Introduction to Clinical Research

Clinical Research:

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more test article(s), and/or to identify any adverse events to one or more test article(s) and/or to study absorption, distribution, metabolism, and elimination of one or more test article(s) with the objective of ascertaining its (their) safety and/or efficacy.

Clinical Trial:

Any investigation, controlled exposure of human to investigational product with the object of ascertaining its safety and/or efficacy.

Clinical Trials are carefully designed scientific studies aimed at finding out the safety and efficacy of a particular drug or intervention. They answer the following questions regarding a drug or an intervention: Is the drug safe? Does it work? Is it safe when used over a long period of time?  Does it work in many people over a long period of time? Are there any long term side effects?

Clinical Trial participants:

Sponsor

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

CRO

A person/organisation contracted by the sponsor to perform one or more of a sponsor’s trial related duties and functions

Monitor (CRA, SM)

Person appointed by the Sponsor to perform monitoring

(…and many other things…)

Investigator:

A person responsible for the conduct of the 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.

Institution (medical)

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

Regulatory authorities:

Body having the power to regulate.

Review submitted data and conduct inspections.

Institutional review board (IRB)Independent Ethics Committee (IEC)

Independent bodies whose responsibility is to ensure the protection of the rights, safety and well being of human subjects involved in a trial.

Subject/Trial subject

An individual who participates in a clinical trial, either as a recipient of the investigational product or as a control

Trials are conducted by the Good Clinical Practices (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.

From idea to marketed drug

PRE-CLINICAL STUDIES

In vitro tests:laboratory experiments to find out if a new drug works on human cells in test tubes. Animal studies: These are meant to ascertain efficacy and safety of the drug or intervention in living creatures. 

Non-clinical studies:

•         Pharmacology profile

•         Pharmacokinetics

•         Toxicity testing

•         Reproductive toxicology

•         Carcinogenicity studies

•         Genotoxicity

Types of Clinical trials:

•         Randomized controlled trial: divides participants randomly into two test groups using computer generated random numbers;

•         Double-blind controlled trial: ensures that neither the participants nor the researchers know who has received which treatment;

•         Randomized double-blind controlled study: which combines both control measures.

•         Randomized open label placebo controlled cross-over trial

CLINICAL TRIALS DESCRIPTION

Phase1: Safety trials.

Phase 2: The dose that has been found to be safe in phase1 is given to a larger number of participants over a longer period of time to see if the drug really works and see if there are long term side-effects.

Phase 3: The trial drug is given to a much larger group of participants usually in many research centers (multi-center trials) over many months or even years to see if the drug remains useful or has any side effects that only show after long term use.

Phase 4: Post-marketing trials. These trials could as well be called ‘surveillance’ studies because they are meant to monitor side-effects or problems that may show up after several years of use.

Phase I

(6 m -1 year)

Inital administration in humans

First time a new compound is tested in human subjects (determine PK and PD – how and how well the drug works).

Phase II

(months-4 year) ~2 years

Exploring the therapeutic effect in patients (exploratory)

Investigate the effect of the drug in subjects with the disease for which the drug was developed.

Phase III (IIIa, IIIb)

(1-4 year) ~3 years / several years

To demonstrate or confirm therapeutic benefit (confirmatory)

Well-controlled comparative trials designed to assess safety and efficacy of the drug

IIIa – before marketing application / regulatory permission request, less subject than III/B

IIIb – answering questions of the studies (can be open labeled)

Phase IV (from months to years)

To demonstrate or confirm therapeutic benefit. Post marketing studies, for optimising the drug’s use e.g. additional drug-drug interaction

Clinical trial phases - summary

Good Clinical Practice

(see also the printed EMEA document)

An international ethical and scientific quality standard for designing, conducting, recording, monitoring, auditing, analyzing, and reporting of clinical trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the data and reported results are credible and accurate, and that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki.

All study participants must comply with GCP

•         All individuals involved in any aspect of the trial must be suitably ‘qualified’ to be able to comply with GCP.

•         Sponsors/CIs are responsible for ensuring that all staff are able to comply with GCP.

How…?

- Follow Protocol exactly (except in emergency situations)

- Personally conduct or supervise investigation

- Determining inclusion/exclusion criteria and enroll only those patients who are qualified

- Performing all required safety/efficasy tests specified by the protocol

- Collecting all requred parameters/values required by the protocol

- Avoiding changes unauthorized by Sponsor

- Conducting visits

- Reviewing concomitant medication taken and procedures performed

- Considering completing withdrawal processes

THE PRINCIPLES OF GCP

1. Clinical trials should be conducted in accordance with the ethical principles and consistent with GCP.

2. A trial should be conducted only if the benefits outweighs risks to both the subjects and society.

3. The rights, safety, and well-being of the trial subjects and society.

4-5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

6. A trial should be conducted in compliance with the protocol that has been approved by the IRB/IEC.

7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.

10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting,interpretation and verification.

11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should

   be used in accordance with the approved protocol.

12+1 Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Compliance with GCP

Basic questions:

Is the design scientifically and ethically sound?

Is the Study Protocol Clinically, ethically and scientifically sound?

Is there an Informed Consent Process following international ethical standards?

Is there an efficacy and safety monitoring system in place?

Is there a quality assurance system in place at all levels of the study process (screening, enrollment, data collection / recording, patient monitoring, data entry)?

Is there evidence that the trial drug has been produced under GMP?

THE CORE CLINICAL TRIAL PROCESS (the 5 steps)

•         Screening

•         Enrollment

•         Treatment (Patient / Data / TA management, recording)

•         Discharge

•         Follow-up

Screening

-  (Inclusion-exclusion) CRITERIA

Enrollment (RANDOMIZATION)

•         Assess for admission to study (See Inclusion Criteria).

•         a general physical exam including: Temperature, Pulse, BCS, assess Pallor, Jaundice, Petechiae.

•         Llab investigations

•         Informed Consent from Parent or Guardian if patient qualifies for study.

•         Enroll the patient and give Identification Number (IN),

•          Admission Routine as per Flow-sheet or CRF

Blinding: open label, single blind, double blind

Informed consent procedure

Is the consenting people qualified for the consent procedure?

Amended consent has been signed timely by the affected patients

All subject will sign and date their consent prior to any study-related procedure. Site must maintan the original, signed ICF with each subject’s source documents. Informed consend amendments require reconsenting of all existing subjects.

Laboratory Procedures

•         Timing

•         Quality control

•         Communication with Clinical staff

•         Storage of specimens for transportation

•         Labeling: Name, Age, Sex, Date, Time, Study No

III. - Data and Safety Monitoring

•         Includes Clinical care of the patient

•         Ensures the safety and wellbeing of the patient

•         Data Safety Monitoring Board

•         The Flow-sheet: Follow the flow-sheet

IV. - Discharge Procedure

•         Discharge orders as per flow-sheet

•         Ensure that PI has all contact person’s full name and residential address

•         Inform the parent or guardian who they should see on review, when and where.

•         Give name of all alternative persons for the parent/guardian to see if at time of review a specific officer is not there,

•         Deal with all possible transport issues necessary,

•         Find out if the address given is permanent or they are just visiting.

V. - Follow up Procedure

•         Ensure that the flow-sheet has all necessary information for follow-up including landmarks to find the village

•         Have a direction map on the discharge/follow up form

•         Field officer to be there at discharge time to appraise himself with the directions and names of contact persons

•         Have good register of all discharged patients

•         Liase well with Clinical monitors

•         Create a computer data base with a ‘prop-up’ facility to remind you of ‘due’ and ‘overdue’(24hours) follow-ups.

•         All defaulting patients must be followed up promptly

Data Management

Data Collection-tools, e.g. Flow-sheets, CRFs

Data entry and storage-data bases, spreadsheets and manual storage (filing).

Data Analysis-data must be entered on data bases or spreadsheets in analysable form

Different computer packages for data analysis.

- Publication and dissemination: Abstracts, Publication into peer reviewed Scientific Journals.

CLINICAL TRIALS IN PRACTICE

I. FEASIBILITY

FROM REQUEST TO QUESTIONNARE ARCHIVING:

Site identification

Occurs after country allocation has been agreed by SPONSOR. Sources may include:

- Regional representative(s) and Regional/Medical Director recommendations.

- Literature, Publications

- Discussions with other SPONSOR representatives

- Investigator databases.

Reviews past performance of the potential investigator:

- Inspections (eg, debarment or restricted lists and investigator disqualifications).

- Internal audit history

- Previous site performance

- Contracting issues

- Previous enrollment data.

Preliminary Contact Form (PCF)

If a PCF is required, the PCF is drafted based on the protocol, operational requirements, and regional input as appropriate. The PCF template and sample cover letter are customized for the study. The study PCF may be customized by a country/region.

PRE- SITE QUALIFICATION VISIT ACTIVITIES:

SITE QUALIFICATION VISIT

This is a critical visit to verify that the site has not only all required physical and technological capabilities necessary to fulfill the requirements of the clinical trial, but to ensure that the potential investigator has an understanding of the sponsor expectations for recruitment,enrollment, and execution of the protocol.

The scope of this visit includes determining if the investigator is qualified to conduct the trial, has adequate staff and subject population, etc. A thorough Site Qualification Visit facilitates choosing the most qualified sites for any given protocol. Conversely, if the Site Qualification Visit is not executed in that manner, it could jeopardize the integrity and timelines of the study.

You may or may not be the SM to whom the site will be assigned, if the site is selected for the trial.

TO PREPARE FOR THE VISIT:

•         Ensure that the PI is available to meet with you.

•         Create a planned visit in eMonitor System

•         If the potential investigative site has more than one location where subjects would be seen, it is your responsibility to visit and assess all satellite locations as part of the SQV. All locations must be qualified.

•         Print off a copy of the SQR guidelines (or save to your desktop)

•         Obtain a copy of the protocol synopsis

•         Prepare yourself and review the synopsis so you are familiar enough to discuss protocol details with the investigator and/or site staff.

