Compliance packaging in clinical trials: from blisters to smart packaging

Most sponsors already use some form of compliance packaging, such as calendar blisters, wallet packs or bottles with a dosing diary in the kit. These make the regimen easier to follow and let the site count what comes back at the end of the study. Adherence packaging, smart packaging and compliance packaging describe the same family of tools, with the emphasis moving from helping the patient take the dose to telling the sponsor whether they did.

This guide goes through that family in order, from the plain blister to the connected dispenser, and sets out what each one tells you about a dose. The useful test for each is whether you can be confident the patient received the doses attributed to them, at the times recorded.

What compliance packaging means, and what sponsors actually mean by it

Compliance packaging is packaging designed to help a patient follow a dosing schedule. A calendar blister that prints the day under each cavity is the usual example. In a trial, sponsors normally want more than that. They want the packaging to show whether the patient followed the schedule, and that is what adherence packaging and smart packaging usually refer to. The terms are used for the same products, and the choice of word tends to depend on whether the person is from a packaging, clinical or regulatory background.

In the adherence monitoring literature the electronic options appear under digital adherence technologies, sometimes shortened to DAT. The packaging-based ones include smart blister packs that detect when a tablet is pushed through the foil, smart bottles and caps that detect when a container is opened, and dispensers that release and count individual doses. Connected inhalers and injector pens belong to the same family for other dosage forms, but this guide covers solid oral medication. What the electronic options have in common is a timestamped record made when the dose leaves its packaging, which goes into the trial’s adherence data without anyone having to fill anything in.

What smart packaging is not

The same phrase is used across the pharmaceutical supply chain for technologies that have nothing to do with adherence. Serialisation gives each saleable unit a unique identifier under regulations such as the FMD in Europe and the DSCSA in the United States, to keep falsified medicines out of the supply chain. RFID and barcode track-and-trace show where a product is between the manufacturing site and the depot or pharmacy. Temperature indicators and cold chain loggers record how a product has been stored. All of these are sometimes sold as smart packaging, and all of them are useful, but they monitor the product rather than the patient, so they won’t give a trial any adherence data.

Why packaging became the adherence tool

Packaging became the way trials measure adherence because it was already part of the process. The site dispenses a pack or bottle, the patient brings it back, and the site counts what is left. Pill count compliance, the number of tablets missing compared with the number that should be missing, is still how most trials work out adherence, and the count overlaps with the drug accountability that GCP requires anyway.

A pill count tells you how many tablets left the pack, but not when they left or whether they were taken. Studies comparing pill counts with electronic monitoring have repeatedly found that counts overstate adherence, partly because some patients empty tablets before a visit. A count also gives one number per visit, so a patient who took nothing for a week and then doubled up can look the same as one who took every dose on time.

Active and passive measurement

The adherence measurement methods divide into two groups. Some methods need the patient to do something beyond taking the dose, such as completing an electronic diary entry, confirming a dose in an app or recording a video of themselves swallowing a tablet. These are usually called active methods. Other methods capture their data as part of the dosing action itself, because the electronics are in the packaging or the dispenser and the record is made when the patient takes the dose. These are called passive methods.

An active method measures whether the patient completed the reporting task, and infers from that whether they took the medication. Unfortunately, it’s possible for that to be wrong. A completed diary entry doesn’t show that a dose was taken, and the best known evidence for this is a study of paper diaries fitted with concealed sensors (Stone et al., BMJ, 2002), in which patients reported completing their diaries at the correct times around ninety per cent of the time while the sensors showed they had done so around eleven per cent of the time. A missing entry doesn’t show that a dose was missed either, because the patient may have taken the dose and skipped the reporting, and the data can’t tell the two apart.

Active methods have a second problem. The data they lose is not spread evenly across the study population, because the patients who stop completing a daily reporting task are disproportionately the ones who have stopped taking a daily medication. A statistician would call this data missing not at random, and in practice it means active methods lose coverage in the group of patients the trial most needs to observe. It is one reason self-reported adherence consistently comes out higher than electronically measured adherence when the two are compared in the same study.

Passive packaging-based methods don’t measure ingestion either. A dispensing record shows that a dose left the device at a given time, and only directly observed therapy or an ingestible sensor confirms that it was swallowed. For most studies the more useful question is what kind of error a method produces. The gap between dispensing and ingestion is small and roughly random across patients, while the gap in an active method is systematic and makes adherence look better than it is.

Smart blister packs: how they work and what they miss

A smart blister pack is a standard blister with a printed circuit laminated into the backing foil. Each cavity has a conductive trace across it, and when the patient pushes a tablet through, the trace breaks. A small module on the card records the time, and the data is read later, either at the site when the pack is returned or by the patient tapping the pack with a phone.

For a once- or twice-daily oral regimen this is a clear improvement on a pill count. You get a time for each cavity rather than a total at the end of the month, so you can see missed days, double doses, and a week of tablets pushed out ten minutes before a visit.

The pack records a cavity being opened, which is not the same as a dose being taken, because a tablet that is pushed out and dropped, pocketed or left on the side looks the same as one that was swallowed. The data also only leaves the pack when someone does something with it. If the pack is read by NFC, the patient has to tap it with a phone, and some patients never do, so a month of data can sit on a card in a drawer until the next visit. Packs read at the site avoid that problem, but the data then only arrives at visits, so there is no real-time view.

Smart blisters also need their own packaging run. The drug has to be blistered into the instrumented card, which means a secondary packaging step at a facility that handles them, months of lead time for a new presentation, and a cost per pack that rises with the number of cavities. For a study that would otherwise be supplied in bottles, that is often the point where a smart blister stops making sense, and our guide to what sponsors use connected dispensing for covers keeping the existing bottle instead.

Smart pill bottles and caps

Smart bottles and caps record when the container is opened. Some are read by NFC, where the patient taps the cap with a phone, and others have a cellular connection built into the cap or bottle. An opening shows that the container was opened, but not how many tablets came out or whether any did. Most fit a standard or near-standard bottle, so the effect on drug supply is smaller than with a smart blister. Our smart pill bottle guide covers what opening data does and doesn’t show.

Connected dispensers: per-dose data without patient action

A connected dispenser attaches to the standard study bottle, so there is no repackaging and nobody has to load pills into a device. Each press releases a single pill, and the dispenser records the time of each one as it happens.

The data is collected automatically by an app on the patient’s phone. The app doesn’t need to be open, it keeps working if it’s swiped away, and the patient doesn’t tap, scan or do anything else to send the data. The phone only has to be near the dispenser, and in our testing that works across a home, including between floors. When the phone is out of range, for example while the patient is away for a day or two, the dispenser keeps recording and the phone collects the backlog the next time it is nearby, so the data arrives late rather than going missing. For a patient without a phone, the dispenser stores every event and the site reads it at the visit.

Each time the phone connects, the platform logs a sync, including syncs with nothing to report. That lets you tell a missed dose, where the phone checked in and nothing was dispensed, from missing data, where the phone hasn’t checked in, without waiting for the next visit. The Pill Connect dispenser works this way.

Comparing the options

Regardless of features, it’s important to review what needs to happen for the data to be delivered. More actions needed and compliance measurement becomes measuring compliance to that tool.

A connected dispenser only reports in real time when a phone with the app installed is near it. Without one, it records every dispense and holds it until the phone comes back into range or the site reads it at a visit. That makes a quiet period a delay rather than a gap. With a cap that needs a tap, a quiet period usually means the data was never collected.

Choosing for your study

The right option depends on the regimen, the phase and where dosing happens. A once-daily oral drug in a study with frequent site visits can be well served by a pill count or a smart blister, as long as the blister run fits the supply timeline. Studies where the timing of each dose matters, such as PK work or dose titration, need a record for each pill. Studies with long gaps between visits, or decentralised designs, need data that leaves the device without the patient doing anything, which is covered in our guide to adherence in decentralised trials. Our guide to monitoring adherence in clinical trials compares all of these with the methods that aren’t packaging based.

Whichever option you choose, a monitored device changes parts of the clinical supply workflow, and these are easier to handle at protocol and kitting design than after the supply plan is fixed.

Kitting depends on whether the device replaces the standard container or attaches to it, whether it ships with the drug or is fitted at site, and how many spares each site holds.

The investigational product label requirements still apply to the primary container, and the device instructions need to travel with the kit in the trial languages, so it is worth raising with the label vendor early.

Someone needs to own how each device is linked to a participant at dispensing, how the site confirms it is working before the participant leaves, and who replaces a unit that fails mid-study.

Alongside the usual accountability of unused medication there is a device to recover and redeploy, and the device’s record of doses dispensed gives the site a count to reconcile against.