"Conducting Clinical Trials A-Z"

Study Coordination & Operations

Study Supplies:

Many industry funded trials will provide most study supplies including CRFs, clinical and laboratory materials.  Contacts for additional clinical supply needs: hospital materials management (323-5645);Kentucky Clinic Central Supply (257-1646); dry ice (257-7111).

Informed Consent Process     

Consent Process PowerPoint (PDF)

Informed consent process involves dynamic and continuing exchange of information between the study site personnel and subject throughout the trial.  The goals are to provide people with sufficient information so that their decision to participate or continue participation is made freely and voluntarily.

Requirements for Obtaining Informed Consent:

• Informed consent must be obtained prior to any study related tasks being implemented

• written consent form with all required and applicable elements

• review, explain, answer questions

• give subject all the time they need

• no false, coercive or exculpatory statements

• assess understanding, ask open–ended questions and address misconceptions.  Informed consent questionnaires can be tailored to your protocol.  You can use the UKCRO Informed Consent Checklist or the ORI sample questionnaire

• required signatures – signed & dated by subject or legally authorized representative and person conducting the discussion. (witness required if consent presented orally due to inability to read)

• signed and dated copy to subject (per ICH guidelines)

• store original in medical record (per JACHO)

• document all details of process (who, what, when, where, etc in medical record); particularly that consent was obtained prior to any research procedures.

• special circumstances (children,  language translation, genetic research, decisionally challenged, physically debilitated, prisoners, etc) involve additional requirements.  See the IRB Survival Handbook and/or call the UKCRO for assistance.

• revise when protocol is modified or there is new information that might affect a subject’s willingness to participate.  All active subjects should be re-consented with the revised form.

• If the subject does not speak English, ensure that the informed consent process is implemented in the subject’s language, using a qualified interpreter (Kentucky Clinic - 257-9805 scheduling; Spanish – 323-6592; Japanese – 257-8463 ;UKMC - Language Services Coordinator - 323-8951; TTD telephone, sign language or foreign language services; Spanish – UK pager 3707). Ensure that both the subject and an impartial witness sign and date the informed consent document that has been translated into the language of the subject and approved by the IRB.

Informed Consent Form – Utilize the current IRB forms and checklist to ensure you have all of the required and applicable elements. In a location that provides privacy, review the informed consent form with the subject by discussing all of the elements:

Required elements:

• state research study
• purpose
• procedures – Standard of care vs. Research
• risks
• benefits –don’t oversell
• alternatives – surgical, medical, lifestyle, none
• contact- PI & ORI 859-257-9428 or toll free at 1-866-400-9428
• voluntary
• confidentiality
• research Related Injury

Additional elements:

• risk to embryo or fetus
• circumstances participation may be terminated
• consequences of subject’s withdraw – risk?
• additional costs – SOC – may still have co-pay or deductibles
• provision of release of new information
• anticipated number of study subjects at this site
• reasons not to participate
• rewards

Formatting 

• Avoid or explain technical, scientific or legal terms – refer to web sites for translation of medical terms or lay explanations of procedures:
  www.findarticles.com
  http://www.pharma-lexicon.com/index.php http://humansubjects.stanford.edu/medical/glossary.html http://www.radiologyinfo.org/content/safety/xray_safety.htm
  http://www.medterms.com/script/main/hp.asp
• 6th grade reading level- use Microsoft grammar check to determine level
• Second person – communicates a choice
• Short sentences
• Verbs in active voice (subject is doer)
• Balance white space with text & graphics
• Right margins ragged
• Headings and captions to break up blocks of text
• Use underline, bold or boxes Upper & lower case letters
• 12 point font or greater
• Don’t shorten margins in effort to reduce # of pages
• Graphics – meaningful, captions, reproduce well
• BOLD on most important thing to prospective subject

Quality Assurance Checks for the Informed Consent Process:

•  ICF signed prior to study activity

• Correct version of ICF signed

• Check documentation of consent process in study/medical record

• Check signature lines

• Any special circumstances

Ongoing IRB Correspondence:

Ongoing IRB Correspondence includes adverse events, continuation review, protocol modifications, protocol violations, etc.:

Initial and Ongoing Communications with the IRB

TIPS to maintain complete IRB records:   

• Keep copies of all submissions to and from the IRB including attachments.
• Put version or serial numbers in the document footers to identify.
• Use cover letters with serial numbers to clearly identify all documents being submitted and track correspondence.
• Ask the IRB to reference the documents in their reply.
• Document all contacts with IRB – “get it in writing.”
• Use flow sheets / tracking logs.
• Maintain chronological files.

Typical Clinical Trial Visit Procedures                      

While the protocol will offer details on conducting study procedures and visits, the study schematic will provide a quick overview and timeline.   To ensure smooth visit flow, prepare a cover sheet table for each visit listing the procedures and box for initials of the staff who performed the procedure. 

Sample Study Schematic

Setting a rapport and establishing early and open communication is vital to obtain a thorough medical history, ensure the subject meets enrollment criteria, and establish all baseline signs and symptoms.  Once that is determined, all other changes in severity or frequency from baseline are considered adverse events.  When reviewing the subject’s current medication, be sure to ask about any commonly used over-the-counter medications, vitamins or dietary supplements.