•         If you have questions, ASK! PRIOR to going to the site!

•         Usually you receive full protocol training prior to your SIV

•         Obtain a copy of the electronic Preliminary Contact Form (PCF) for review.

•         BE SURE TO VERIFY ENROLLMENT PROJECTIONS

•         Clinical study team may have additional questions for potential sites (these questions will be sent to you prior to the SQV).

If it is determined, that the site is exempt form an on-site SQV, CRA must still write a SQV report.

E.g. the same PI, at the same site, has participated or previously deemed qualified based on a site QV in a same SPONSOR study as the PI within the last 12 months, and no significant changes (eg, in key site personnel, facilities, or data collection) have been identified

Minimum Requirements for Discussion and/or Evaluation, that the PI /Institute…

•         Has adequate documentation of qualifications (eg, medical license or equivalent) to practice in the respective region.

•         Understands the nature of the protocol or investigational plan.

•         Understands the requirements for an adequate and well-controlled study.

•         Has access to an adequate number of suitable subjects to conduct the investigation.

•         Has adequate resources (eg, facilities, equipment, storage, time, and staff) for conducting the clinical investigation.

•         Understands and agrees to follow the SPONSOR trial related processes and expectations.

•         Has a privacy process

DURING THE SITE QUALIFICATION VISIT:

Refer to the SQV CHECKLIST / SQV template you will receive

CLARIFICATION MAY BE REQUIRED FOR THE FOLLOWING ITEMS:

•         Discuss the potential need for increased monitoring frequency relating to monitoring findings/study timelines/data freeze, etc.

•         Assess potential competing studies and if the staff resources are reasonable for the complexity of the trial and volume of procedures.

•         Document all questions/ answers in the Narrative of your report after the visit is completed.

•         Verify that there is a signed and dated Confidentiality and Disclosure Agreement filed on site.

•         Direct access to source documents MUST be discussed prior to a site being initiated and that certified copies of source data as a long-term systematic solution for a site is not acceptable.

•         Review standard of care issues/institutional practices, exercised by the PI or institution.

•         If the potential investigative site has more than one location where subjects would be seen, make sure that you visit any/all locations.

•         Make sure any additional location(s) is documented as being qualified, and include specific addresses (i.e. office locations, floor numbers, etc.)

•         Tour the subject waiting area, exam rooms, source document and Case Report Form storage area (if applicable), Monitoring area, etc.

•         Discuss the following with the Potential Investigator: research/trial experience, inspection history, GCP/ICH training, electronic data capture experience, staff background/roles/training, language issues for staff/subjects.

•         Determine if the site has any specific monitoring rules that restrict the SM from monitoring at the site (e.g. monitors can only come every 6 weeks, etc.)

•         Internet capability/wireless. Inquire about firewall issues.

•         Assess the site having paper or electronic medical records and the need to review those records in the research office vs. medical records away from research staff/records.

•         Document that there is a temperature log kept for the area where Test Article (TA) will be kept. Document how often this log is maintained (Daily, weekly, etc.) and by whom.

•         Verify the capacity for on-site destruction.(if applicable)

•         Verify that the information reported on the ePCF is accurate-especially pertaining to enrollment projections.

•         Document any changes/corrections to the information in the Narrative section of the trip report, but do not make changes to the actual ePCF.

POST VISIT

Complete SQV report.

Remember to enter only information that is factual and do not enter subjective / opinionated information.

Send the document to your manager and the designated personnel from the clinical team.

II. SUBMISSION

Regulatory Process in Hungary:

Submission Components – From Central Study Team:

Cover Letter components:

Sponsor Name, Date, Header/footer, Phase,  Subject,  Protocol#,  Protocol title,  EudraCT#, IMP, Period of use,ASUR dates,Proposed Hun sites with PI, Brief summary, Number of subjects to be enrolled in the MS, Length of trial, Planned start date

Submission Components – Country specific information

Submission Components – Other:

Quality Check:

- Quality Check on Initial Submission package (read all docs carefully, date, version checks)

- Prepare 3 copies of all items (one for NIP one for CEC one for Archives)

- File hardcopy in your office files (binders)

- Update Regulatory Tracker excel sheet (if applicable)

- CTA Archiving Process – follow local SOP

CTA Substantial Amendments (SAs) Requirements:

•         Cover Letter (2 copies)

▫         Reason for Amendment

▫         Reason for Qualifying as a SA

(Core cover letter generally prepared by Central Study Team. However, there is a Hungarian language cover letter that is differs from  the core cover letter, including sites, Hospital name and address, Name of Department, PI names, usually DRAFT letter is available).

•         SA Form hardcopy

•         Updated xml file on CD

•         Summary of changes

•         Amended docs

▫         Track changes version

▫         Clean copy

•         Confirmation of payment to CA!!! (plan ahead)

•         Be careful with supplementary submissions!!!

Local (Member State - specific) Amendments:

III. SITE INITIATION VISIT (SIV)

The general purpose of SIV are:

- to give the site the necessary study information,

- training (on all important details of the study): Protocol and Procedures (Vendor manuals), Safety aspects SPONSOR’s technology and processes (CRF completion), Local Law, clinical trial materials (CRFs, test article and laboratory kits etc.)

- to allow them to recruit patients into the clinical trial in accordance with the protocol and to conduct the clinical trial at an acceptable standard from both a regulatory (ICH/FDA/Local regulations) perspective as well as a business one.

SIV Prerequisites

-All critical documents available in Central Archives

- TA/IP on site (mock TA or training material)

- All other supplies available on site (questionnaires, lab kits, ECG machine, e-diary, etc.) = All vendor material

- Completed Investigator Site File (ISF)

-  electronic data capture accounts are set up

- Necessary trainings for site and CRO personnel

Walk into SIV without surprises, plan visit accordingly, ie, ready to close any remaining training gaps, outstanding training.

Monitor responsibilities during SIV are:

- Ensure the site has all the required regulatory and local approvals to start the trial  

- Review the outstanding action items from the SQR

- Ensure there were no significant changes (e.g. major staffing turnover, change from paper to electronic source documents, enrollment estimate significantly decreased etc) since the site was qualified.

Assess the site’s capability to enroll subjects, randomize subjects, obtain informed consent, unblind (if necessary), complete the CRFs, dispense Test Article. The site should be able to recruit the first subject immediately after the SIV.If there are issues noted at the SIV, corrective actions should be created and implemented as quickly as possible to ensure site is properly prepared to conduct the study!

-.Document who has been trained

- Ensure that the site is aware of SPONSOR’s Policy (not allowing waivers!)

- Comment on IEC re-approval schedule (e.g., quarterly, annually)

- Provide details on the recruitment process

For eCRF studies:

If there are any outstanding training requirements (eLMs) preventing the site personnel from accessing the RDC application (BIR report), please document the details in the issues section. All training requirements should be met prior to the SIV!

SIV Related Documents:

- Delegation of Site Tasks and Signature Record Form (Other name(s): Signature Page)

- Site Information Form

- Subject Master List (Other name(s): Screening and enrollment liste)

- Laboratory documentations (Laboratory Normal Ranges (Reference Values), Laboratory Certificates)

Laboratory-related Documentation:

Local Laboratory (if applicable) to be recorded on the FDA 1572 form or Site Information Form (in Non-IND studies)

- The Laboratory Quality Certificates must be valid from the date of FPFV till the date of LPLV.

- Quality Documents (Laboratory Accreditation (ISO Certificates), Laboratory Certification (established quality control document or external quality assessment))

- Laboratory Normal (Reference) Ranges documents

Must be obtained from the Head of Local Laboratory (if the Protocol requires local laboratory assessments) who will provide a CV and signed statement as well.

The documents should be available no later then the date of SIV. The document must contain at least the study required laboratory parameters. In case of eCRF, sponsor Data Management Team will set up the electronic data capture system at the beginning of the study according to the content of the Lab Normal Ranges Doument (parameters, value ranges, units of measurements)

III. SITE MONITORING VISITS (SMVs)

SMV – General purpose

To ensure:

- that human subjects are protected;

- that the data are accurate, complete, and verifiable from source documents; and

- that the conduct of the trial is in compliance with the approved protocol/amendment(s), GCP, and the applicable regulatory requirements

Preparation for a monitoring visit:

Check out

- previous Monitoring reports for outstanding issues,

- Case Report Forms (CRFs)/Data Clarification Forms (DCFs) for paper CRF studies, reports for  eCRF studies,

- SAE information

- Test article related documentation.

- If an electronic system is being used to store source data and it is not accessible to the SM, then the SM needs to review certified copies provided by the PI or designee.

. If access to the electronic system is provided, the SM needs to ensure that his/her access is only to SPONSOR study subjects (for confidentiality/privacy).

General monitor responsibilities during monitoring visits:

•         drive and execute monitoring plans

•          ensure site GCP compliance

•         monitor safety at the site

•         resolve issues and facilitate open issue resolution

•         write trip reports / follow-up letters

As the main point of contact for the site during a study the SM receives, resolves (directly or by driving resolutions), and documents site communications.

Specific CRA responsibilities during SMV are:

- Document which ICFs (subjects numbers) have been verified and were found valid.

- Reference the latest IND safety report that has been confirmed as received at the site and submitted to the IRB/IEC

- Perform a full review of the Investigator Study File (ISF) at least once every 4 visits (follow the Monitoring Plan)!

- Document the new method for recording source data

- Make sure that all required documentation is transmitted to SPONSOR!
- Provide protocol training of site staff as necessary.

- Provide technical support and training (Can escalate to superusers or appropriate technical support if necessary

- Concerning external vendors:

perform a quality check on everything sent out to external vendors before the first shipment from site:

•         Confidentiality / Blinding

•         Sample labeling

•         Packaging

•         Cold chain maintenance

- If other personnel accompanied the SM on this visit, (e.g., line manager or co-monitor), who and the reason should be captured in the report narrative.

