Responsibilities in Handling and Accountability of Investigational Product

Part of Good Clinical Practice (GCP) — ICH E6(R3): Investigational Product (IP) Management.

About 7 minutes. Free, in your language, no account needed.

Why this matters

Investigational product accountability is a common source of inspection findings. A missing bottle, an unexplained count, a dispensing entry with no date. Each raises the same question: did this participant receive what the protocol said? If the records cannot answer that, the participant's data may not be usable. Accountability is the evidence that the trial happened as designed.

Who is responsible

International Council for Harmonisation (ICH) guideline E6(R3) for Good Clinical Practice (GCP) is direct about this. Section 2.10.1 states:

"Responsibility for investigational product(s) management, including accountability, handling, dispensing, administration and return, rests with the investigator/institution."

The same section adds that the sponsor "may facilitate aspects of investigational product management," for example by providing forms and computerized systems, and by arranging distribution to trial participants. Facilitating is not owning. Responsibility stays with the investigator and institution.

Section 2.10.2 covers delegation. Where the investigator or institution delegates some or all investigational product activities to a pharmacist or another individual, in accordance with local regulatory requirements, that person works under the investigator's oversight.

Even when the principal investigator delegates tasks to pharmacy or study staff, responsibility cannot be delegated.

How much oversight is enough

Section 2.10.3 makes the level of oversight proportionate rather than fixed. It depends on:

• the characteristics of the investigational product
• the route and complexity of administration
• the level of existing knowledge about the product's safety
• the marketing status of the product

A first-in-human intravenous infusion needs closer oversight than an authorized oral tablet used unmodified. This is Principle 7 applied to the pharmacy.

The accountability record: exactly what E6(R3) requires

Section 2.10.4 is the most examinable text in this lesson. The investigator or institution, or a pharmacist or other appropriate individual, should maintain records of:

• the product's delivery
• the inventory
• the use by each participant, including documenting that participants were provided the doses specified by the protocol
• the return to the sponsor, and destruction or alternative disposition of unused product

Those records should include these fields:

• dates
• quantities
• batch or serial numbers
• expiration dates, if applicable
• the unique code numbers assigned to the investigational products and to the trial participants

Section 2.10.4 allows flexibility for authorized medicinal products. For those, alternative approaches may be considered in accordance with local regulatory requirements.

Storage, use and participant instruction

Three short sections carry a lot of weight.

• Section 2.10.5 — the investigational product should be stored as specified by the sponsor and in accordance with applicable regulatory requirements.
• Section 2.10.6 — the investigator should ensure the investigational product is used only in accordance with the approved protocol.
• Section 2.10.7 — where applicable, the investigator or a designated person should explain the correct use of the product to each participant, and should check "at intervals appropriate for the trial, that each participant is following the instructions properly."

Section 2.10.7 is an active duty. Explaining once at randomization is not enough. You must check, more than once, that the participant is taking the product as instructed.

Supply to the participant's location

Section 2.10.8 is new in R3 and changes what site staff must plan for. The verified text:

"The investigational product may be shipped to the participant's location or supplied to/dispensed at a location closer to the participant (e.g., at a local pharmacy or a local healthcare center). The investigational product may be administered at the participant's location by investigator site staff, the participant themselves, a caregiver or a healthcare professional."

Under the previous revision, R2, the assumption was that the product moved from sponsor to site to participant. R3 explicitly allows direct-to-participant supply and administration away from the site.

Nothing else changes. The accountability duties of 2.10.1 and the record fields of 2.10.4 still apply. For a product that never entered your building you must still show who shipped it, when, in what quantity, under which batch number, to which participant code, and what happened to what was not used. Section 2.10.9 adds that investigational product management must follow applicable regulatory requirements, with safeguards for product integrity, use per protocol, and participant safety.

Practical accountability at the site

The guideline sets the requirement. These are the practices sites use to meet it.

• Receipt — record the date and time received, verify contents against the packing list, record quantity, batch numbers and expiry dates, and record the shipment condition including any temperature indicator. Report discrepancies to the sponsor at once.
• Reconciliation formula — starting inventory plus received, minus dispensed, minus destroyed or returned, compared against the physical count. Reconcile by lot and, where applicable, by participant.
• First-expire, first-out (FEFO) — dispense the stock expiring soonest, so usable product is not lost.
• Two-person verification — a second trained person independently checks the dispensing entry against the physical product before it leaves the pharmacy. This is site practice, not an E6(R3) requirement, but it prevents the errors inspections find.
• Segregation — keep quarantined, expired and returned product physically separate from dispensable stock.

Section 3.11.4.5.3 tells you what a monitor will confirm: that storage conditions are acceptable, that supplies are sufficient and used within their shelf life, that the correct product went only to eligible participants at the protocol-specified dose, and that receipt, storage, use, handling, return and destruction "are controlled and documented adequately."

In practice

Tomas is the research pharmacist at a hospital site running an oncology trial for ABC Pharmaceuticals. He holds the delegated investigational product activities under section 2.10.2. Dr. Sarah is the principal investigator.

A monitoring visit finds a discrepancy. The accountability log shows 48 capsules dispensed to participant 014. The physical count of returned product suggests 42.

Tomas works the reconciliation: starting inventory plus received, minus dispensed, minus returned. The count is short by one bottle of six. He finds the bottle in the returns bin, logged as received back but never entered against the participant.

Two things follow. The record is corrected with a dated, attributed entry explaining the correction, without obscuring the original. Dr. Sarah then documents the root cause: returns were logged on paper at the counter and entered into the system hours later.

The corrective action is a process change. Returns are now entered at the point of receipt, and a second staff member verifies the entry. Dr. Sarah reviews the accountability log monthly rather than only at monitoring visits.

Under section 2.10.1 this is Dr. Sarah's responsibility, even though Tomas does the work.

Key takeaways

• Section 2.10.1 places responsibility for investigational product accountability, handling, dispensing, administration and return with the investigator and institution.
• Delegation to a pharmacist under section 2.10.2 keeps the delegated person under the investigator's oversight; responsibility cannot be delegated.
• Section 2.10.4 requires accountability records to include dates, quantities, batch or serial numbers, expiration dates where applicable, and the unique code numbers of the products and participants.
• Section 2.10.3 makes the level of investigator oversight proportionate to product characteristics, route and complexity of administration, safety knowledge and marketing status.
• Section 2.10.7 requires the site to explain correct use to each participant and to check at appropriate intervals that instructions are being followed.
• Section 2.10.8 permits shipment to the participant's location and administration there by site staff, the participant, a caregiver or a healthcare professional, without reducing accountability duties.
• If the accountability record cannot show what a participant received, the trial cannot prove it happened.