Unblinded study medication for better clinical trials

12 January 2018

Providing subjects with unblinded medication in studies and supplies is fraught with difficulty. Clinical Trials Insight examines how traditional processes cope with the challenge, and asks how studies might be made more flexible and affordable while increasing safety and adherence.

You can tell how important packaging is by the number of regulations that govern it. The huge list of rules dictating how to write accessible information, use Braille, and explain dosages, as well as the guidelines addressing naming rights, copyright and so on can be a headache for any compliance officer.

Another thing to consider is the possible effect of packaging on patients. This is usually minimised by blinding products; the current method of preparing supplies is to remove any commercial packaging prior to repacking.

Blinding or masking, according to CRO Almac Group, is “intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial”.

It is used as a means to stop prior knowledge of treatments having an effect on how patients are recruited, allocated and cared for, as well as their attitudes towards the treatments they receive, the assessment of endpoints, the handling of withdraws and the exclusion of data from analysis.

Blinding makes patients “less likely to have biased psychological or physical responses to intervention; less likely to seek additional adjunct interventions; [and] less likely to leave [the] trial without providing outcome data, leading to lost follow-up”, according to CRO Almac.

Blinding makes patients less likely to have biased psychological or physical responses.

Investigators are also less likely to transfer their inclinations or attitudes to trial participants administer co-interventions, adjust dose and withdraw participants, and less likely to encourage or discourage participation in a trial.

The burden

Easing these ‘burdens of blinding’ is an interesting challenge, but one that could bring amazing rewards. Providing subjects with unblinded medication and supplies may be a better way to approach the conundrum. Unblinded study medication and supplies can create greater flexibility, and cheaper study management, as well as better subject safety, adherence and retention.

The World Health Organization (WHO) disagrees. In its recent report, ‘Placebo and drug kits in clinical trial design’, it argued that, as many trials involved multiple clinical sites, blinding was absolutely essential. WHO is backed by Applied Clinical Trials Online (ACTO), which advises that successful blinding reduces bias in randomised trials.

However, a study’s integrity may be at risk when a blind is unintentionally broken. One idea is to regard this eventuality not as a problem, but instead as an opportunity for new ideas to flourish. One is arguably better off working from a position that acknowledges that total blinding is effectively impossible to guarantee.

Factors working against total blindness may include conditions in which packaging conditions cannot be met (sterile fill), or a sponsor lacking stability data for unpacking/repacking, or where the original packaging is essential to the operation of the product, or where equivalent components (inhaler parts, or syringes, for example) cannot feasibly be obtained elsewhere.

Almac Group adds that pack-matching, whereby placebo treatments are designed to resemble certain commercial products, enable double-dummy designs to be used, while some dosage forms – such as inhalation devices – may be blinded using new technology. In short, the system is so heavily flawed that a rethink may be in everyone’s interests. Unblinded trials require collaboration in the early design stages. According to WHO, “Cooperation among regulators, ethics committees, and sponsors to reach consensus on key ethical and regulatory questions is essential, and has proved particularly valuable in situations of urgency and in low-resource environments.

“Efficient conduct of the trials without unnecessary regulatory barriers is equally important. Regulations on importation and dispensing of placebos for clinical trials, could delay access.”

Safety mechanisms

Well-designed clinical trials should also be complemented by post-approval safety assessment mechanisms, as many new medicinal products are introduced early, or into developing countries with limited pharmacovigilance capacities.

This applies particularly to unblinded trials.“New guidance has become available on safety surveillance,” says WHO, which proposes a structured process for evaluating whether or not significant knowledge gaps exist, or if passive safety surveillance is adequate.

Easing these ‘burdens of blinding’ is an interesting challenge, but one that could bring amazing rewards.

According to ACTO, in terms of packaging, one must ensure that proper technology configuration for adaptive trials is set up and working efficiently. “Interactive response technology plays a large role in designing and controlling adaptive trials,” it says. This means that randomisation, the supply chain, and blinding strategy can remain robust and secure. “Preparing an adaptive design without adequate technology is not recommended, especially in larger trials.”

If a study sponsor does not have this technology in place, clinical supply professionals can help to select the appropriate software. Trial operators using unblinded procedures must therefore provide input into how drug packaging lists are configured; communicate batch releases that are recognised in the response technology; and establish a process for shipping materials based on orders sent by the technology to the depots, as well as providing input or authorisation to the materials being managed by the interactive response technology. Lastly, but not least, it must also ensure the naming and unitisation elements align with the physical nature of the materials.

The goals of blinding in clinical trials packaging should always be to prevent or minimise the risk of patients’ ability to differentiate between products due to the shape, size, colour, texture, weight, taste, smell and rattling (for encapsulated products). It is essential, therefore, that new ways of achieving these goals continue to be developed.

Packaging can influence patients’ attitudes to the treatments they receive in trials.
A primary goal of blinding should be to limit the likelihood of patents being able to differentiate between products based on appearance.

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