Prepare the required documents to be submitted to the IEC/IRB: according to ICH

Prepare the required documents to be submitted to the IEC/IRB:

Documents usually required by Ethics Committees

·   Investigator Brochure and up-to-date safety information.

·   Trial protocol (final version and amendments).

·   Consent form(s) and subject information sheets.

·   Subject recruitment procedures (e.g. advertisement

·   Information on payment and compensation available to subjects.

·   Current curriculum vitae for each investigator.

·   Any other document requested by the IEC/IRB.

                                                                   See ICH Guidelines 3.1.2

Obtain approval document from the Ethics Committee, which must identify the documents reviewed and state that the study is acceptable and can be initiated.

Send the approval document of the Ethics Committee, with a list of Committee members, to TDP/TDR/WHO as a supporting document for approval of the WHO Secretariat

Committee on Research Involving Human Subjects (SCRIHS).Prepare the application for Health Authority clearance in collaboration with TDR and other sponsoring agencies.

Prepare the application for product exportation/importation in collaboration with TDR and other sponsoring agencies.

If the IEC/IRB and others approve the trial, sign the final copy of the protocol and confirm in writing that he/she has read and understood, and will adhere to, the protocol, study procedures and ICH Good Clinical Practice, will collaborate with the monitor, and accords with TDR/sponsoring agencies on publications policy.

Submit requested documents to the Clinical Monitors, including:

1. Signed agreement to comply with this SOP (page 1).

2. Approved protocol, signed and dated.

3. Approved informed consent form and other subject information, advertisement (local language and English translation).

4. Investigator’ s and co-investigator’ s curriculum vitae (C.V.s).

5.  Authorized Staff Form (ASF).

6.  Product exportation/importation authorization.

7. Laboratory certification/list of normal laboratory ranges, dated and signed by Investigator.

8. Technical services agreement (TSA), signed and dated.

9. Signed agreement that the product will not be used before the Trial Initiation Monitoring Visit has been made and authorization obtained from the TDR Clinical Coordinator (if applicable).

10. Signed FDA 1572 form (if applicable, e.g. study under Investigational New Drug - IND).

Make sure that the local ethics committee fulfils the ICH GCP requirements. ICH GCP Composition and Operations of IEC/IRB

Make sure that the local ethics committee fulfils the ICH GCP requirements.

ICH GCP Composition and Operations of IEC/IRB

   The IRB/IEC should determine the authority under which it is established and the  composition (names and qualifications)of its members, which should consist of:

Ø      A reasonable number of members who collectively have the qualifications and experience to review and evaluate the science, medical aspects and ethics of the proposed trial.

Ø      At least five members.

Ø      At least one member whose primary interest is in a non-scientific area.

Ø      At least one member who is independent of the trial site.

An IEC/IRB may invite nonmembers with expertise in special areas to give assistance.

The Investigator may provide information on any aspect of the trial, but may not participate in the IEC/IRB deliberations, vote, or provide opinion.

Only members who participate in review and discussion of the protocol, and who are independent of the investigator and the sponsor, can vote or provide opinion.

The IEC/IRB should perform initial and continual reviews of the trials according to the written operating procedures, and maintain records of activities and minutes of meetings.

The IEC/IRB should notify promptly, and in writing, all trial-related decisions and opinions, specifying the reasons for each.

                                                                                                   See ICH Guidelines 3.2

PRIOR TO INITIATION OF THE CLINICAL RESEARCH STUDY

PRIOR TO INITIATION OF THE CLINICAL RESEARCH STUDY

The Investigator should:

Be interested in the scientific aspects of the study and ensure that the study is responsive to the needs of public health within the country of the population in which it will be conducted.

Ensure the confidentiality of the product, the protocol and trial procedures by giving a confidentiality agreement in writing to TDP/TDR and/or sponsoring agencies.

Have sufficient time free from other obligations to prepare and conduct the trial. Clinical trials are time consuming and the Investigator should ensure that sufficient time can be dedicated to the study, including for informing and supervising study staff.

