investigational product accountability

Investigational Product Accountability

Nicole Cortez, M.S.EdClinical Research Monitoring SpecialistOffice of Clinical Research

April, 2016

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Learning Objectives

At the end of this training, you will be able to:• Recognize the importance of investigational product (IP) accountability

• Understand Principal Investigator (PI) responsibilities pertaining to IP

• Manage investigational product throughout the life of a study

• Maintain accurate and complete IP documentation• Ensure preparedness for an inspection• Know what resources are available

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Agenda IP accountability definitionPI responsibilitiesWhy is this important?The Basics:

• Using IDS• Receipt and storage• Prescribing and dispensing• Return and destruction• Close‐out

Inspection preparationCasesResources

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IP accountability definition

Accountability:Inventory records document that IP was used only:• in the clinical trial • for study participants• in accordance with the approved protocol

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IP accountability definitionChain of Custody• Investigational product accountability records should document a product “chain of custody” which serves as a tracking document to assure that any member of the research team or outside reviewer can track the investigational product from the time it leaves the sponsor/manufacturer until the time it is used by a subject, destroyed, or returned back to the Sponsor.

Don’t break the chain!

Resource: Penn Manual

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PI Responsibilities

Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator.

The investigator must maintain: • records of the product's delivery to the trial site • inventory at the site • use by each subject, and the • return to the sponsor or alternative disposition of unused product(s)

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PI Responsibilities continued …

The investigational product(s) must be stored as specified by the Sponsor’s protocol and in accordance with applicable regulatory requirement(s).

The investigator must ensure that the investigational product(s) are used only in accordance with the approved protocol.

Resource: Principal Investigator Acknowledgement of Responsibilities

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Why is this important?

Subject Safety• Ensure subjects that have signed consent receive IP:

– that has been stored properly – that is not expired– from appropriately trained personnel who can accurately address questions

Data Integrity• Ensure complete, accurate, consistent documentation

• If it’s not documented, it hasn’t happened!

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Why is this important?

What is the impact of poor accountability?• Loss of clinical trial data

– Missing data affects study analysis• Sponsor may suspend drug shipments/enrollment at site

• Impacts Sponsor’s selection for future trials• Common FDA and EMA audit finding:

– “Failure to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects.”

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Using IDS

Protocol training of IDS at study initiation• Ensure IDS is fully trained on protocol‐specific IP procedures:– Submit protocol to IDS before IRB submission

○ Feasibility to be considered– Submit IRB approved protocol to IDS

○ IDS to draft dispensing procedure– IDS staff member should attend SIV

Resource: A Guide to Working with the Investigational Drug Service, Penn Manual

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Using IDS

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Using IDSIDS training does not stop after SIV!• Current version of protocol always at IDSIP Reconciliation at regular intervals:• Monitors

– Industry, NIH– Independent (Investigator‐initiated studies)

○ CRC‐ review monitoring reports/letters for issues– Self‐monitoring

○ CRC‐ set up a timeline for regularly scheduled reconciliation. Do not wait until end of study!

• Blinded Studies

Resource: Principal Investigator Compliance Assessment (PICA)

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PICA Investigational Product Section

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Quick check

When should investigational product reconciliation occur?• When packing the records for storage.• When returning all medication to the sponsor.• Never, that’s IDS’s job.• At regularly scheduled intervals.• Once the last participant has returned all of their medication.

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Receipt and Storage Determine storage BEFORE receipt

• What conditions are required?– Room Temp (15‐25°c)– Refrigerated (2‐8°c )– How monitored?

• How much space is needed?– Not just initially – how much will I receive later? – Save everything until the end of the trial?

• Special conditions?– Controlled substances – requires ‘securely locked, substantially constructed enclosure’ (21 CFR 312.69)

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Receipt and Storage

Methods of temperature monitoring

• Daily check / paper log

• Min / Max thermometer

• Temperature wheels/charts

• Systems tied to phone, email, etc

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Receipt and Storage

Uh Oh…. What to do if there is a temperature deviation:• Do Not Dispense• Notify the sponsor

– Sponsor will ask details (number of degrees deviated, length of time deviated)○May recall medication and provide a new supply.○May allow to use.

Document and save all communications.

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Receipt and Storage

Storage Facility• Locked• Limited Access

– Authorized study personnel (for THIS study)• How secure is the space?• How suitable is the space for IP storage?

– How close to a source of moisture or heat/cold?

– If refrigerated – commercial vs. household use?