Test Article Accountability, Reconciliation, and Return

Drug Inventory Records (DIRs) must be used at each site even if a site (or its dispensing facilities) has its own forms

All full or partially full test article containers must be returned to the appropriate distribution center, unless documented approval is obtained for their destruction at the site.
 Full or partially full diluents may be destroyed at the site after  test article accountability has been performed by the SM.

Empty TA containers may be destroyed at the site after TA accountability has been performed by the SM.

If a discrepancy is discovered during the verification of TA accountability, instructs the investigator and/or site personnel to investigate and document the outcome on the DIR. If the investigator documents the outcome in a memo, the memo will be referenced in the DIR.

Inventory Record  can be used also for Unassigned (and returned) TA.

IMP temperature and storage requirements

- Site and Investigator are  responsible to monitor and ensure that the IMP is stored and maintained according to the parameters specified in the protocol

- For any deviation the corrective and/or preventive measures must be documented

- At a minimum, the site should have a certified mercury-in-glass thermometer, or other equivalent certified device

- For continous recording devices:

Tracing record is reviewed periodically (eg. weekly), the reviewer signs and dates the tracing

- Room temperature (25 Celsius or below, do not freeze)

- Refrigerated (Store at 2-8 Celsius, do not freeze)

- Frozen

- All out-of-range excursions must be referred to Sponsor Clinical Pharmacy for assessment

Product shall be quarantined and not used/administered until adequate documentation of permission for use is received from Clin Pharmacy.

Weekend Temperature Monitoring: When there is no site staff available, the site should arrange for representative temperature checks at least once per month to ensure that the environment is not substantially different on non-working days

Cold Chain Shipment Tracking:

- This procedure applies to all GMP shipments between 2°C and 8°C during normal winter conditions.

- Use of cold shipping boxes (described in SOPs)

- For all Clinical Supply shipments Cold Chain tracking form must be completed and included with the site shipment paper work. The sites must be trained in the cold chain shipping procedure and the training must be documented.

Test article delivery to sites

TA delivery should be made directly to the named individuals on the delivery note rather than the institution’s reception area

 

Source Data Verification activities (SDV)

For paper studies and non-eCRF studies:

•         Example: Data Monitored During Visit

•         Patient Identifiers (W-R Number)/Visit #s and/or Tests

For eCRF studies only:

•         The SDV activity will be copied into the Narrative section from the RDC application when the report is committed!

Sample documents checked during SDV:

How can the site avoid  DCFs?

Answer each question on CRF. If answer is ‘unknown’, ‘not done’ or ‘not applicable’ write ‘UK’. Write only one character per box, do not leave any box empty. Review spelling and accuracy of informations (be careful with abbreviations). If data needs correction, maintain the audit trail (no white fluid correction inks etc). Review the consistency of the answers.

Site issues

As the Site Manager, CRA is responsible for identifying, escalating (if necessary) and resolving all issues at his/her sites.

If there are any significant issues detected during the site visit the SM must immediately notify the Regional Site manager / medical monitor of the significant issue from the site.  The SM also documents the required action in the Site Monitoring Report and notify the site in writing (follow-up letter) of the agreed action. If immediate action is required the SM should follow up with the site before the next monitoring visit.

Categories of issues:

•         Adverse Event / Safety

•         Essential Documents

•         Informed Consent

•         IRB / IEC

•         Pharmacogenomic

•         Protocol Violation

•         Sample Management

•         Site Management

•         Subject Records

•         Technology

•         Test Article

Issue status:

Open

Closed But Not Resolved: If there is no action that can be taken to rectify that particular instance of the issue

Resolved: Only when there is an actual change to data or the status of documents

The goal is to close as many issues as possible before inserting the report.

Protocol Violation: Issue related to any departure from the protocol that has a significant effect on the subject's rights, safety, or welfare, or the integrity of the resultant study data (e.g., the sponsor's ability to use the data in support of the product). Sponsor will not grant any prospective protocol waivers from eligibility criteria (inclusion / exclusion)!

Issues solving – general process

- Call Regional Site manager / Medical maager

- Contact PI

- Solve the issue (provide necessary documents / data etc.)

- Write a Note to File (if applicable), or Process Memo

- Train the site

- Document the training

Monitor responsibilities after SMV are:

- File the collected documents

- Write a report

- Write a follow up letter

Writing Monitoring Reports

When reporting issues in a Report, consideration should be given to:

- Subject rights and safety

- Data quality

- Protocol compliance(criteria, processes)

- Regulatory and local ethics approval

- Site personnel qualifications and training

Reporting Issues:

Similar issues for a group of patients may be grouped as one issue, e.g., the following five patients were incorrectly dosed. Any open issues are carried over to the next site monitoring report. Most issues are GCP related with the exception of those related to Sponsor systems (technology issues) or additional tests (pharmacogenomic issues) but if in doubt the default of  „Yes” should be indicated.

Clearly indicate:

-What the issue is,

- What the subject number is,

- Whether the issue is closed or not,

- What actions have been taken by the SM, RSM or others to close the issue,

- What action plan has been discussed with the site to resolve the issue,

- What actions and outcomes have occurred to prevent re-occurrence of the issue at the site,

- Whether additional input is required from another person to bring about closure / resolution of the issue, and who is required to provide additional input e.g. RSM, MM etc.

IV. SITE CLOSEOUT VISIT (SCOV)

                                                     (end-of-study-visit)

SCOV – General purpose

- All SAE documentation should be complete

- Documentation should indicate that all IND Safety reports have been submitted to the IRB/IEC

- All CRF/eCRF pages should be sent in house/submitted and all unused (paper) CRFs should be destroyed in a confidential manner

- All specimens should be shipped

- All temperature logs should be available in order to document the storage conditions

- Dosing records for all subjects should be complete

- DIRs should be complete, including unused, unopened, previously returned /empty drug containers

- Documentation of TA destruction

- Check returned TA reception and its documentation, if applicable

-  Verification that the blind was not broken (return of unused blinding envelopes etc.) If blind was broken, verify that SPONSOR was notified in time

- Arrange unused drug return / destruction according to SOPs and contracts

Specific CRA responsibilities during SCOV are:

(see also SCOV checklist, final)

-Review & collect all CRFs, accounting for and destroying unused CRFs

-Make final accounting of all drug (TA) supplies

-Ensure proper arrangements of return / disposal of unused drug and relevant non-drug supplies

-ensure proper arrangements of records archiving

-ensure that PI and site staff are in compliance with GCP / local regulatory requirements

-Remind PI of post-study obligations (records retention, and IRB/IEC informing that study have been completed)

-Performed when there is no further subject activity at the site (LSLV submitted)

-All issues should be closed

-The Record Retention and Publication Policy should be restated

-The Investigator Site File (ISF) should be complete

Documents:

Original Subject Master List (=Screening & Randomization List),

Original Site Visit Sign-in Log,

Original Site Information Form (completed only for non-IND studies), and

Original Delegation of Site Tasks/Responsibilities & Signature Record must be completed

If it is discovered during the site visit that there is an open issue that you will not be able to close within or very close to the 10-day insertion requirement and/or it will require CRA to go back to the site, then a SCOV report should not be completed and instead the visit should be considered an interim visit (SMV)!

Documents that usually must be filed in ISF at SCOV

•         IB (+ updates)

•         Signed protocol & sample CRF (+amendments)

•         Sample ICF  (+amendments)

•         Sample advertisement, if applicable (I/A)

•         Local regulatory documents -e.g. 1572 signed- (+revisions)

•         Financial agreements sponsor-PI (I/A)

•         Insurance

•         Signed agreements (Institute/PI/sponsor)

•         IRB/IEC approval of study (dated), with composition of IRB/IEC

•         CA regulatory approval of protocol (&  amendments)

•         CVs of PI, SubI with qualifications (new staff included)

•         Lab. Normal values & certificates/validations (+ udpdates)

•         Instructions for TA handling (if not in protocol/IB)

•         Shipping record for TA, and related materials

•         SIV monitoring reports (I/A)

•         Relevant communications (SM-site)

•         All subject ICFs, signed

•         Source docs

•         Copies of signed, dated, completed CRFs (I/A)

•         Notificatons to sponsor of SAEs and related reports

•         Updated safety information (ASUR, CTSUR)

•         Interim/annual reports of enrollment to IRB/IEC

•         Subject screening logs, enrollment information (Subject Master List)

•         DIRs, (&final DIR) shipment forms, destruction forms

•         Copy of signature sheet/ Staff Responsibility Form

•         Completed subject ID code list (I/A)

•         Clinical study report (I/A)

•         Copy of the Monitoring Visit Log

End of Trial Notifications

Requirements:

- End of Trial Notification Form (I/A)

- Submission deadlines (note: 90+90 days rule)

- Official Cover Letter

End of Trial Notifications, Hungarian Cover Letter includes (in a table):

Site name& address, Site number, Name of PI, Date of SIV, Date of SCOV, Number of subjects screened, Number of subjects randomized, Number of subjects completed the trial, Number of SAEs, any other important events

Filing of Regulatory Documents:

All Regulatory Correspondence must be filed in Archives (CEC correspondence to be separated). You need to arrange time for translation. Mark the front page of the document to indicate which SA# or NSA# it belongs to. You should file all original hardcopy docs in the office files and update Regulatory Tracker – if used

End of Trial activities:

Within 90 days of completion of the clinical trial in the territory of a MS, the sponsor must notify the concerned CA that the trial has ended. At the end of the trial worldwide the relevant clinical group should inform EU of the end of the trial and provide the end of trial date according to the definition for that trial.Central Study Team completes an end of trial form and obtains approval for the completed form from clinical. Then provides the form to

concerned local affiliates RA and the Clinical Study team Leader.

Follow Up After a Trial is Terminated

If a new event occurs after the termination of the trial that is likely to change the risk/benefit

analysis of the trial and could still have an impact on the trial participants,the sponsor should

notify the CA and ECs concerned and provide a proposed course of action.