Best practice is to providing several forms of information about the study and your contact information so that the informed consent is not the only source for the subject to refer to.  Using the following items takes the guess work and unknowns out of participating in a clinical trial and can improve compliance:

• Initial brochure or handout on participating in clinical trials

• business cards for all study staff

• wallet cards stating that the subject is on a clinical trial and who to call in case there is a study-related event

• a version of the study procedure schematic translated into lay-language and noting special instructions such as when to fast for labs or when to return study drug

• visit reminder cards

• diaries (considered a source document if collected)

• refrigerator magnets with site contact information

Paying Research Subject Stipends:

Payment of research subjects is intended to reimburse subjects for their time and inconvenience.  Amount of reimbursement should be reasonable and should not be correlated to risk level. The IRB will review the payment amount to ensure it is not viewed as an undue inducement to participate and will ensure that the payment terms to ensure partial payment for subjects who withdraw before completion of the trial.  The UK business procedure manual outlines new options of compensation that are available under section E-9-1including imprest cash fund or gift cards. Consider your protocol and consult with your business manager to determine the most convenient method of payment considering the length of the trial and payment schedule.  Departmental Authorization and Voucher (DAV form) for subject payment (use object code Research subjects payments 3615) should be signed by the PI and list the following statement.

I certify that this reimbursement is for funds that were duly authorized and made solely as payments to the recipients for participation as a human subject in an official research project of the University of Kentucky, and that detail supporting documentation is maintained by the department in the project files for audit purposes.

Have subject sign a W-9 form and send original W-9 with initial DAV and keep copies of both documents.

Subject Documentation and Data

Each trial will require two categories of documentation – Study specific and subject specific.

Study Specific Documentation:

Study specific documentation include all of the documents filed in the regulatory binder as well as any study tracking logs, equipment logs, etc. 

As mentioned above the initial regulatory and IRB documents serve as the foundation for the Study Regulatory Binder, however documents will quickly multiply once a trial is initiated.  The Regulatory Binder(s) will contain all study specific documents in an organized fashion with sections clearly labeled.  Use the Regulatory Binder Document Checklist as a guide.

Maintenance of the binders is critical to creating a paper trail for the trial.  Remember the binder documents must be retained and maintained for the life of a trial.  Documents such as investigator’s medical licenses or lab certifications that are re-issued annually should be added to the binder.  So a five year trial would have at least five lab certifications.

TIPS:

• If the regulatory binder has been divided into several binders, the original should have notation indicating where to find sections (i.e. Drug accountability records maintained in the Investigational Drug Service)

• Use serial numbers to track back and forth correspondence with sponsor and IRB.

• Study records are for the life of the study (i.e. 5 year trial will have 5 medical licenses, 5 lab certifications, etc)\

• If study has multiple binders, label, number 1 of 3, or color code.

• Keep all study records in secure area, available only to authorized personnel.

Keeps a separate fiscal binder including contract and internal paperwork, budget, billing, etc.

•     Explicit Regulatory Requirement

-     312.62 (b) An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug….

Case histories = Case Report Form (CRF) + Source Data

Source Documents -

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. 

Examples:

• Medical record charts/ certified copies
• Lab printouts & test reports
• Physical exam checklist/notes
• Signed informed consent forms
• Patient logs, questionnaires or diary
• Progress notes
• Adverse events
• Concomitant medications
• Study drug assignments/collection
• Appointment sign in sheets
• Subject specific IRB correspondence

CRF – these are a concise translation of pertinent data that reflect a subject’s status while participating in a research trial. They are confidential tools, usually in format for data entry with protocol specific elements that will be gleaned from the source documents.  The sponsor will create and provide the CRFs.

General rule – CRFs are not designed to be source documents and should not be photocopied and used as source. The sponsor monitor will use source documents, test results, physicians progress notes, medical history and coordinator notes to verify data on CRF. 

Rarely some forms such as questionnaires may allow for direct data entry, however it will be clearly documented in the protocol if it be the case.

Guidelines for completing CRFs:

• Typically transcribed by CRC
• Contemporaneously completed
• Maintained in secured area with limited access 
• Corrections - single line, initial & date
• Black ink, no white-out or erasures
• Press hard if using NCR triplicate forms
• Complete header and identifiers at top of page
• Use leading “0”, no blanks or dashes
• May use sponsor approved abbreviations
  • UNK/unknown, ND/not done, NA/not applicable
• Be aware of units of measure and calculations
  • centimeters vs. inches; kilograms vs. pounds
• Investigator reviews, makes notations on abnormal labs, initials and dates
• PI responsible for review and signing and dating CRF where indicated per sponsor requirements (date at time of review)
• Various formats –Paper or Electronic

TIP: Websites that provide additional resources, calculators, and guides for clinical study operations include: On Line Clinical Calculators and UK Careweb

Adverse Event Management and Reporting

The investigator and site personnel should know the protocol and study drug and be aware of IRB and sponsor requirements for documenting, tracking and assuring care of adverse events. 

Adverse Event (AE):

Any untoward deviation from the subject’s baseline health either in occurrence, frequency or severity and which does not necessarily have a causal relationship with the study treatment.  May include signs, symptoms, syndromes, diagnosis, changes in lab values or other clinical measures or observations.

Severity levels: