6.3 Investigational Product Return and Destruction

Subject Returns and Compliance

The accountability cycle for a dispensed IP is not complete until the subject returns the product to the site. Managing these returns is crucial for determining subject compliance and ensuring the IP does not end up in the community.

Collecting Returns

Subjects must be instructed at every dispensing visit to bring back all IP at their next appointment. This includes:

• Unused pills or full vials.
• Partially used bottles or inhalers.
• Empty blister packs, boxes, and vials.

When the subject returns the IP, the coordinator must physically count the remaining product in the presence of the subject (if possible) or shortly after the visit. The return must be documented immediately on the Subject-Specific IP Log.

Calculating Compliance

Subject compliance (or adherence) is a measure of how well the subject followed the protocol's dosing instructions. It is usually expressed as a percentage.

Standard Compliance Formula: Compliance % = (Number of doses taken / Number of doses expected to be taken) * 100

To find the number of doses taken: Doses Taken = (Total dispensed) - (Total returned unused)

Real-World Example: A subject is dispensed 60 pills and instructed to take 2 pills daily for 28 days.

• Expected doses to be taken: 56 pills (2 pills * 28 days).
• At the Day 28 visit, the subject returns 6 pills.
• Doses taken: 60 dispensed - 6 returned = 54 pills taken.
• Compliance: (54 taken / 56 expected) * 100 = 96.4%.

Most protocols define acceptable compliance as being between 80% and 120%. If a subject falls outside this range, the coordinator must document the reason (e.g., 'Subject forgot to take doses on weekend', 'Subject took an extra dose for pain') and notify the Principal Investigator, as severe non-compliance may lead to subject withdrawal.

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Final Reconciliation

Before any IP can be destroyed or returned to the sponsor, a Clinical Research Associate (CRA), also known as a monitor, must perform final reconciliation. This usually occurs during a close-out visit or a routine monitoring visit.

The Reconciliation Process

The CRA will perform a three-way match to ensure accountability:

1. Physical Inventory: The CRA counts the physical IP currently in the storage area (active, quarantined, and returned by subjects).
2. Master IP Log: The CRA reviews the overall site log to ensure all shipments received minus all IP dispensed matches the physical inventory of un-dispensed stock.
3. Subject IP Logs: The CRA reviews individual subject logs to verify that what was dispensed minus what was returned matches the physical inventory of returned stock.

If the CRA finds that a bottle of 30 pills was dispensed, the subject returned 5 pills, but the physical count of the return is only 4 pills, this is a discrepancy. The site must investigate and write a note to file explaining the missing pill (e.g., 'Recounted by CRA on 10-Nov; original count by coordinator was incorrect. One pill missing, subject states it was dropped in the sink.').

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IP Return and Destruction

Once the monitor has verified the accountability logs and reconciled the inventory, the final step is the disposition of the used, unused, and expired IP.

On-Site Destruction

Many modern clinical trials prefer on-site destruction to save on shipping costs and reduce the risk of IP diversion during transit. However, on-site destruction is only permitted if:

1. The sponsor explicitly approves it in the protocol or a separate written agreement.
2. The clinical site has a formal Standard Operating Procedure (SOP) for drug destruction that complies with local and federal environmental regulations.
3. The destruction is documented on a specialized IP Destruction Form, detailing the kit numbers, quantities, method of destruction (e.g., incineration via a contracted biohazard waste company), and signatures of the person performing the destruction and a witness.

Handling Biohazards: IP that has been used (e.g., used pre-filled syringes, empty vials that contained biologics) is often considered biohazardous waste. These must be disposed of according to the site's institutional policies for sharps and biohazards, and this process must be documented.

Return to Sponsor or Depot

If the site cannot perform on-site destruction, or if the sponsor requires central destruction, the IP must be shipped back.

• The site must pack the IP securely, often separating used from unused product.
• A detailed Return Shipment Form or transfer of custody document must accompany the shipment.
• The site must retain copies of the shipping manifest and the Return Shipment Form in the pharmacy binder.
• Once the depot receives and verifies the shipment, they will send a final certificate of destruction to the site, closing the loop on the IP's chain of custody.

Key Takeaway on Documentation

Whether destroyed on-site or returned to a depot, the golden rule remains: If it wasn't documented, it wasn't done. The site must be able to prove the final disposition of every single unit of IP years after the study has closed.