 EMEA requires a summary of the clinical trial report within one year of the end of the

trial to the EC(s)and the CA of the MS concerned. The synopsis/summary of the final clinical

study report (CSR)will fulfill this requirement.The format of the report should comply with

ICH E3 guidelines for structure and content ‘as much as possible ’. The report should only be provided to CAs,ECs or investigators according to SPONSOR policies, practices or procedures and should not be distributed unnecessarily as it is likely to contain highly sensitive business information that is required to be kept confidential and shared only on a

need to know basis.

APPENDIX 1:) Summary of CRA tasks

I. FEASIBILITY (generally not a visit)

II. QUALIFICATION (SQV)

III. SUBMISSIONs (-in parallel with other activities)

IV. INITIATION (SIV)

MONITORING (SMV)

CLOSE-OUT (SCOV)

APPENDIX 2: Good Documentation Principles

• Clinical study file documents at the investigator/institution’s site and at SPONSOR / Sponsor’s office must be created at the beginning of the trial.
• The investigator/institution and SPONSOR / Sponsor files must contain all necessary documents before the final completion of a trial.
• Electronic records and signatures are considered equivalent to full handwritten signatures, as applicable per local requirements.
• Paper documents submitted for archiving should be originals or submission quality (high-quality) copies in accordance with local requirements.
• Documents should  be accurate, use clear and objective language,
• Drafts should be clearly labeled as such.
• All work should be documented at the time it is performed.
• Entries should not be predated or backdated.
• Documents and attachments should be consecutively paginated using the format “x (page number) of y (total number of pages)”.

Signature and Initials

• Delegation of signature should be formally documented when required and can be signed usingthe format “signed for <insert name>”.
• Copying and pasting signatures from multiple documents into a single document is prohibited.
• Where individual signatures appear on separate documents, each document must be scannedelectronically, when appropriate, and the original documents retained per local archivingprocedures.

Notes to File/Correspondence

• Provide sufficient information to identify the project, study, and site and/or subject number, if applicable.
• Provide sufficient information for the reader to understand the trail of events or content (eg,specifically address subject safety/conduct of the trial).

Error Correction on Hard-Copy Documents:

• All corrections are made with a single-line strike out(keeping the original entry legible to a reviewer) through the incorrect entry and should be dated and initialed by the person making the correction. A brief explanation may be added, if needed.
• Error corrections should not obscure the original entry (eg, erasures should not be made,correction fluid should not be used).
• Errors of omission should be initialed/dated with current date by the person making the entry and include an explanation.

Corrections should not be made by SPONSOR staff to documents received from investigator sites orother third parties

APPENDIX 3: GLOSSARY OF TERMS

Accreditation - Documentation that a laboratory facility has undergone and passed an examination of its policies, procedures, and performance by an external organization (ie, accrediting body) to ensure that it is competent to perform required tests and to support reliability of those tests.

Adverse event of special interest- Product-specific adverse event designated and transmitted to Global Safety Surveillance & Epidemiology and Global Labeling in the same time frame as a serious adverse event, even if it does not meet serious reporting criteria.

Adverse event with special circumstances -1. Adverse experiences or events (AEs) that, regardless of seriousness, are transmitted to Global Safety Surveillance & Epidemiology in two business days.

2. AEs that, regardless of the absence of objective serious criteria, are always upgraded to medically important and treated as serious AEs (SAEs) (referred to as product specific medically important [PSMI] AEs).

Note: An AE not designated as PSMI AE may, based on medical judgment, still be considered medically important and upgraded to serious in certain circumstances. A designation of “no” under PSMI indicates that the event does not always need to be considered medically important.

3. AEs requiring special follow-up.

4. AEs that are expedited to regulatory authorities regardless of whether they meet the regulatory criteria for expedited reporting.

Adverse experience or event-  Any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a person administered a Sponsor product or enrolled in a Sponsor study. The event does not need to be causally related to the Sponsor product or Sponsor study. An adverse experience or event (AE) includes, but is not limited to:

1. Any clinically significant worsening of a pre-existing condition.

2. An AE occurring from overdose of a Sponsor product, whether accidental or intentional.

3. An AE occurring from abuse (e.g. use for non-clinical reasons) of a Sponsor product.

4. An AE that has been associated with the discontinuation of the use of a Sponsor product.

5. For spontaneous reports and reports from post-marketing studies, any failure of expected pharmacological action. For over-the-counter products, the recommended daily dose must be administered before failure of expected pharmacological action can be attributed.

6. Any spontaneous device report resulting from the malfunction of a Sponsor device.

An AE's causal relationship to the product has no bearing on the AE's reportability.

Affiliate - Sponsor operating unit conducting business outside the United States.

Alternative reference range - Range obtained from accepted medical references such as textbooks, journals, or assay validation documentation.

Analysis and Database Design - Process of determining what data needs to be collected and how it should be recorded, processed, and analyzed.

Appendix - Ancillary documents that accompany the clinical study report.

Archive - To store documents for short-term or long-term to enable future access.

Assay - Analysis performed to find and/or measure the amount of a specific substance.

Assay  validation:               Procedures demonstrating that a particular method used for the measurement or detection of a substance in a given biological matrix (ie, body fluids, tissue) is reliable and reproducible for its intended use.

Assent form:        Form, based on the main informed consent form, used to document a subject's affirmative agreement to participate in a trial, after having been informed about the trial to the extent compatible with his or her understanding. Used when the trial includes subjects (eg, minors, individuals with severe dementia) who can only be enrolled with the consent of the their legally acceptable representatives, assent forms only contain elements appropriate for the audience.

Assigned publication writer:           Generic term to describe an individual who assists the publication author(s) with preparation of the publication.

Audit:    Systematic and independent examination of GCT processes, systems, or trial-related activities and documents to determine whether the evaluated trial-related activities were conducted and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor's standard operating procedures, Good Clinical Practice, and the applicable regulatory requirement(s).

Audit report:        A written evaluation by the auditor(s) of the results of the audit.

Audit Trail:  Documentation that allows reconstruction of the course of events.

Authorized unblinded staff:             Generic term to describe Sponsor staff or staff delegated by Sponsor (eg, contract research organization staff) identified in the study documentation as having approval to access treatment assignments and/or unblinded study information.

Back-translation:               Process of translating a document that has already been translated back to the original language for the purpose of verifying the accuracy and completeness of the original translation.

Biomarker:          Component that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.  This excludes routine clinical testing.

Biostatistician      Staff: responsible for applying statistical methodology to the analysis of clinical data.

Blinding A procedure in which 1 or more parties to the trial are kept unaware of the treatment assignment(s). Single blinding usually refers to keeping the subject(s) or the investigator(s) unaware of the treatment assignments. Double-blinding usually refers to keeping the subject(s), investigator(s), and the sponsor staff or representatives (ie, contract research organization staff) involved in the clinical evaluation of the subjects unaware of the treatment assignments.

Business day       Any day except weekends, December 25, and January 1.

Business partner                 Non-Sponsor company with which Sponsor has a contractual relationship regarding developing, marketing, distributing, or manufacturing (for example, a co-marketer, a licensing partner, a joint venture, or a co-manufacturer of a Sponsor product).

Case report form(CRF):    Printed, optical, or electronic document designed to record the protocol-required information to be reported to the sponsor on each trial subject.

Causality assessment:      An assessment of the likelihood that there is a reasonable possibility of causal relationship between test article and an adverse experience or event (AE). All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a product qualify as adverse reactions/adverse drug reactions. When assessing relationship between a test article and an AE, the following parameters are considered:

1. Is the causal relationship reasonable based on clinical judgment and given the current available data causality options and definitions?

2. Temporal relationship between the test article/protocol and the AE.

3. Biologic plausibility of relationship.

4. Subjects' underlying clinical state or concomitant agents/therapies.

5. Where applicable, does the event abate on discontinuation of the test article (dechallenge).

6. Where applicable, does the event reappear on repeat exposure to the test article (rechallenge).

Note: Causality assessments are not collected for other reportable information unless there is also a serious adverse event (SAE).

7. Causality options and definitions:

The relationship of each AE to test article must be recorded on a binary scale, answering yes or no to the following question: “Is there a reasonable possibility of a causal relationship between test article and AE?”:

a. Yes: There is a reasonable causal relationship to a test article, i.e., related.

b. No: There is not a reasonable causal relationship to the test article.

i. If not related to the test article, assess relationship to the protocol.

c. The phrase “reasonable causal relationship” means to convey in general that there are facts, evidence or arguments to support a causal relationship with test article.

Note: When an investigator assesses there is a reasonable possibility of a causal relationship between test article and AE or if the investigator does not provide an assessment (considered unknown), the relatedness assessment defaults to product-related for regulatory reporting purposes.

Central laboratory:            Laboratory that performs processing, management, and/or analysis of specimens collected from all or several investigational sites participating in a Sponsor-sponsored study.

Certification:       Documentation that a laboratory facility has passed an inspection survey performed by a government agency.

Certified copy:     Copy of original source document/information that has been verified, as indicated by a dated signature, as an exact copy having all of the same attributes and information as the original.

Change request:                 Documented request to modify or enhance a computer system.

Child assent form                Form used to document a child's affirmative agreement to participate in a clinical trial.

Classification dictionary: Reference source used to standardize medical terminology (eg, adverse events, medications, medical history).

Classified information:     Information that affords its owner a competitive advantage. Within Sponsor, this term collectively describes restricted and confidential information.

Clean patient group:          A subset of data that has progressed through the data-cleaning process including data validation. The amount of data, cleanliness, and timing of release are defined in the data review plan.

Clinical endpoint:               Target measurement described in the protocol of a clinical trial.

Clinical grant        Authorization to commit funds directly related to a clinical trial (eg, investigator payments, medical tests, investigational product).

Clinical hold:       Order issued by a regulatory authority to delay a proposed investigation or suspend an ongoing investigation.  Clinical holds may be complete (applicable to all studies with the investigational product) or partial (applicable to specific studies or study sites).