Review Investigator’s Brochure and any up-to-date information on the investigational product. The Investigator must be familiar with the product, including pre-clinical toxicology, pharmacology, pharmacokinetics and up-to-date clinical data.

Review and discuss in detail, the ICH GCP guidelines, investigators' SOPs and protocol with the Clinical Monitor.  The Investigator should clearly define:

1. Factors that may alter the feasibility and acceptability of the trial.

2. An adequate recruitment rate for the trial by providing retrospective data on numbers of patients who would have satisfied the proposed entrance criteria during preceding time periods.

Make sure that the procedures stated in the study protocol are applicable in his/her centre and fully understood. The Investigator should ask the Clinical Monitor to clarify any points of possible misunderstanding.

Make sure that there are sufficient medical, paramedical and clerical staff to support the study and deal with foreseeable emergencies.

1. Provide a list of study personnel and functions in the study to the Clinical   Monitor/Product Manager (Authorized Staff Form - ASF).

2. Provide curriculum vitae of the Sub-co Investigators in the responsible laboratory.

Make sure that the physical location and facilities are sufficient to allow the study to be undertaken efficiently. Ensure:

1. Confidentiality and safety conditions for trial subjects.

2. Adequate equipment/facilities for subject follow-up, examination and care.

3. Adequate facilities for product storage.

4. Adequate facilities for laboratory assay. The laboratory assay should be validated  under good  laboratory practice (GLP) principles.

5. Adequate facilities for retention of trial documents, ensuring confidentiality of all  information about trial subjects and information supplied by TDR/sponsoring agencies.

Discuss the Case Report Form/SAE reporting forms and source documents in detail with the Clinical Monitor.  Clearly define :

1. Who will be responsible for CRF completion.

2. Source documents/source data and access to source data.

Arrange archiving of trial documents according to GCP and regulatory requirements.  It is important to check the duration of retention of patient records with the Institution's archive.  In case the Institution's archive does not ensure retention of documents for the period of time requested by TDR/sponsor, the Investigator must arrange for the retention of the subjects’ source documents/records for the period requested by TDR/sponsor and regulatory requirements.

Finalize informed consent forms and associated trial subject information materials (advertisements); establish procedures for application for local clearance (e.g. dean of the institution) and Independent Ethical Committee (IEC)/Institutional Review Board (IRB) approval.

Clearly define how subjects will be approached and informed, who will inform them, and what material will be used.  The informed consent form and all information (leaflet written in simple language, video) should be developed collaboratively with head members of the study population/ community to ensure methods are appropriate.

In case of the need for screening tests, including biological specimen collection, before entering a trial, two types of consent form should be developed: one for biological specimen collection and analysis, and one for participation in the study after obtaining satisfactory laboratory results and respecting inclusion criteria.

As a rule, the advertisement must not make reference to TDR or the compound, nor make any claims. Informed consent and advertisements must be submitted to TDR for review and must be included in documentation submitted to the Independent Ethical Committee and/or Institutional Review Board (IEC/IRB).

Operating procedure for NMR spectrometer : Bruker Avance DPX-300 NMR spectrometer

Note:

Unless otherwise specified, statements such as “click on calib” mean to move the cursor on top of the calib button on the screen, and click with the left-hand mouse button. Consider the left-hand mouse button the default; if another button is required, it will be explicitly stated. 

Commands such as “Enter zg” mean to type zg followed by a return on the

keyboard. Commands must be followed by <return> before they are accepted.

Words written in bold Arial font, e.g., acqu, refer to buttons or pull down menus on the screen (items that can be selected with the mouse).  Multilevel menu choices written like this, Windows/lock, mean choose the first menu choice by left clicking with the mouse.  Choose the second menu choice from the menu that appears when the first choice is made.

Words written in bold Courier font, e.g., edsp, refer to commands that can be typed at the keyboard.  Commands must be followed by <return> before they are accepted.

General Procedures For All Spectra

 1.  Preliminary Notes

A.     This manual is a condensed and incomplete account of instrument usage.  It is in no way a substitute for reading the detailed instruction manuals available in the NMR room (M-02).  Please get to know them. This manual is written in a similar format to the Tufts AM-300 manual, to facilitate the transition from the AM to the DPX.

