to form test patterns. The testing environment is configured to provide a plurality of test patterns. The testing environment may have a large suite of tests and it can be configured to provide a plurality of test patterns, all of the tests patterns or sub-sets of the tests or mixture of tests to the first computer sub- system.

The first computer sub-system is further configured to select from the provided plurality of test patterns a first test pattern of cognitive performance and a second test pattern of cognitive performance. The first test pattern and the second test pattern may be same or different. The test patterns are selected based on the pre-information related to the group as well as based on the target of the study. Further, the first computer sub-system is configured to indicate, via the user interface, to the user of the first computer system a first dose of a simulation drug and a second dose of a placebo drug to be used for the tests. The first dose and the second dose may be calculated in the first computer sub^¬ system (for example mg/kg/h), or they may be pre-set as a fixed amount (for example in mg) . The first computer sub-system is further configured to divide the group of persons to a first sub-group and a second sub-group. Preferably, the first computer sub-system is configured not to disclose to the user which of the sub-groups, the first or the second, will be the one tested using the simulation drug and which is tested using the placebo drug.

The first computer sub-system provides the test pattern to the first sub^¬ group and to the second sub-group and collects first results via a communication interface. The communication interface can for example be a web interface. As an example, a web interface is provided. In an alternative embodiment, the actual test is in the second computer sub^¬ system and the persons conduct the test in said testing environment. After collecting the first results, the first computer sub-system may prompt the user to administer the second dose of the placebo drug to the first sub-group and the first dose of the simulation drug to the second sub-group. The computer system may provide such information via a user interface at the start of the tests or during the tests.

After administering phase, the first computer sub-system is configured to provide the second test pattern to the first sub-group and to the second sub-group and to collect second results via the communication interface.

The first computer sub-system is configured then further to compare the first results and the second results to determine a relative impact of a simulation drug to the second sub-group in relation to the first sub-group and use the determined relative impact to estimate an impact of the medical substance on cognitive performance.

Additionally, the system is further configured to provide means to receive an input from biomarker sensors. As an example, biosensors of the group of persons can be configured to provide information before, during and after tests to the first computer sub-system. This way, continuous or substantially continuous data related to the simulation drugs' effects on cognitive performance can be obtained. The continuous data can be calibrated using the cognitive test inputs. Furthermore, collection of biomarker data may be additionally used to support analysing the cognition test data. As an example, time dependent effects the simulation drug in a person can be analysed at during the tests (time stamp the test with respect to the biomarkers) . It is also possible to use, in the analysis, biomarkers and biomarker data obtained from other sources, such as from blood sample analysis or a blood pressure measurement apparatus (and not only from sensors) . AN EXAMPLE PROTOCOL FOR ESTIMATING IMPACT

Below is an outline of estimation or assessment of effect of a medical substance on cognitive performance. Based on the example, an impact of a medical substance on cognitive performance is estimated in healthy persons.

Step 1 : As a first step a system is used to provide a user interface to select a disease of interest. In the example protocol the user interface is configured to prompt user to select one of: a) Schizophrenia, b) Bipolar disorder, c) Attention deficit hyperactivity disorder (ADHD). In the present example "a" = Schizophrenia is selected. Based on the selection a set of questions are triggered.

Step 2: Which cognitive effect of a medical substance is to be tested? In present example alternatives are: a) Cognition-enhancing (positive effect) or b) Cognition-attenuating (negative effect). In the present example "a" = Cognition-enhancing (positive effect) is selected and ketamine is being used as a simulation drug.

Step 3: What is the administration route of the medical substance? a) oral, b) intravenous or c) other (for example dermal, inhalation). In the present example "a" oral is selected.

Step 4: What is the timing of the administering the drug? a) Before starting ketamine or b) simultaneously with ketamine. In the present example "a" before taking ketamine is selected.

Step 5: What dose of ketamine to induce cognitive deficits is selected: a) Mild cognitive deficits (bolus X mg/kg, infusion Y mg/kg/h), b) Moderate cognitive deficits (bolus 2X mg/kg, infusion 2Y mg/kg/h) or c) Severe cognitive deficits (bolus 3X mg/kg, infusion 3Y mg/kg/h). In present example b) Moderate is selected. Step 5: Define study design: a) Within-subjects design (crossover treatments, each subject gets all treatments) or b) Between-subjects design (independent treatment groups - treatment group(s) and control group). In present example "a" is selected.

Step 6: Define number of test days. In present example 4 test days (treatment days) is selected.

Step 7: Define interval between treatments visits. In present example 14 days is selected.

Step 8: Define size of study group (group of persons). In the present example, a 16 persons group is defined.

Step 9: Define how the group is divided to a first sub-group and a second sub-group a) Latin square - random allocation of subjects to treatments & treatment sequences using pre-programmed command b) User-defined - user does randomization by a separate tool. In present example "a" is used.