Clinical investigator:        Any investigator or subinvestigator listed or identified (eg, on the Form FDA 1572) who is directly involved in the treatment or evaluation of research subjects. For the purpose of financial disclosure the term also includes the spouse and each dependent child of the investigator.

Clinical manager:              Generic term to describe a member of the team responsible for coordinating the scientific execution of a study. The clinical manager is the liaison between the medical science strategy team and the operations trial execution team and may perform some of the scientific tasks during the study (eg, develop the protocol and informed consent form, conduct clinical safety data reviews).

Clinical Project Team (CPT):         Single team responsible for planning and executing the clinical plan, directed by the global clinical program leader.  Clinical Project Team is responsible for the clinical strategic input into the clinical plan and for overall management of the project (ie, guiding the study team(s) to perform the studies and prepare reports).

Clinical scientist:              Generic term to describe an individual responsible for providing medical and scientific study-level support in conjunction with the global medical monitor.

Clinical study agreement (CSA, CTA)          Agreement between Sponsor and the institution (any public or private entity or agency) controlling the terms and conditions under which a clinical study is performed.→

Clinical Trial Agreement

Clinical study report:        Written description of a 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 report and its appended material.

Clinical trial (interventional):         Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more test article(s), and/or to identify any adverse events to one or more test article(s) and/or to study absorption, distribution, metabolism, and elimination of one or more test article(s) with the objective of ascertaining its (their) safety and/or efficacy. This includes clinical trials carried out in either one site or multiple sites, whether in one or more than one country.

Clinical trial (noninterventional):  Study in which the medicinal product(s) is (are) prescribed in accordance with the terms of the marketing authorization. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiologic methods shall be used for the analysis of collected data.

Clinical trial application: Generic term to describe a request submitted to the applicable regulatory authority to conduct trials of an investigational product in humans (eg, Investigational New Drug application, Clinical Trial Authorisation, Clinical Trial Notification).

Clinical trial assistant      (CTA): Generic term to describe an individual who supports clinical trial execution by performing specific operational tasks and supporting the study team(s) as appropriate.

Clinical trial safety update report (CTSUR):               A safety report that is produced and delivered at regular time intervals or as necessary to meet regulatory and local law requirements.

Clinical writer:   Generic term to describe an individual responsible for the planning and preparation of clinical regulatory or publication documents.  Clinical writers work with other subject matter experts from the project team to draft and finalize clinical documents necessary to support clinical development, registration, and marketing of a product.

Company information:       Information that is proprietary in nature. It includes information that may or may not have achieved trade secret status, as well as business-related personal information. Company information may take many forms; for example, notebooks, letters, memoranda, hard drives, computer disks, photographs, tapes, cards, printouts, dictation disks and tapes, proofs, reproduction masters, drawings, videotapes, slides, reports, typewriter ribbons, chemical rolls from facsimile machines and photocopiers, magnetic tapes and cards, microfilms, telecommunications, electronic communications, and verbal communications.

Compliance:  Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, and the applicable regulatory requirements.

Computer system requirement:      Condition or capability that a computer system or system component must meet or possess to satisfy a contract, standard, specification, or other formally imposed document. A computer system requirement specifies a function that the system must be capable of performing, defines what the system is expected to do, and/or describes the context in which the system will operate.

Computer system validation:           Confirmation by examination and provision of objective evidence that a particular computer system requirement for a specific intended use can be consistently met.

Confidential disclosure agreement (CDA):  Agreement preventing disclosure of confidential information other than to authorized individuals.

Confidential information: Information that is either trade secret, proprietary or personal in nature, and/or which describes the commercial, financial, or scientific/technical operations of the Company or its business partners.

Consultant:          Healthcare professional, opinion leader, or other professional (eg, medical, pharmacy, or scientific) who has specialized skills or knowledge and who provides paid services, information, or advice that Sponsor needs and intends to use.

Contract research organization (CRO):       Person (including independent contractor[s]) or organization to whom the sponsor has transferred the responsibility for one or more of a sponsor's obligations, trial-related duties, and functions.

Core claim:          Factual statement or assertion regarding a product’s efficacy, safety, tolerability, or use that supports global brand positioning and is supported by adequate scientific evidence.

Core Data Sheet:                Also known as Core Labeling. Sponsor Research internal reference information for the creation or revision of country or regional medical labeling. Developed and maintained by the Global Labeling Division, the Core Data Sheet includes the minimal information, including safety information, that the company believes should be submitted to regulatory authorities for inclusion in medical labeling in all countries where the product is marketed.

Country prototype informed consent form: Model informed consent form (ICF) used as the basis for site-specific ICFs in a particular country. Based on the study prototype ICF, the country prototype ICF incorporates content that is required by the country's laws and regulations and/or a central institutional review board/independent ethics committee.

Covered clinical study:      Any study of a drug, device, or biological product in humans submitted in a marketing application or reclassification petition that the applicant or the US Food and Drug Administration relies on (ie, IND studies) to establish that the product is effective or any study in which a single clinical investigator makes a significant contribution to the demonstration of safety.

• Covered studies include phase 1 studies that are critical to an efficacy determination, most phase 2 dose-ranging studies, phase 3 efficacy studies, studies of bioequivalence to an effective (ie, approved) product, and phase 4 studies in support of additional indications.

• Studies that are generally not covered include phase 1 tolerance and pharmacokinetic studies (including bioequivalence studies to link formulations, such as studies to show bioequivalence between an early-phase formulation and a formulation to be used in phase 2 or phase 3 trials, most clinical pharmacology studies (unless they are critical to an efficacy determination), large open-label safety studies conducted at multiple sites, and compassionate-use and treatment protocols.

Curriculum            A set of planned learnings for a given job function or role.

Customized response         Text that is derived from a standard response that is intended for a one-time response to a specific product inquiry.

Data blinding requirements:           Specifications (other than treatment and randomization) to mask data or data points, as detailed in the protocol.

Data clarification form (DCF):        Form utilized in studies using paper case report forms that contains a list of queries used to clarify discrepancies identified in the clinical data reported on case report forms. This form documents modifications (changes, additions, or corrections) made to the clinical database after the initial data entry, and records the investigator’s endorsement of such modifications.

Data monitoring committee (DMC):              Group established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and/or the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop the trial.

Database view:     Presentation of data in a format that allows the viewer to see prespecified data categories to perform clinical data review, statistical analysis, and reporting.

Date received by Sponsor:                Date any Sponsor employee (including an employee of a Sponsor Affiliate) or agent of Sponsor (including contract research organizations) receives or learns of the adverse experience or event (AE) or other reportable information, for example, oral communication, telephone call, letter, fax, or electronic transmission.

1. First business day following the “date received by Sponsor” is considered business day one for purposes of reporting to Global Safety Surveillance & Epidemiology.

2. Examples of date received by Sponsor:

a. Date Sponsor receives AE information from post-marketing study from a Business Partner.

b. Date the Local Medical Monitor received AE information.

c. Date the Sponsor employee first received AE information in an e-mail.

d. Date the Product Quality Specialist received AE information.

Designee:             Person with the appropriate qualifications to whom the responsible person delegates a task without relinquishing responsibility for that task.

Deviation:             A departure from one or more process steps described in a standard operating procedure or a standard practice instruction. A deviation may be:

•              prospective – a departure from one or more process steps anticipated and for which authorization is requested before the deviation takes place.

•              retrospective – a departure from one or more process steps identified after it has already occurred and for which authorization was never granted prospectively.

Direct Access:  Permission to examine, analyze, 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, sponsors, 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 subject’s identities and sponsor’s proprietary information.

Disclosure statement:       A completed Form FDA 3455 for all clinical investigators for whom a certification statement is not prepared that completely and accurately discloses any financial interests and arrangements as described under “Disclosable financial interests” above, and any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments.

Discrepancy:       Data issue that is identified during manual or electronic (edit validation check) review.

Document:            Records of any media type (eg, paper or electronic versions, text, graphic, CDs, microfilm, videotape, audio, pictorial, data, or other materials, regardless of form or characteristics).

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.

Document owner:               Person responsible for the quality and proper handling of documents either generated or collected by them and/or who is ultimately responsible for that information.

Double-blind sponsor unblinded study:         Study in which the subject(s) and the investigator(s) are kept unaware of the treatment assignment(s).  The treatment assignment(s) are known to the sponsor staff or representatives (ie, contract research organization staff).

Drug supply management:               Generic term to describe individuals responsible for coordinating and monitoring a study drug supply for clinical trials (eg, Chemical Pharmaceutical Development, Clinical Supplies Manufacturing and Distribution, and/or Drug Supply Manager).

Electronic data    Clinical data collected electronically, rather than using a paper case report form.

Electronic data capture:    Electronic technology that allows sites to transcribe subject data from source documents into electronic case report forms via the web.

Electronic learning module                Training materials delivered through digital means.

Electronic randomization code assignment system      System that allows study site personnel to assign trial subjects to a random treatment or control group by accessing a centralized database that is available 24 hours a day (eg, interactive voice-activated response system).

Errata:   Documentation of errors identified in a snapshot or final database and a summary of the effect of the errors on the data analyses.  It is used to document errors that exist in the database and to explain apparent discrepancies between text and the clinical data reports or to justify the correction of serious errors within the database.

Essential Documents:  Documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.

Exploratory trial:                Trial that serves to set direction (ie, generate hypotheses) for possible future studies. Exploratory clinical trials have significant statistical limitations; provide only preliminary information about a disease, condition, or product; and are not intended or designed to provide final conclusions on product claims.

Extension study: A clinical study in which subjects enrolled in an original study meet the protocol requirements of the second study to be enrolled into the second study. Generally, an extension study provides additional research on the same investigational product (eg, long-term safety) and is carried out by the same investigator/sites conducting the original study.

External trial arrangements                Investigators, subinvestigators/supporting staff, research facilities/trial sites, and institutional review boards/independent ethics committees participating in the conduct of a clinical trial.

Fair market value compensation:   A mutually acceptable fee within a range of payment levels for specified activities provided by healthcare professionals. Fair market value compensation includes:

1.             Payment for the expected duration of the event, including preparation/post event time requirements, and travel payment for any time commitment associated with the activity.