B.      All users should sign the logbook before they do anything else.

C.      Log into the computer.  The screen may be illuminated by hitting any key on the keyboard.  You should see a Welcome to IRIS window.  Enter your user name and password.  When the UNIX shell window appears, type xwinnmr.  The XWIN-NMR window will appear, as shown below.

D.  Only the active window will accept typing.  To make window active, position the mouse cursor inside it.  To bring a window to the front, left click in its title bar.

E.  Most commands are accessible from the menu bar.  Alternatively, any command may be typed into the command line below the spectrum window.  Most commands are the same as the AM-300.

F.  Parameters may be changed by typing the abbreviation for that parameter followed by the (return) key (hereafter <rtn>.  The computer will respond by popping a window with the current value of that parameter.  Typing the new value of the parameter followed <rtn>by will replace the old value with the new value.  Alternatively, groups of parameters can be edited with various ed commands.  For example, eda presents a window of all acquisition parameters, edp presents a window of all processing parameters.

G.  Sample control is provided through the BSMS (Bruker Smart Magnet System) control panel.  To access the BSMS Panel choose Windows/BSMS Panel from the menu. Lock, Shim, and Sample panels are similar in appearance to the hardware buttons on the AM-300, except control is through a slider bar and +/- button, rather than through the knob.  For all buttons the left mouse button decreases the value, the middle button increases.  Step size is changed by left (decrease) or right (increase)clicking on the :2/*2 button

2.  Loading the Sample

 A.  The probe should contain a sample at all times.  When you arrive at the instrument with your research sample, you should remove the standard sample from the magnet and replace it with your sample as follows:

From the XWIN-NMR menu choose Windows/BSMS panel.  Then click on the Shim button

-Click on the LOCK button to unlock the instrument.  The color of the button will change from yellow to gray

- Click on the SPIN button to stop the spinning of the sample The color of the button will change from yellow to gray

- Click on the  LIFT button.  The standard sample should rise out of the probe on a stream of air. Remove the standard sample from the top of the probe. Remove the standard from the spinner.

-Place your sample tube in the appropriately sized spinner and adjust the precise depth of the tube within the spinner by using the depth gauge.  Note that the depth gauge should be set at 10mm regardless of the tube size for a 10 mm probe. (and at 5 mm gauge for a 5 mm probe).  Note: 10 mm tubes cannot be run in a  5 mm probe. For best shimming set tube 1mm below the appropriate line to assure a uniform sample in the active region of the probe.

- place your sample in the top of the probe. Do not release the sample unless you are sure it is supported on the air current.

- Click on the LIFT button again.  Your sample should slowly lower into the tube as the air stream decreases. Click on the SPIN button.

B.  The rate of the sample spinning should be 20-25 rps.  To check this:

-Press the Sample  button on the BSMS panel.  Then click on the SPIN MEAS button on the Sample panel that pops up.  To change the spin rate, click on the SPIN RATE button, and usethe slider bar to change the value.

3.  Locking the Instrument

 A.  To display a swept lock signal, choose Windows/lock from the XWIN-NMR menu. You should now see a continuous wave deuterium NMR spectrum of your solvent.  This should be a trace across the screen with the signal in the middle of it.

B.  To lock the sample, type lock, then click on the solvent from the list that pops up.  Lock power, phase, and gain will be adjusted automatically.

C.  The lock can also be adjusted manually, using the buttons on the Lock panel from the BSMS panel.   Note: Appropriate power and gain levels are different from the AM-300.

 4.  Shimming the Magnet

 A.  To obtain a high resolution spectrum it is essential that all parts of the sample are exposed to the same magnetic field.  The homogeneity of the field is generally assessed by noting the intensity of the lock signal, the more intense the signal the better the field.  In practice, the shims most likely to require adjustment are the spinning ones, namely Z Z² and Z³ shims, and the non-spinning shims X and Y.  To adjust the homogeneity by hand (often adequate for routine spectra and almost always faster than by automated computer shimming) you must first make sure that the lock trace is visible.  If it has gone off the screen during the locking procedure it can be brought back by lowering the LOCK GAIN level.  A sample procedure follows:

- Click on the LOCK GAIN button. Use the +/- button to adjust the lock gain until the trace is in the top two squares of the grid. Press the Z button. Use the +/- button to maximize the lock signal.  Change the step size if needed.  Repeat for the Z² button. Continue to alternate between the these buttons maximizing the lock signal each time until no further improvement can be seen. You may have to adjust the Lock Gain if the trace goes off the screen.