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Receipt and StoragePackaging Investigational Product • IP should be packaged per protocol/CMC• Penn IDS complies with all regulations while also adding any appropriate ancillary labeling or warnings– USP <795> , USP<797>– cGMPs

• New QC officer at IDS• Outpatient trials should use IDS for:

– Repackaging– Compounding– Distribution to other sites

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Receipt and Storage

Receiving IP• Verify contents match shipping documents• Shipping documents become part of site records

Questions to ask:• Where do we confirm receipt (fax, IWRS/IVRS, email,

other ?)• Process for receiving if damaged (including: out of temp

range at time of receipt)• For a refrigerated IP, what do we do with temperature

devices in packaging?• Is the sponsor’s log mandatory or can we substitute

our own?

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Receipt and Storage

What to document – receiving IP• Name • Lot, batch or serial information• Dose • Date received• Quantities• Expiration or Retest date • Name of the person receivingStudy staff must be delegated by the PI.Resource: OCR’s Investigational Product Accountability Site Log

21 CFR 312.57 (a)GCP E6 Section 4.6.1

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IP Accountability Site Log

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Receipt and Storage IP expiry

• All IP should have either expiration or retest date– Expiration‐ fixed date– Retest = date may be extended after further testing

• Compare date against window for next visit– Will any IP expire prior to the next subject visit?

• In IDS:– Monthly audit of all stock for upcoming expiries– Computer flags (warnings) for IP < 30 days– IDS dispensing procedures include expected visit schedule

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Prescribing and Dispensing

Prescribing/ordering IP• Investigational Product must be prescribed/ordered by a licensed practitioner.– MD, DO, DMD, DVM– State law allows CRNP or PA under an existing collaborative practice agreement ○ CRNP, or PA may prescribe IP. They must be identified on the Form FDA‐1572, and identified on the Delegation of Authority Log.

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Prescribing Options:• EPIC Willow (outpatient), Sunrise/SCM (inpatient) or BEACON (parts of Perelman)

• Paper Rx:– Traditional Rx (fax or drop off)– IDS will create pre‐printed prescription blank (to complete/sign/fax)

• Where fixed regimen is dispensed multiple times, prescription may be written with refills– New prescription required when dose changes

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Quick Check

Who is not allowed to sign a prescription for IP?• Principal Investigator• Sub‐Investigator• Physician’s Assistant• Nurse Practitioner• Research Coordinator

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Dispensing IP• When?

– Once IP is prescribed by PI, Sub‐I• Who?

– Individuals who are delegated by PI on the Delegation of Authority Log.

• How?– Per IRB approved protocol– In accordance with the IDS procedures/recommendations

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Dispensing vs. Administering IP• Dispensing

– the preparation, packaging, labeling, record keeping, and transfer of a prescription drug to a patient or an intermediary, who is responsible for administration of the drug○ Licensed Pharmacist (after it is prescribed) to CRC, subject

○ Delegated research staff per IRB approved protocol

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Dispensing vs. Administering IP• Administering

– The giving or application of a pharmacologic or other therapeutic agent○ Dependent upon state regulations, but usually includes physicians and nurses.

○May administer IP that has been approved for use as part of a research clinical trial and only to subjects involved in the trial

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What to document – dispensing IP• Subject ID• Name of IP• Lot, batch or serial information• Dose • Date dispensed• Quantity • Name of the person dispensing

• *Subject calendar to be distributed

Resource: OCR’s Investigational Product Accountability Log; Study Log, Subject Log

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IP Accountability Study Log

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IP Accountability Subject Log

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Quick Check

All of the items should be captured on the IP accountability log except• Dates of dispensing• Dates return• Subject name• Subject ID• Dose increases or decreases

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Return and DestructionIP Returns• Document exactly what was/wasn’t used

– Ability to calculate patient compliance

• Demonstrate lifecycle of product– Each container – used by who, how much used, how much returned, where did those go?

– Prove error/misuse did not occur

• Must have documentation showing what returns left site, when, and to where

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Return and Destruction

What to document – returning IP• Name of medication• Lot, batch, or serial information• Dose• Date returned• Quantity returned• Name of the person receiving• Any reason for conflicting information

– i.e. “I dropped 2 pills on the floor and had to throw them out.”

• *Subject calendar to be reviewed

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IP Accountability Study Log

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IP Accountability Site Log

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Drug Return Challenges• Returns not logged in promptly• Returns need to be stored securely

– Higher potential for discrepancy• Returns not brought back promptly• Counts don’t match clinic records

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Return and Destruction Tips for Success when returning IP

• Clarify with sponsor – return vs destroy, how frequent, how to document

• Return as soon as possible post‐visit• Document

– Return date– Return quantity (once you’ve counted in clinic)

• IDS– Will count/log upon return– Can destroy drug or return to Sponsor for destruction– Maintains destruction logs

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What to document – destruction• Name of medication• Lot, batch or serial information• Dose• Date destroyed• Quantity destroyed• Means of destruction• Name/title/signature of the person destroying• Name/title/signature of at least one witness