2.             Rates based on salary survey data by specialty with annual cost-of-living adjustments.

3.             Opinion leader premium that recognizes a healthcare professional level of expertise, experience, and influence (eg, regional or national opinion leader).

Final database:    Highest database-protected status, which is applied to a database that has reached a point of no further modification, other than by errata.

First-In-Man         Phase of development that represents the initial administration of an investigational product into humans.

(AE) Follow-up:    Information regarding an adverse event that was previously submitted to Global Safety Surveillance & Epidemiology. Follow-up information is reportable in the same manner and time frames as initial information.

Frozen database: Highest database-protected status, which is applied to a final database (ie, when all data have been locked, and have reached a point of no further modification) after unblinding, if applicable.

Global Clinical Database:                 An official database that houses information for Sponsor clinical trials.

Global trial leader (GTL): Generic term to describe an individual responsible and accountable for leading the operational execution of a study.

Guidance documents:        Reference documents (eg, guidelines, checklists, job aids, training materials) describing best practices for activities that support process execution. They serve as a management tool for completing tasks where further detail is needed and/or some task or responsibility variance may be appropriate.

Good Clinical Practice (GCP):  A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, 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.

Healthcare professional:  Any member of the medical, dental, pharmacy, or nursing professions or any other person who in the course of his or her professional activities may prescribe, recommend, purchase, supply, or administer a pharmaceutical product.

Hospitalization:   Official admission to a hospital. Hospitalization or prolongation of a hospitalization constitutes a criterion for an adverse experience or event (AE) to be serious; however, it is not in itself considered a serious adverse event (SAE). In absence of an AE, a hospitalization or prolongation of a hospitalization should not be reported by the investigator through a Form 7443. Situations include, but are not limited to the following:

• A hospitalization required for a protocol specified procedure (eg, biopsy) is not considered an SAE; however, if the biopsy results in a complication (eg, hemorrhage) that prolongs the hospital stay, the SAE criterion would be met.

• A hospitalization that is part of a routine procedure followed by the center (eg, stent removal after surgery) is not considered an SAE.

• A hospitalization for a surgical procedure to treat a preexisting condition that has not worsened does not constitute an SAE (eg, elective hospitalization for a total knee replacement due to a preexisting condition of osteoarthritis of the knee that has not worsened during the course of the study).

Hypothesis-testing trial:   Well-controlled study designed to provide meaningful results by examining prestated questions (hypotheses) with predefined statistically valid plans for data analysis, allowing solid conclusions to be drawn to support specific product claims. This includes all phase 3 studies, some earlier phase studies, and many phase 4 studies.

Independent publication:   Educational and/or scientific publication for which Sponsor provides funding, but that is conceived, developed, and submitted for publication without Sponsor's control or influence.

Informed consent (IC):      Process by which a subject (or a subject's legally acceptable representative) 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.

Informed consent form (ICF):          Form used to document a subject's (or a subject's legally acceptable representative's) legally effective voluntary agreement to participate in a clinical trial.

Inquiry: Query, request, or report with the intent of providing or seeking information or disseminating knowledge. This may include, but is not limited to, study-related medical issues, Sponsor investigational/marketed products, or personal information about subjects or investigators.

Inspection:           Act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority 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 facilities, or at other establishments deemed appropriate by the regulatory authority.

Institutional review board/independent ethics committee (IRB/IEC):    Independent body constituted of medical, scientific, and nonscientific 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 trials, protocols and amendments, and methods and material to be used in obtaining and documenting informed consent of trial subjects.

Interim analysis: Analysis of clinical trial data performed before the planned formal completion of a trial.

Interventional trial:  Investigation that prospectively assigns subjects or groups of subjects to one or more medical interventions to discover or verify clinical or pharmacologic effects and/or to identify adverse events associated with the intervention.

Investigational product:    Pharmaceutical form of an active ingredient or placebo, comparator, nutritional product, dietary supplement, herbal product, vaccine, biologic product, or device being tested or used as a reference in a clinical trial, including a product with a marketing authorization, when used or assembled in a way different from the approved form, or for an unapproved indication, or used to gain further information about an approved use.

Investigator:        Person responsible for the conduct of the study at a study site.

Investigator database:        A repository of information about investigators that allows the study teams to compile a preliminary list of potential investigators for possible participation in the clinical study.

Investigator Letter:            Letter containing serious, unexpected and possibly related adverse event information from a study on a particular product.

Investigator originated proposal:    Request by non-Sponsor organization personnel (ie, investigator, hospital, institution, or scientific organization) for support of clinical or preclinical research, sample acquisition, post-marketing authorization, and non-interventional studies. The proposal may request financial and/or material support. The idea for the study must have been first developed by non-Sponsor personnel.

Investigator's brochure (IB):           A compilation of the clinical and nonclinical data on the investigational product that are relevant to the study of the product in human subjects. Its primary purpose is to provide a description of the possible risks and side effects to be anticipated on the basis of prior experience with the product under investigation or with related products and of precautions or special monitoring to be done as part of the investigational use of the product.

Investigator's Brochure Addendum               An attachment to the current IB regarding a specific topic that is considered by the project team to be important enough that all distributed current IBs should be updated to contain it.

Issue:     Event, action, or omission that could materially affect the conduct of the study including data quality, the participation of an investigational site in the study, subject eligibility for or continuation in the study, or regulatory approval of the study.

Issued protocol:   Approved protocol that is suitable for submission to a regulatory authority and/or institutional review board/independent ethics committee. Issued protocols are stored in the final area of the Sponsor official electronic repository.

Labeling               Healthcare professional prescribing information texts (eg, Summary of Product Characteristics), user/patient information texts (eg, patient package insert), and container labeling. For the purposes of this standard operating procedure, the term labeling excludes advertising material.

Laboratory quality documentation:                Laboratory accreditation, certification, or other documentation attesting to the quality of the laboratory and associated equipment to be used for a Sponsor study.

Laboratory reference ranges:         Upper and/or lower limits of clinical laboratory test results, including associated units, for a normal patient population as determined by the laboratory.

Legally acceptable representative (LAR):    Individual, 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.

Local laboratory:                Laboratory facility utilized by a specific investigator other than a

Locked database:                Database-protected status applied to a complete clinical database (ie, when all expected data have been entered, imported, validated, and reviewed by all appropriate staff). All issues have been addressed and integrated into the database before freezing.

Malfunction:        Failure of the device to meet its performance specifications or otherwise perform as intended. Performance specifications include all claims made in the labeling for the device.

Marketing authorization application:           Generic term used to describe an application for authorization to market a product in a country or region.  This includes the US New Drug Application, Canadian New Drug Submission, and European Registration Dossier (which is sometimes referred to as the Marketing Authorization Application).

Medical monitor:                Generic term to describe a physician responsible for medical oversight of a clinical study and/or project, including ongoing review of safety data.

Medication errors:             Administration or consumption of the wrong product, or to the wrong patient, or by the wrong route, or at the wrong time, or at the wrong dosage strength due to human error.

Monitoring:         Act of overseeing the progress of a clinical trial and ensuring that it is conducted in accordance with the protocol, standard operating procedures, Good Clinical Practice, and the applicable regulatory requirements.

Monitoring plan:                Protocol-specific document that provides guidelines for conducting monitoring activities throughout the study.

Monitoring report:             Written report that documents the activities conducted during each site visit.

Non-independent publication           Publication by Sponsor employees and/or external authors based on research sponsored by Sponsor or secondary analyses, review articles, journal supplements, and symposium proceedings funded by Sponsor that are developed with Sponsor involvement.

Noninterventional trial     Study in which the medicinal product(s) is (are) prescribed in accordance with the terms of the marketing authorization. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiologic methods shall be used for the analysis of collected data.

Notice of confidentiality    Statement added to an electronic transmission stating that the information contained in the transmission is of a confidential nature for the intended recipient and should not be copied, disseminated, or distributed.

Obvious data modification Change to reported data that can be made to the database without having to issue data clarification forms to investigative sites.

Open-label study:               Study or phase of a study in which the treatment assignment is known to the subject(s), investigators(s), and the sponsor staff or representatives (ie, contract research organization staff).

Opinion leader:   Healthcare professionals who are likely to contribute to future trends in healthcare because of

their leadership, influence, expertise, and credentials.

Original:              The initial media type used to record information that has subsequently been copied to one or more media types.

Other reportable information (ORI):             Certain information, while not meeting the above definition of an adverse experience or event (AE), is reportable. This information includes:

1. Report of pregnancy exposure to a Sponsor product, except for the exposure to pre-natal vitamins. Information about use in pregnancy encompasses the entire course of pregnancy and delivery, perinatal and neonatal outcomes, even if there were no abnormal findings. Both maternal and paternal product exposure is collected.

2. Report of lactation exposure to a Sponsor product.

3. Overdose with or without an AE. Note: Baby formula overdoses without any AEs are excluded.

4. Abuse with or without an AE (for example, use for non-clinical reasons).

5. Inadvertent or accidental exposure with or without an AE .

6. Device malfunction with or without an AE .

7. Spontaneous reports of an unexpected therapeutic or clinical benefit associated with the use of a Sponsor product.

8. Medication errors where a product was administered or consumed.

Note: Reports of administration of an expired product with no associated AE should not be forwarded to GSSE.

Overdose:             A dose higher than the labeled dose or higher than prescribed by a health care professional for clinical reasons. For test articles, overdose is greater than the dose specified in the protocol /Investigator's Brochure, as applicable. When not defined in the protocol, if the prescribed dose is less than the labeled dose and the patient takes more than prescribed dose, but less than or equal to the labeled dose, there is no overdose. For example, it is not considered an overdose if the health care provider prescribes 1mg, the patient takes 2 mgs, and the label states that 3 mgs is the recommended dose.