Step 9: Select a cognitive first test pattern to be used from a set of test patterns. Existing test batteries such as a) CANTAB, b) THINC-it, c) CogState or d) BrainCare/NeuroTrax can be provided as alternatives. In present example "a" is selected.

Step 10: Providing alternatives to select a sub test pattern of the selected first test pattern a) CANTAB schizophrenia battery small (2-3 tests, e.g. MOT, RVP, PAL), b) CANTAB schizophrenia battery medium (4-5 tests, e.g. MOT, RTI, RVP, PAL, SWM), c) CANTAB schizophrenia battery large (6-7 tests, e.g. MOT, RTI, RVP, PAL, SWM, VRM, MTT). In present example "b" is selected.

Step 11 : Selecting test interval for the test pattern a) no intervals, b) 5min interval between tests. In present example "b" is selected. Step 12: Is cognitive pre-screening with selected test battery needed? In present example "yes".

Step 13: Which biomarkers are to be tested? a) Ketamine plasma levels b) Blood pressure c) Heart rate d) EMG, e) EEG. In present example "a" is selected.

Step 15: What is timing of taking the biomarker tests (plasma levels)? a) After, b) Before, c) Before and after. In present example "c" is selected.

After the above steps (questions, prompts in the user interface) the system is configured to provide a study protocol (e.g. ketamine dose, randomization table, CANTAB test battery choices etc.)

In this example, the selections yield the following protocol :

• The testing is being done in healthy volunteers

• Ketamine dose bolus 0.23 mg/kg + infusion 0.58 mg/kg/h, infusion time 60 min

• Test drug is given orally 2 h prior starting ketamine administration

• Cognitive tests start 15 min after initiation of ketamine infusion (15-60 min)

• There are 4 treatments: ketamine+placebo, ketamine+medical substance_dosel, ketamine+medical substance_dose2 and ketamine+medical substance_dose3

• All study subjects receive all 4 treatments according to balanced latin square design for four treatments at two weeks intervals (the first test pattern takes place on day 0, the second on day 14, the third on day 28 and the fourth on day 42)

• The treatments (1-4) are randomly assigned to the treatment codes (A-D) as well as the subjects to the treatment sequences

• The cognitive tests are performed by using CANTAB battery medium, and there is a 5 min interval between tests • Blood samples for ketamine analyses are taken before starting ketamine infusion and after ketamine infusion

Tests are then run to select a group of persons (16) to estimate an impact of a medical substance intended for treatment of schizophrenia to cognitive performance. Ketamine is used in the test as a simulation drug to induce equivalent cognitive effects as illness would result in the test person(s). Further, this way a group of healthy persons can be used in the estimating test or protocol. Pre-information of the group of persons is collected and a first test pattern of cognitive performance is selected and provided to the group of persons. A second test pattern can be a sub test pattern of the first test pattern or the first test pattern may be run twice (first run is the first test pattern and the second test pattern is the second run of the first test pattern). The group is divided to a first sub group and to a second sub-group based on randomization. This way, a double-blind test can be performed. The simulation drug (ketamine) is administered using the first dose and the placebo is administered using a second dose. After the test runs (and also between them), the second test pattern is run to the sub-groups (which can be same as the first test pattern). Further, biomarkers can be determined before, during and after tests.

The collected data is analysed after the above test protocol. For the analysis, the system is configured to prompt user to provide information such as:

Step 16: Is MOT test to be taken in consideration to exclude subjects with motor adverse effects? a) Yes - subjects with motor adverse effects are excluded from further statistical analyses b) No - all subjects are included in the statistical analyses. In given example "a" is selected.

Step 17: Which cognitive tests are to be analysed? a) All tests (CANTAB schizophrenia battery small (e.g. RTI, RVP, PAL, SWM) in this example), b) Select tests (user selects only certain tests to reduce amount of analyses and data output). In present example "a" is selected.

Step 18: Which selection of measures are to be included in the statistical analysis (each cognitive test in selected battery gives several measures)? a) Key measures - only key cognitive outcome measures or b) All measures - all cognitive outcome measures. In present example "b" is selected.

Step 19: Should effect size be calculated (to be used as a supportive data)? a) Yes (effect size is calculated for measures selected previously), b) No. In present example "a" is selected.

At this stage, pre-programmed statistical analyses are performed to compare subjects by treatment. Then, additional or supportive statistics can be performed as follows. Basically, the first results (before) and the second results (after) are compared to both sub-groups. The first sub- group has been administered the placebo, so no effect should be visible. The second sub-group has been administered ketamine as the simulation drug so there may be a visible effect depending on demographics, dose of the ketamine etc. of the test persons.

Step 20: Further selection of biomarker data to be correlated with cognitive data (select one) is prompted. As the ketamine plasma was measured, the ketamine plasma levels can be used to correlate or calibrate findings.

Step 21 : Selection of cognitive tests for correlation analysis (select 1-4 tests) is prompted in the user interface of the system a) RTI, b) RVP, c) PAL, d) SWM. In present example "c" is selected.

Step 22: Selection of measures to be included in correlation analysis (each cognitive test in selected battery gives several measures) is asked: a) Key measures - only key cognitive outcome measures are correlated with biomarker b) All measures - all cognitive outcome measures are correlated with biomarker. In present example "a" is selected.

Thus, in this example, correlation between ketamine levels and PAL key measures is being analysed by pre-programmed statistical analyses. DETAILED DESCRIPTION OF THE DRAWINGS

Fig. 1 provides a system diagram for a person conducting a test protocol for estimating an impact, the system comprising a user terminal 100. In step Sl. l, the user terminal 100 is used to select a group of persons for a test and to provide pre-information to a first computer sub-system 110. In step S2.1, the first computer sub-system 110 selects a first test pattern of cognitive performance, a second test pattern of cognitive performance and receives related test data or pointers from a second computer sub-system 120. The first computer sub-system further indicates doses for the protocol. In step S3.1, a user belonging to a first sub group of the group of persons conducts a first test pattern (with user terminal 104), takes the placebo drug (as belonging to the first sub-group although the person does not know it) and conducts a second test pattern after taking the placebo drug. In step S4.1, a user belonging to a second sub group of the group of persons conducts a first test pattern (with user terminal 102), takes a simulation drug (as belonging to the second sub group although the person does not know it) and conducts a second test pattern after taking the simulation drug. In step S5.1, the results are compared in the first computer sub-system 110. In step S6.1, the results are provided to the user terminal 100. Figure 2 is an illustration of a system 200 according to an embodiment of disclosure. A first computer sub-system 210 is a data collection and analytics platform. A database 212 is an integral part of the computer sub-system 210. The first computer subsystem 210 can be accessed with a user terminal 242. The user terminal 242 is analytics' desktop or laptop. The first computer sub-system 210 has an interface to early development phase information module 242, a healthy volunteers' information module 244, a clinical studies module 246 and an operational clinical use module 248. Each of the modules are provided with an access to a user terminal 240. The access to each of the modules can be open or restricted with access control. The first computer sub-system 210 has an interface to a second computer sub-system 220. The second computer sub-system is used to host test patterns and conduct tests over web interface.

Modifications to embodiments of the present disclosure described in the foregoing are possible without departing from the scope of the present disclosure as defined by the accompanying claims. Expressions such as "including", "comprising", "incorporating", "have", "is" used to describe and claim the present disclosure are intended to be construed in a non exclusive manner, namely allowing for items, components or elements not explicitly described also to be present. Reference to the singular is also to be construed to relate to the plural.

Claims

1. A method for estimating an impact of a dose of a medical substance on cognitive performance, comprising :

- selecting a group of persons;

- obtaining a pre-information of the group of persons;

- dividing the group of persons to a first sub-group and a second sub group;

- providing the second test pattern to the first sub-group and to the second sub-group and collecting second results;

2. A method according to claim 1, wherein the pre-information comprises at least one of: demographics such as age and gender; education; medical history; laboratory assessment; and vital signs such as weight and height of each of the persons in the group of persons.

3. A method according to claim 1 or 2, wherein the first, second and third test patterns of cognitive performance are selected based on the pre information of the group of persons.

4. A method according to any of the preceding claims, wherein the first dose and the second dose are selected based on the selected first, second and third test patterns and the pre-information.

5. A method according to any of the preceding claims, wherein the group of persons is divided to sub-groups using randomization.

6. A method according to any of the preceding claims, further comprising updating the first test pattern to comprise a first additional test based on the collected first results, if the collected first results have an average score above a first predetermined limit.

7. A method according to any of the preceding claims, wherein the simulation drug is ketamine and the first dose is selected based on a pre estimated impact of the dose of medical substance on cognitive performance.

8. A method according to any of the preceding claims, further comprising updating the second test pattern to comprise a second additional test based on the collected second results, if the collected second results have an average score above a second predetermined limit.

9. A method according to any of the preceding claims, wherein the impact is at least one of: - no effect, if the relative impact is within a first range;

- mild effect, if the relative impact is within a second range;

- moderate effect, if the relative impact is within a third range and

- severe effect, if the relative impact is within a fourth range.

10. A method according to any of the preceding claims, further comprising obtaining biomarkers from the group of persons before and after the administering step.

11. A system for estimating an impact of a dose of a medical substance on cognitive performance, the system comprising:

- select a group of persons;

- obtain pre-information of the group of persons;

wherein first computer sub-system is further configured to:

- divide the group of persons to a first sub-group and a second sub group;

- provide the first test pattern to the first sub-group and to the second sub-group and collect first results via a communication interface;

- provide the second test pattern to the first sub-group and to the second sub-group and collect second results via the communication interface; - provide the third test pattern to the first sub-group and to the second sub-group and collecting third results;

- compare the first results, the second results and the third results to estimate an impact of the dose of medical substance on cognitive performance.

12. A system according to claim 11, wherein the system is further configured to provide means to receive input from biomarker measurements.