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Study Close-out

Involves an overall reconciliation of IP from start to finish

Remaining drug (unused as well as used)• Make sure logged out of site accountability when returned or destroyed

Blinded studies with un‐blinded records• Could be multiple ‘closeouts’ (unblindedmonitor, blinded monitor after data lock, QA/QC monitor)

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Close-out – Records

Sponsors may collect originals OR copies• Ensure a copy of all IP accountability records remain at site

• FDA will review all recordsIDS maintains its own electronic inventory• Secure, retrievable on demand after archivalIDS archives separately• Copy originals for regulatory binder or memo stating that originals are with IDS

• If copy – need to copy all records

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Bringing it all together IP flow through study

• Investigator(CRC)/IDS receives IP and logs into site/pharmacy– If IDS receives, CRC may pick‐up some IP to store on‐site: this step must be logged as well!

• Investigator(CRC)/IDS logs IP dispensation to patient• Investigator(CRC) logs subject returns

– Log intermittent IDS returns and reconciliation• Close‐out:

– Log final reconciliation– Log IP return (all used and unused IP) from site to IDS/Sponsor for destruction

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Inspection (Big Picture)Element Think About ExampleAll IP Received How was this captured? Supporting

documents (packing lists, log entries, IVRS)

Plus 45 bottles

= All IP used by subjects

Was IP dispensed only to subjects enrolled in the trial? Do return logs match diaries?Were correct doses dispensed?

Minus 17 full bottles and 20 partial (X tablets total used)

and IP damaged or lost

How accurate and complete is theexplanation for this?

Minus 4 tablets fell through grate in floor

and IP returns/ destruction

Are return or destruction documents complete? Do they detail everything that was actually returned/destroyed?

Minus 8 fullunused bottles and (20 minus X) tablets= 0 if no discrepancies

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Inspection Preparation Storage

• Is there documentation product was properly stored throughout the trial

• If any variances – are they documented? How?

Discrepancies• How are they documented?• If errors in documentation, how corrected?

• Is there evidence that the problem was identified and addressed appropriately?

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Case #1- New TrialYour site has been contacted by a pharmaceutical company to participate in an upcoming open label, randomized, oral drug trial. In planning, the PI discusses this trial with your site’s research staff. You notice that investigational product will be provided in this trial by the Sponsor.

Your first step should be?

1. Discuss the use of IDS with the Principal Investigator.2. Locate a locked storage shelf in our office to keep the

medication.3. Run. Run far away. You’ve already got 7 studies and you just

can’t handle any more!

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Case #1- New TrialYour site has been contacted by a pharmaceutical company to participate in an upcoming open label, randomized, oral drug trial. In planning, the PI discusses this trial with your site’s research staff. You notice that investigational product will be provided in this trial by the Sponsor.

Your next step should be?

1. Purchase a new lock with a unique identifying number for the medication cabinet.

2. Contact IDS to discuss budget and plan.3. Train research staff on how your site plans to distribute the

medication.

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Case #2-OCR You are the CRC for a drug trial and all of your participants have completed all of their treatment visits and are currently in follow up. You’ve been contacted by the Office of Clinical Researchand informed that your site will be scheduled for a compliance review.

As a CRC you need to…?

1. Stuff all of the paperwork you have waiting to be filed in the bottom drawer of your desk and hope that they don’t ask for it.

2. Ensure all IP accountability forms are complete3. Quickly create an accountability log for all medications given

to participants in this trial.

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Case #3- Your trial is completeYou are the CRC for an open label medication trial and all of your participants have completed all of their visits, the data has been locked. The Sponsor has conducted their close out visit. You have closed the trial with the IRB.

As a CRC you need to…?

1. Assure that all of the paperwork associated with the trial is filed.

2. Place the trial files in boxes and place in the hall for storage.3. Contact IDS and request a copy of the final study medication

records for your files.4. Call the FDA and tell them to come on in, you’re ready.

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Resources OCR website: https://www.med.upenn.edu/ocr/

• Forms, Tools, and templates– Principal Investigator Compliance Assessment (PICA)– IP Accountability Study Log; Subject Log

• Penn Manual for Research, – FDA Regulated Drug and Device Research

○ Investigational Product Management –IDS– Coming Soon: A Guide to Working with IDS

• IDS email: – [email protected] ‐Main Facility– [email protected]‐ IDS North

• IRB website: – Principal Investigator’s Acknowledgement of Responsibilities

http://www.upenn.edu/IRB/sites/default/files/PI_Acknowledgment_of_Responsibilities_14‐Oct‐2015.pdf

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Questions??

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Thank you!

Nikki Cortez, M.S.Ed• Clinical Research Monitoring Specialist• Tel: (215) 349‐5297• Email: [email protected]

Office of Clinical Research• Tel: (215) 746‐8334• Email: [email protected]

investigational product accountability

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