1. A dose is the amount taken within the time frame specified in the label.

2. For over-the-counter products, overdose is greater than the total daily recommended dosage.

Patient reported outcome:                Measurement of any aspect of a subject's health status that comes directly from the subject (ie, without the interpretation of the subject's responses by a physician or anyone else).

Periodic report:  Report that is produced and delivered at regular time intervals (eg, quarterly, annually) to meet regulatory and local law requirements.

Personal information:       Any information relating to an identified or identifiable natural person. An identifiable person is one who can be identified, directly or indirectly, by reference to factors specific to that person's identity. Certain categories of information (eg, health, race, religion, sexual preference) may be subject to special safeguards under applicable laws.

Post site closeout visit       Onsite visit conducted to resolve significant issues that have been identified after the site closeout visit.

Post-study event :               Any adverse experience or event (AE) that starts after the last day of the follow-up period specified in the protocol. The follow-up period for safety is usually 15 calendar days after last dose of test article administration, but may be longer if medically or pharmacologically required.

Pre-existing condition:     A clinical condition (including a condition being treated) that is diagnosed before an informed consent form is signed and is documented as part of the subject's medical history.

Pregnancy Exposure Report:           Unless otherwise stated in the protocol, any report of pregnancy exposure for a study subject or partner of a male subject, with or without an adverse experience or event (AE), that occurs during the active phase of a study with a Sponsor test article. These reports are handled as other reportable information and processed in the same time frame as serious adverse events (SAEs) unless otherwise specified in the protocol.

Preliminary Contact Form               (PCF): Printed, optical, or electronic protocol-specific form that assists in evaluating potential investigators against protocol and operational requirements.

Prescribing information: Generic term to describe information used by health care professional(s) to determine the use of medicinal product(s) (eg, package insert, summary of product characteristics).  This definition does not include investigator brochures.

Prestudy package:             A package of required study documents submitted to the investigator after the site selection decision is final to enable the investigator to participate in the study.

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Process flow:       A graphical depiction representing a series of steps, decision points, and sequential

relationships within a procedure that must be executed to achieve a defined set of objectives.

Processing:         Any operation or set of operations that is performed upon data, whether or not by automatic means, such as collection, recording, organization, storage, adaptation or alteration, retrieval, consultation, use, disclosure by transmission, dissemination or otherwise making available, alignment or combination, blocking, or destruction.

Product complaint:             Report regarding a physical, chemical, microbiological, or other alleged defect of a product or its packaging or labeling. This type of complaint may also be a report of an adverse event that may merit investigation.

Product-related:  An adverse experience or event (AE) is considered “product related” for the purposes of regulatory reporting if an investigator or Sponsor medical monitor (including local monitor and/or headquarters monitor) assesses there is reasonable possibility of a causal relationship between test article and an AE. This is not a conclusive determination of causal association between the test article and the event.

The AE is treated as product-related for the purposes of reporting to regulatory authorities whenever the investigator's assessment is not provided or is unknown.

Promotion Traffic                Group within U.S. Sponsor Marketing and Sales Services that facilitates the review and approval process for all promotional materials from conception through completion.  Promotion Traffic resolves issues through interaction with product management, the Copy Clearance Committee, agencies, vendors, and internal departments.  Promotion Traffic serves as the link between the advertising agency, the brand team, and the Copy Clearance Committee.

Promotional materials:     Print, electronic, digital, audio transmissions, programs, images, and graphics, regardless of format or medium, that are intended to promote the prescription, supply, sale, or administration of a Sponsor product to healthcare professionals or consumers, and that mention a specific product or contain one or more promotional claims, including medical content and/or a product-specific message.

Proof of concept: Stage of drug development that confirms that the efficacy findings from animal studies are applicable to humans and that supports a decision to continue clinical development (eg, early phase 2).

Protocol: Document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol (term that may also refer to a protocol amendment) usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. In noninterventional/ observational trials, the protocol may be called the observational plan.

Protocol-related: A protocol-related adverse experience or event (AE) is an AE occurring during a study that is not test article-related, but is considered by the investigator or the medical monitor (or designee) to be related to the research conditions, i.e., related to the fact that a patient is participating in the study. For example, a protocol-related AE may be an untoward event occurring during a washout period or an event related to a medical procedure required by the protocol.

Protocol synopsis:              Brief summary of the important aspects of a protocol.

Protocol violation:              Departure from protocol that has a significant effect on the subject's rights, safety, or welfare, or the integrity of the resultant study data (eg, the sponsor's ability to use the data in support of the product).

Publication:         Includes, but is not limited to, any proposed disclosure of medical, scientific, or technical information in the print media (eg, journals), oral presentations (eg, scientific symposia), and electronic presentations (eg, the Internet). Examples of publications include manuscripts, abstracts, posters, editorials, letters to the editor, review articles, books, book chapters and other materials for external consumption, including presentations posted on the Internet.

Publication plan: Listing of the publications related to Sponsor data for a prospective 12 month period.

Qualification visit: (SQV)                A generic term to describe the visit to a site that is conducted to ensure that the investigator under consideration is capable of conducting the trial according to the study design and in accordance with company policy and appropriate guidelines.

Quality Assurance (QA):  All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and the 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

Quality Evaluation:            For studies using paper case report forms, a comparison between the data entered on the paper case report form and/or supplied by data-clarification forms and the database for a randomly selected set of subjects. This review is performed in accordance with clinical data management guidelines, the protocol, and other supporting study-specific documentation.

Quality plan:        Document that describes the desired functionality of a computer system; how the functionality will be tested; how the system will be deployed, operated, and maintained; and what documentation will be required.

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

Randomization code           A unique numeric or alphanumeric identifier for a study subject that is associated with a treatment or control group for a given study (ie, treatment assignment code).

Recall:   Removal of finished product from the market, with full knowledge of one or more regulatory authorities, due to regulatory action or noncompliance with Sponsor quality standards.

Records management:       Group or organization responsible for the systematic receipt, control, maintenance, security, accessibility, and archiving of documents

Regional medical monitor (RMM): Generic term to describe a physician responsible for providing medical expertise in a region.  The regional medical monitor serves as the physician to physician contact for an investigational site and answers and/or escalates to the global medical monitor, as appropriate, medical questions from the site, local institutional review board/independent ethics committee, and site manager.

Regional study manager (RSM):    Generic term to describe an individual accountable for clinical trial execution in a region.

Remote Data Capture (RDC):          Electronic technology that allows sites to transcribe subject data from source documents into electronic case report forms via the web.

Restricted information:    Defines or describes the Company's most important products and processes. It shows long-term operational direction and is extremely relevant to technical or financial success. If improperly disclosed, restricted information could cause significant damage to the Company, its employees, customers, and/or business partners.

Retention schedule:           Length of time, beginning with a particular event (often referred to as a ‘trigger event'), during which records of a specific type or in a particular category are retained and after which time are destroyed.

Review article: Publication that is based only on previously published literature and does not contain unpublished data.

Safety Attachment:            An attachment to the Investigator's Brochure that is used to provide information on the product's safety profile. The Safety Attachment is reviewed on a regular basis and updated at the direction of the Safety Review Team. The Safety Attachment accompanies the Investigator's Brochure and is composed of the following:

• Selected definitions.

• Developmental Core Safety Information.

• List of all drug-related serious adverse events.

• List or summary of all other serious adverse events (at the discretion of the Safety Review Team).

• Other considerations as appropriate (eg, nonclinical events not yet seen in humans but being monitored, events and interactions that might be expected based on similar products).

Safety Review Team           Team established for each clinical project to provide a forum for the review and assessment of safety data trends and the safety profile of Sponsor investigational and marketed products.

Members of the Safety Review Team include the following:

•              Clinical Pharmacology medical monitor (prior to Decision Point 3).

•              Global clinical program leader(s).

•              Clinical Project Team medical monitor.

•              Global Clinical Communications representative.

•              Global Labeling Division representative (when the product reaches the phase 3 management milestone of development).

•              Global Medical Affairs medical monitor (after Decision Point 3 or as specified by the head of Global Medical Affairs).

•              Global Safety Surveillance and Epidemiology (GSSE) medical pharmacovigilance physician.

•              Global medical monitor(s).

Ad hoc members may include:

•              Biostatistician.

•              Clinical data management representative.

•              Clinical scientist.

•              Drug Safety & Metabolism representative.

•              GSSE representative.

•              Legal representative.

•              Regulatory affairs representative.

•              Statistical programmer.

Sales training materials      Materials, programs, multimedia training tools, images, and graphics, regardless of format, that are intended to build and strengthen the knowledge and skill base of Sponsor sales personnel.  Training material content is product or medically related and is intended for internal use only.

Serious adverse event:

A serious adverse event (SAE) is defined by Sponsor as an adverse experience or event (AE) that:

1. Results in death.

2. Is life-threatening (see below).

3. Requires inpatient hospitalization or prolongation of an existing hospitalization.

4. Results in a persistent or significant disability or incapacity (see below).

5. Results in cancer.

6. Results in a congenital anomaly or birth defect.

7. Results in an important medical event.

Important medical events: AEs that may not result in death, be life-threatening, or require hospitalization, may be considered serious AEs when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in hospitalization; or the development of drug dependency or abuse.

Life-threatening refers to immediate risk of death as the event occurred per the reporter. A life-threatening experience does not include an experience that, had it occurred in a more severe form, might have caused death but as it actually occurred did not create an immediate risk of death. For example, hepatitis that resolved without evidence of hepatic failure would not be considered life-threatening even though hepatitis of a more severe nature can be fatal. Similarly, an allergic reaction resulting in angioedema of the face would not be life-threatening, even though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be fatal.

Disability is defined as a substantial disruption in a person's ability to conduct normal life functions.

If there is any doubt whether the information constitutes a serious AE, the information is treated as a serious AE.

Serious breach: Event or series of events likely to affect to a significant degree either the safety or physical or mental integrity of subjects or the scientific value of the trial.

Service provider:                Non-Sponsor person or organization contracted by the Global Clinical Team (eg, contract research organization, vendor, investigator, or institution).