-If the sample must be shimmed to highest standards, adjust the non-spinning shims by pressing the SPIN button and waiting until the sample stops spinning. Spin rate can be used to monitor this. Raise the lock level by adjusting the lock  gain until the level is in the upper half of the screen. Now press the X button and use the +/- button to adjust the lock level to maximum. Then press the Y button and repeat this procedure until no further improvement is possible. Start the sample spinning again by pressing the SPIN button and repeat the Z and Z² shimming as above.

Running a ¹H Spectrum

 5.  Setting the Parameters

 A.  From the XWIN-NMR menu choose File/New. A edc window will appear containing the file name parameters.  Enter a new NAME. Generally only the Name parameter needs to be changed. NOTE:  The first time you use XWIN-NMR you will need to change other parameters to EXPNO=1, PROCNO=1, DU=datanmr, User=<username>. Click on SAVE

B.  Data files containing typical parameters for a proton spectrum are stored in the hard disk for easy access.  To retrieve these:

Choose File/Copy/parameters from file from the menu, or type rpar. A list of standard parameter files will appear.  Use the scroll bar to access the entire list.  Click on proton. In the next window that pops up, click on Copy All.

Type eda to edit acquisition parameters.  Always change Prosol to True by clicking on its value, which loads all default pulse lengths and also check that the solvent is correctly identified, otherwise calibration will be off. IMPORTANT:  Failure to set Prosol to True will result in all pulse lengths not set by you will be of zero length and rga will go off scale trying to find a signal.

Change any other acquisition parameters desired, then click on SAVE. Acquisition,  Ones you might want to change are

TD (time domain size)-Defines the number of data points of the fid.

NS (number of scans)

P1 (pulse length in microseconds)

SW, SWH (sweep width in ppm, Hz)

AQ (acquisition time in seconds)

RG (receiver gain)

B.  You may wish to tune the probe before beginning acquisition.  You can see this on another post Probe tuning.

C.  The last parameter to be set is the receiver gain (rg) which adjusts the gain of the signal coming out of the probe.  This will vary from sample to sample.  To set this gain type: rga (receiver gain adjust). The computer will automatically take a few sample pulses and alter the RG between each.  When the best value is found, the computer will type rga: finished.  You may see this value which the computer has selected by typing: rg. If you want this value then type: <rtn>.  If you wish to select another number then type in the new number  and then type <rtn>. Do not increase the value, but you may decrease it.

6.  Acquiring the Spectrum

 A.  To start the acquisition type zg to zero the memory and go (start the acquisition).  You can watch the progress of the acquisition by choosing Acquire/observe fid window from the menu, or by typing acqu.

B.  The acquisition will automatically end when the number of scans taken equals ns.  However if you wish to stop it prematurely or abort the run then you will have to click on the STOP button to the left of the FID in the acquisition window.

7.  Transforming the Data

 A. A complete description of processing parameters and their meaning can be found in the  XWIN-NMR Software 

B.  The time domain data can be processed by typing bc, then em, then ft (or type ef to do all three at once).

C.  It is not necessary to wait for the acquisition to end before transforming the data.  Type tr to transfer the data to disk at any time during the acquisition.  Once written to disk, the data can be transformed.  Time domain (fid) and frequency domain (spectrum) data are always stored in separate files. All data acquired so for can be processed while the acquisition continues in the background.