Site and subject identification numbers:      Unique subset of subject numbers allocated to a site based on the estimated number of subjects to be screened at each site.

Site closeout visit (SCOV):              Onsite visit conducted when there is no further subject activity, all data have been received in-house, editing is complete, and all outstanding issues on the monitoring report can be closed (except for long-term follow-up for survival data).

Site initiation visit (SIV): Onsite visit at an investigator study site to provide training to the investigator and study site staff to ensure they are adequately trained to verify that all regulatory and other requirements are met at study start.

Site manager       (SM): Generic term to describe the blinded or unblinded individual responsible for planning,

monitoring, verifying data, and/or reporting progress for a trial site.

Site monitor (SM, CRA):  Generic term to describe the blinded or unblinded individual responsible for planning, monitoring, verifying data, and/or reporting progress for a trial site. The person is responsible for monitoring the site and writing the monitoring report.

Site monitor manager (SMM):        A generic term to describe an individual responsible for assigning and overseeing site monitors.

Site-specific informed consent form:            Informed consent form (ICF), based on the study or country prototype ICF, that is implemented at an investigational site. The site-specific ICF includes site contact information and local site and institutional review board/independent ethics committee requirements.

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, records (e.g., hospital records, clinical and office charges, 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 and complete, and records kept at the pharmacy, at the laboratories, and a medico-technical departments involved in the clinical trial).

Specimen:            Any biological fluid or tissue collected from a subject for the purpose of investigation as described by the clinical protocol.

Sponsor:               Individual, company, institution, or organization that takes responsibility for the initiation, management, and financing of a study.

Spontaneous adverse event report: Unsolicited report of adverse experience or event (AE) information or other reportable information associated with the use of the product, which is not derived from a study or any organized collection scheme. For regulatory reporting purposes, spontaneous AEs are treated as “related” to the Sponsor product regardless of whether causality is explicitly stated or ever defined.

Sponsor official electronic repository:         Sponsor official repository that is a validated computer system.

Sponsor official repository:             Location or computer system where documents are archived and indexed which is protected, secured, and ensures documents are readily retrievable that has been assessed and deemed to be an official repository by Research & Development Records Management. This includes local repositories and Sponsor official electronic repositories.

Sponsor product:                Human drug (including prescription and over-the-counter [OTC]), nutritional product, dietary supplement, herbal product, vaccine, biologic product, or a device manufactured by, marketed by, supplied by, distributed by, or used in a study by Sponsor or

Sponsor Affiliates: 1. For studies, this includes products that are blinded, placebo, or control (comparator) agents used in studies.

Stakeholder:        Person or group who is affected by activities or results of a project; can influence, support, or resist the outcome; and has personal, financial, or professional interest in the outcome.

Standard operating procedure (SOP):           Documented procedure, including any documents required by the procedure (eg, forms), that describes a key business process with a high-level description of the activities in the form of roles and action steps that must be performed.

Standard operating procedure/standard practice instruction deviation:               A departure from a standard operating procedure/standard practice instruction that is anticipated (prospectively) or identified after it has already occurred (retrospectively) for which authorization is requested.

Standard practice instruction (SPI): Documented procedure, including any documents required by the procedure (eg, forms), that provides a more detailed description, in the form of roles and action steps that must be performed, of

•              one or more steps for a GCT SOP(s).

•              other processes not specified in an SOP.

•              a computer system.

Standard response:            Text that is intended to be used repetitively to respond to product information inquiries received from Sponsor customers, that has been prepared, reviewed and approved by the appropriate personnel, and is stored in the Sponsor official electronic repository.

Standard Response Letters:            Medically related correspondence that has been reviewed and approved by the appropriate Global Medical Affairs personnel.

Statistical analysis plan: Documented technical and detailed elaboration of the principal elements of the analysis that includes detailed procedures for executing the statistical analysis.

Stock recovery:   Removal of final or finished product from distribution centers, warehouses, and/or other Sponsor consignees (ie, depot or investigational site).

Study:Any interventional or non-interventional trial. For the purposes of adverse experience or event (AE) reporting to Global Safety Surveillance & Epidemiology, the following are also to be considered studies:

• Compassionate use/treatment use/named patient programs/single subject emergency use.

• Planned contacts for the active solicitation of information from patients (eg, in home use test, marketing study, repeat insult patch test [RIPTS], company-sponsored patient support programs and disease management programs).

• Patient registries.

1. Post-marketing study – A study (including interventional and non-interventional clinical trials) completed after a product's approval within the conditions of the approved label or under normal conditions of use (e.g., Phase IIIb, Phase IV).

a. Post-authorization study : Any post-marketing study conducted within the conditions of the approved product labeling or under normal conditions of use. A post-authorization study may sometimes also fall within the definition of a post-authorization safety study (PASS). In relation to AE reporting and Periodic Safety Update Report requirements, reference to a post-authorization study means any post-authorization study of which the marketing authorization holder is aware.

b. Post-authorization safety study (PASS) : A pharmacoepidemiological study, or a clinical trial carried out in accordance with the terms of marketing authorization, conducted with the aim of identifying or quantifying a safety hazard relating to an authorized medicinal product.

2. Non-interventional trial – A study in which the medicinal product(s) is/are prescribed in the usual manner in accordance with the terms of the marketing authorization. Assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol, but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data. An example of a non-interventional trial is a registry.

3. Clinical trial (interventional) – Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more test article(s), and/or to identify any adverse events to one or more test article(s) and /or to study absorption, distribution, metabolism and elimination of one or more test article(s) with the objective of ascertaining its (their) safety and/or efficacy. This includes clinical trials carried out in either one site or multiple sites, whether in one or more than one country.

Study file manager              Generic term to describe an individual responsible for supporting the study teams by managing clinical trial regulatory documentation (eg, facilitate the transmission of study documents into the Sponsor official repository [WOR] and perform quality reviews of documents within WOR).

Study medical monitor (SMM):       Physician responsible for medical oversight of a clinical study, including ongoing review of safety data.

Study prototype informed consent form:       Model informed consent form (ICF) used as the basis for country prototype and site-specific ICFs.

Study reference manual: (SRM)     Protocol-specific instructional resource for study site personnel and site monitors on relevant regulatory requirements and Sponsor processes (including protocol adherence, quality data completion, and safety reporting requirements).

Study team:          Generic term to describe a team responsible for preparation of the protocol, execution and completion of the study, and study analysis and reporting.  Study team member responsibilities include, but are not limited to, study design, site set-up and monitoring, data entry, database finalization, and document management.

Subject master list:           List(s) of all subjects screened and enrolled at a site in the trial.

Subject matter expert          An experienced employee from a departmental/regional area worldwide who is familiar with current research practices and technical or regulatory aspects described in Standard Operating Procedures/Standard Practice Instructions.

Subject narrative:              Report created in the event of death, other serious adverse event, or other clinically important adverse event experienced by a subject during a clinical study, and that includes relevant subject information and comments.

Substantial amendment:

Amendment that is likely to have a significant impact on 1 or more of the following:

• Subject safety or physical or mental integrity.

• Scientific value of the trial.

• Conduct or management of the trial.

• Quality or safety of any investigational medicinal product used in the trial.

Support Disbursement of funds and/or materials for use in conducting research.

Test article/ investigational product: (TA or  IP)        Pharmaceutical form of an active ingredient or placebo being tested or used as a reference (ie, a comparator product) in a clinical trial, including a product with a marketing authorization when either used or assembled in a way different from the approved form, when used for an unapproved indication, or when used to gain further information about an approved use.

Third-party unblinded dispenser:   Consented site member participating in a double-blind, third-party unblinded study who is responsible for dispensing investigational product and maintaining the blinded integrity of the trial.

Translation package: Set of documents consisting of the original language version of the document, the translated version, the back-translation (if applicable), and the completed Translation Request and Approval Form, including the Translator’s Certificate, as applicable.

Treatment and Randomization Specification Report:                A report that specifies and communicates information related to planned treatments and randomization requests for clinical studies.

Treatment and randomization specifications: Definitions of treatment patterns (ie, how treatments are assigned to a subject throughout the course of a study, and the specifications of how they are to be randomly assigned to study subjects).

Trial manager     Generic term to describe a member of the study team responsible for managing and/or leading the operational execution of a study plan.

Unblinded site manager:   Individual other than the blinded site manager assigned to the specific site for a double-blind, third-party unblinded study who is responsible for test article accountability, reconciliation, and maintaining the blinded integrity of the trial.

Unblinded site monitor:     Individual other than the blinded site monitor assigned to the specific site for a double-blind, third-party unblinded study who is responsible for test article accountability, reconciliation and maintaining the blinded integrity of the trial.

Unblinding representative:              Generic term to describe an individual responsible for releasing randomization codes.

Unexpected adverse event:                An adverse experience or event (AE) that is not listed in the product labeling. The current product labeling is either the company approved label (for marketed Sponsor products) or the current investigator's brochure (for investigational Sponsor products).

An unexpected AE includes any event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the labeled event because the nature, severity or outcome is not consistent with the labeling.  For example, hepatic necrosis is unexpected, by virtue of greater severity, if the product labeling referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis are unexpected, by virtue of greater specificity if the labeling only listed cerebral vascular accident.

• An AE is considered unexpected for local reporting purposes if it does not appear in the approved labeling for the country to which the AE is being reported.

• Outcome Death is considered unexpected for local reporting purposes if it is not mentioned explicitly as the result of a particular event in the approved labeling for the country for which the product is approved.

• An AE is considered unexpected for core labeling purposes when it does not appear in the company's approved core data sheet (if one exists).

User       Employee or other individual granted access to an information asset by the system owner, but without being granted control over the asset. The individual is identified within the system through his/her user identification (user ID).

Vendor: Person or organization providing goods or services.

Working files:    Drafts or copies of documents or other supporting documentation and personal files (eg, copies of meeting minutes, internal e-mails, correspondence, memos, external reference documents, and documents in the draft area of the Sponsor official electronic repository).