8.  Manipulating the spectrum

 A.  The spectrum can be expanded vertically and horizontally using the mouse, clicking on the buttons to the left of the spectrum.  *2, /2, *8, /8 multiply or divide the vertical scale by 2 or 8.  To expand the horizontal scale, left click anywhere in the spectral window. Then middle click on the desired expansion limits.  Left click again to unlock the mouse from the expansion.  To expand the vertical scale by an arbitrary amount, left click and hold the double arrow button to the right of /8.  Move the mouse vertically until the peaks are desired height.  Release the mouse button.  

 9.  Phasing the Spectrum

 A.  The spectrum will usually not have all the signals upright in an absorption phase. To correct this type apk (automatic phase correction).  For spectra with well separated narrow lines, apk will usually work well.

B.  If the automatic phase correction does not work well, click on the phase button to the left of the spectrum, then click on biggest.  A marker will appear under the biggest peak in the spectrum. Left click and hold the PH0 button.  Move the mouse vertically until the largest peak is phased correctly.  Release the mouse button and click and hold the PH1 button. .  Move the mouse vertically until the other peaks are phased correctly.  Release the mouse button.

 10.  Setting the Reference

 A.  The spectrometer cannot provide an exact chemical shift without being calibrated to a standard (usually TMS).  Click on the calibrate button to the left of the spectrum.  A small arrow will appear on the spectrum.  move the arrow to the reference peak with the mouse, and click the middle mouse button.  A window will appear with the current frequency value.  Enter the reference frequency. A chart of chemical shift values for solvents is on the console.

11.  Changing SW and O1 for Increased Resolution

The default parameters display the spectral range 16 to –4 ppm.  This range can be changed for greater resolution.  Click the left mouse button somewhere in the spectral window to tie the cursor to the spectrum. Position the cursor at the left limit of the desired spectral width. Click the middle mouse button to set a marker at this frequency. Move the cursor to the desired right hand limit and click the middle mouse button to expand the spectrum. The expanded region now appears in the window. Click the left mouse button to release the cursor from the spectrum. Click on sw-sfo1 while the expanded region is displayed. This adjusts sw so that it has the same value as the expanded region and also adjusts o1 (and thus sfo1) so that the carrier frequency lies in the center of the expanded region. (You can verify these changes by checking the eda table.) Notice that by reducing the spectral width, the acquisition time aq is increased while the parameter fidres is reduced. Finally, now that the acquisition parameters are optimized, it is a good idea to repeat the automatic receiver gain adjustment (rga).  Notice that since the spectral width has been changed, it may be necessary to readjust the phase correction.

 12.  Integrating the Spectrum

 A.  It is often useful to integrate ¹H spectra. The simplest way to define the integral range is by entering abs. The command abs performs an automatic baseline correction and also automatically defines the integral ranges.  The integrals will not appear on the screen, but will appear on the plot.

B.  To display the integral on the screen:

Choose Analysis/Manual integration from the menu, or simply click on the integrate button of the button panel at the left side of the XWIN-NMR window.  Additional buttons, like those that control vertical and horizontal scale for the spectrum, will appear in the lower left.  The upper part of the button panel is identical to the standard layout, and allows you to shift and scale the integral data on screen. In addition, there are three special sections headed by current:, all:, and mouse:. The command buttons in these sections work on the current integral marked by the user, on all integrals on the screen, and on the mouse sensitivity, respectively.

Defining integration regions

Move the cursor into the data area of the XWIN-NMR window. Click the left mouse button. The cursor is now bound to the spectrum, and moves along the spectrum trace when you move the mouse. It can be released from there by clicking the left button again. Clicking the middle button will mark the current position (the mark can be removed using the right button). Clicking the middle button a second time at a different cursor position will define the area between the mark and the current cursor position as the integration region, and the corresponding integral trace is displayed along with the value of the area under the integral. By default, the first integral region defined will be assigned the value 1.0. This procedure can be continued for all desired regions, and need not proceed left to right. Click the left button to release the cursor from the spectrum when you are finished.

In order to mark one of the defined integrals as current integral, move the cursor into the data area of the XWIN-NMR window. Click the left mouse button. The cursor is now bound to the spectrum, and moves along the spectrum trace when you move the mouse. Select the integral you want to make the current integral by moving the cursor under it, and release the cursor by clicking the left button again. The integral will be marked with an asterisk. All button panel commands in the section current: can now be applied to this (and only this) integral.

To calibrate the integrals, mark an integral as the current one, then click on calibrate.  Enter the integral value in the dialog box.

When all integral regions have been defined, click on return. Click on save as ‘intrng’ and return to save the regions to a disk file.

13.  Peak Picking

The most straightforward way to produce a peak list is through the command line.  First display the Y axis in cm, if it is not already displayed.  The Y button to the left of the spectrum window will toggle the y-axis, the YU button will change the units from cm to absolute.   Choose the region for peak picking by setting the parameters f1p and f2p to the ppm values for the left and right limit, respectively. (If the x-axis is in Hz, use f1, f2 instead of f1p, f2p.) Set the parameter mi to the desired minimum intensity in cm.  Type edo and check that CURPRIN is set to hplj5l. The command pp will produce a peak listing on the printer.  Use pps to print to the screen.

14. Plotting the Spectrum

A straightforward way to plot 1D spectra is by using most of the plotting parameters found in the plot parameter file standard1D. Read in the file by choosing File/Copy/parameters from file from the menu, selecting standard1D from the menu of parameter file names, and then selecting plot from the menu of parameter file types that appears.  Then click on Copy. This sets the plotting parameters to values appropriate for most 1D spectra.  1D and 2D Plotting Parameters’. For basic 1D spectra no changes need to be made within the parameter menu edg itself; however, the spectral region and the integral range must be defined, and the spectrum title must be written. To select the spectral region (full or expanded) to be plotted, first make sure the spectrum appears as desired on the screen, and then click DP1and simply hit return in response to the following three (3) questions:

F1 = <return>

F2 = <return>

Change y-scaling on display according to PSCAL?<return>

You may change the values of F1 and F2 if you wish.

Other plot parameters can be changed by typing edg (edit graphics) and changing the values, mostly yes/no, which determine whether integrals, parameters, etc appear on the plot. The edg window is analogous to the DPO command on the AM-300. Some plot features have a button labeled ed.  Clicking on this button will open another window, with parameters that control the position and style of these features.  If simply editing the yes/no parameters in the edg dialog box will not give the plot you want, it is usually easier to use XWIN-PLOT, rather than to change other plot parameters.  XWIN-PLOT is a graphical plot layout program.

Next create a title for the spectrum. Enter setti to use the editor to open the title file. Write a title and save the file.  The title must end with a <return>.

To preview the plot, as it will appear on paper, type view.

To plot the spectrum, type plot (provided the correct plotter is selected in

edo).

(ICH definition – International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use)

(ICH definition – International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use)

Adverse Drug Reaction (ADR)

In the pre-approval clinical experience with a new medicinal product or a product’ s new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions (the phrase ‘ responses to a medicinal product’ meaning that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out).

Regarding marketed medicinal products:  a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function.

Adverse event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Applicable regulatory requirement(s)

Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.

Approval (in relation to Institutional Review Boards)

The affirmative decision of the Institutional Review Board (IRB) that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.

Audit

A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data recorded, analysed and accurately reported, according to the protocol, sponsor's SOPs, GCP, and the applicable regulatory requirement(s).

Blinding

A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s), being unaware of the treatment assignment(s).

Case Report Form (CRF)

A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

Clinical trial/study

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.

Clinical trial/study report

A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see ICH Guideline for structure and content of Clinical Study Reports).

Compliance (in relation to trials)

Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements. Confidentiality Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.

Contract

A written, dated, and signed agreement between two or more involved parties that sets out any arrangements regarding delegation and distribution of tasks and obligations and, if appropriate, financial matters. The protocol may serve as the basis of a contract.

Direct access

Permission to examine, analyse, verify, and reproduce any records and reports that are  important to evaluation of a clinical trial. Any party (e.g. domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and the sponsor’ s proprietary information.

Documentation

All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.

Essential documents

Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.

Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

Impartial witness

A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’ s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.

Independent Ethics Committee (IEC)

An independent body (an institutional, regional, national, or supranational review board or committee), constituted of medical professionals and non-medical members, whose responsibility it is to ensure protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, suitability of the investigator(s), facilities, and methods and materials to be used in obtaining and documenting informed consent of the trial subjects.

The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.

Informed consent

A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.

Inspection

The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’ s (CRO’ s) facilities, or at other  establishments deemed appropriate by the regulatory authority(ies).

Institution (medical)

Any public or private entity or agency or medical or dental facility where clinical trials are conducted.

Institutional Review Board (IRB)

An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and materials to be used in obtaining and documenting informed consent of the trial subjects.

Interim clinical trial/study report

A report of intermediate results and their evaluation based on analyses performed during the course of a trial.

Investigational product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Investigator

A person responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the Principal Investigator.  See also Sub-investigator.

Investigator/institution

An expression meaning  ‘ the investigator and/or institution, where required by the applicable regulatory requirements’ .

Investigator's Brochure (IB)

A compilation of the clinical and nonclinical data on the investigational product(s) relevant to the study of the investigational product(s) in human subjects.

Legally acceptable representative

An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.

Monitoring

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory requirement(s).

Monitoring report

A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’ s SOPs.

Multicentre trial

A clinical trial conducted according to a single protocol but at more than one site, and therefore carried out by more than one investigator.

Opinion (in relation to Independent Ethics Committee)

The judgement and/or advice provided by an Independent Ethics Committee (IEC). Subject/trial subject An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.

Subject identification code

A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial- related data.

Protocol

A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term ‘ protocol’ refers to protocol and protocol amendments.

Protocol amendment

A written description of a change(s) to, or formal clarification of, a protocol.

Quality assurance (QA)

All those planned and systematic actions that are established to ensure that a trial is performed and data generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and applicable regulatory requirement(s).

Quality control (QC)

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.

Randomization

The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.

Regulatory authorities

Bodies having the power to regulate. In the ICH GCP guideline the expression  Regulatory authorities includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities.

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)

Any untoward medical occurrence that, at any dose:

- results in death,

- is life-threatening,

- requires inpatient hospitalization or prolongation of existing hospitalization,

- results in persistent or significant disability/incapacity,

or

- is a congenital anomaly/birth defect

- results in important medical events that may not be immediately life-threatening or results in death or hospitalization but may jeopardize the patient or may require intervention to prevent the other outcomes listed above.

Source data

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

Source documents

Original documents, data, and records (e.g. hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, laboratories and medico-technical departments involved in the clinical trial).

Sponsor

An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

Standard Operating Procedures (SOPs)

Detailed, written instructions to achieve uniformity of performance of a specific function.

Study site/Trial site

The location(s) where trial-related activities are actually conducted

Sub-investigator

Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or make important trial-related decisions (e.g. associates, residents, research fellows). See also Investigator.

Trial site/Study site

The location(s) where trial-related activities are actually conducted. Unexpected

Adverse Drug Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH guideline for clinical safety data management: Definitions and standards for expedited reporting).

Well-being (of the trial subjects)

The physical and mental integrity of the subjects participating in a clinical trial.

Reconciliation of the Serious Adverse Events

Reconciliation of the Serious Adverse  Events

Requirement:

3.1 Reconciliation of SAEs captured during the conduct of clinical research trials and SAEs recorded in the Safety Database will occur several times during the lifecycle (the conduct) of the clinical research trial. 

3.2 Timing and number of the reconciliation cycles will be determined by the frequency of data received, the scheduling of safety updates and the timing of interim and final reports to regulatory authorities on serious adverse event findings.

3.3 The capture of SAEs in both the clinical trials database and the safety database should be standardized with regard to data captured and coding of terms (e.g., event description, start and stop date, relation to study drug, verbatim term coding, etc.). 

3.4 All information (data and metadata elements) to be reconciled during this procedure shall be identified and documented in the study plan before the first patient is enrolled in the clinical research protocol.

3.5 A cut-off point will be identified in the study plan, after which, no SAEs will be added to the clinical research database, even if the safety database is updated. 

3.6 Changes to either database, as a result of reconciliation activities, will be made in a timely manner to expedite clinical study closure activities and/or safety reporting requirements.

3.7 Local QA formally conducts a review of the reconciliation results for accuracy

Role	Responsibilities
Study Coordinator	 Work with the Drug Safety Officer and the Clinical Research Study Team to reconcile SAEs captured in the clinical data management application with SAEs captured and recorded in the Safety Database.  Make the necessary changes and/or updates to the clinical data management application.
Drug Safety Officer	 Assist in reconciling SAEs in line with this SOP  Make the necessary changes and/or updates to the Safety Database.
Clinical Study Team	 Provide the necessary clinical information or interpretation input on SAEs captured during the conduct of the clinical research trial, including input on coding of events
Local QA	 Conduct a formal review of the reconciliation processes and performs a quality check on updates to the databases.

Conduct of Clinical Research study

Conduct of Clinical Research study

Role	Responsibility
Study Coordinator	 Maintain and update the study plan for managing clinical data collected in accordance with protocol specifications and/or requirements.  Receive data and log receipt of CRFs in a timely and appropriate manner.  Transfer or hand-over received CRFs to the relevant entry personnel for processing.  Perform overall discrepancy resolution and data validation checks in line according to agreed timelines.  Resolve all coding issues prior to locking the database.  Reconcile the SAE data with adverse event data collected in the clinical study in line with the SOP on SAE Reconciliation.  Create, submit and manage queries to investigator or clinicians monitor the clinical research trial.  Manage data updates and/or query closure(s) responses from the investigator or monitoring personnel.  Manage the timely loading of electronic data from external sources (e.g., patient positions, site and investigator information from C3PR; laboratory data; or, other electronically submitted data for the conduct of the clinical trial).  Manage clinical study conduct activities through data freeze and lock activities.  Manage the export of extract data views or datasets to clinical trials personnel (e.g., statistician for analysis; PI or clinical monitoring personnel for data review; QC for audit activities, etc.).  Ensure coding of data are consistent with the coding guidelines as detailed in the plan for the specific study.  Log all coding discrepancies or non-matches.  Take action on coding discrepancies with the Drug Safety Office in a timely and consistent manner for resolution.  Manage timelines for issue resolution and communicate coding review completion to clinical data manager.
Data Entry	 Input CRF response data received in line with this SOP.  Manage the timelines for completion of the data entry activities to meet study milestones.  Flag or indicate any outstanding data entry issues or items for review and resolution by data management or clinical monitoring personnel.  Update data, when applicable, and when access is appropriately assigned.
Clinical Investigator	 Review data queries to respond to concerns or questions from clinical data management.  Resolve queries by appropriate means (e.g., data correction; no additional information; data recorded is correct).  Contact the clinical data manager if additional clarification is required.  Resolve with Clinical Data Manager any clarification issues.
Drug Safety Office	 Provide input required during coding review in a timely and adequate manner and according to request submitted.  Provide all drug safety input required for resolution of coding review issues.  Assist in reconciling the adverse events capture in the Safety Database with the adverse events captured in the clinical data database - in line with SOP on SAE Reconciliation.  Assure drug safety requirements are met according to protocol requirements and regulations, prior to unblinding
Local QA	 Assure all data are entered and cleaned in line with the GCP guidelines.  Audit data to verify all quality standards are met during performance of the process.  Suggest necessary corrections and assure changes are implemented, making the rationale behind changes clear and fully understood.  Provide detailed advice / guidance on any data quality matters.  Assure that error levels meet the predetermined acceptable levels as defined in the study plan.  Indicate areas of further quality improvement, document recommendations and provide input on issues to the clinical research team members
Statistician	 Assure that there is sufficiently clean data on subjects to run analysis programs.  Work with clinical data manager to update study plan if the statistical analysis plan changes and if those changes reflect collection request for data or new CDEs.
Analytical Programmer	 Review and test analysis programs for functionality, utilizing identified test data and assure that the testing process is closely monitored throughout.  Resolve any analysis program malfunctions to ensure optimal program performance.  Modify analysis programs in line with input from Statistician and following the relevant specifications.