Have you ever experienced a drug shortage in a clinical trial? The affects can fall anywhere between small and fixable (i.e. a minor delay or a few rescheduled site visits) to big and catastrophic, like when serious supply issues put a study at risk. Avoiding problems at both ends of the pain scale and everywhere in between, is both crucial and challenging.

If your study is already underway or on a collision course with disaster, there may not be an opportunity to provide the “perfect” solution, but with parameter-driven Interactive Response Technology (IRT) tools you can avoid facing the same predicament next time. Here are some first-hand-insights. 

Impacts of Shortages
Some of the hardest-hitting impacts of drug shortages include: subject loss; lowered enrollment; budget escalation; delays and even study discontinuation. Let’s examine each of these impacts a bit closer to understand the potential outcomes of drug shortages and how to steer clear of them in your own studies.   
 
Greatly Lowered Enrollment Expectations
Have an inkling that drug supply may get complicated in your study before it even starts?  Time to ask some tough questions and the earlier the better. Get answers about the following issues during preliminary planning:

• Can the study support fewer subjects than intended if we run into drug supply issues?
• Are there country supply issues that require enrollment of fewer subjects at certain locations?
• If so, does this place heightened expectations for enrollment on other sites or countries?
• If a study has multiple treatment arms, is there potential need to lower enrollment for one arm?
• If so, will this throw off the expected balance?

Significant Subject Loss
Not having the right treatments available on site when and where needed can prevent subject randomization. This is an especially troubling consequence when initial consent has already been given as it can delay participation, or worse, cause subjects to be withdrawn mid-study. Subject loss can create undesirable affects at a site level, and depending on how widespread the problem is, may impact multiple sites and countries.

Serious Budget Escalation
Delays associated with drug shortages can cause budget escalation in a variety of areas, some easily overlooked until someone tallies up budget overruns. This includes extra costs associated with site and technical services. Unexpected shipping costs can for instance total hundreds of thousands of dollars for certain treatments. One practice study teams often resort to—shipping small supply quantities—is not cost-effective, neither is making unanticipated country-to-country or site-to-site shipments. The latter “fix” involves navigating regulations and requirements of various countries, which adds another layer of complexity. Opting instead to manufacture more supply to cover unanticipated needs is yet another tough choice as it will swell the budget and introduce delays.  

Study Delays & Discontinuation
While the wait is on for more supplies, delays in supply manufacturing and packaging can lead to a slowdown in subject enrollment or even inclusion in the study. This may not only protract the enrollment period, but also the overall study timeline. Supply problems that cannot be readily solved may even cause discontinuation of the entire study.

These are some of the most serious impacts of drug shortages in clinical trials. Understanding the root causes can help study teams to address, or ideally avoid them altogether. Here are a few tips to help you have a successful trial.

Avoiding Drug Shortages
With so many factors playing a role, a drug supply issue in one area can touch many others. By far the best practice is to anticipate where problems may arise and take steps to keep them from escalating if they do occur. With a few simple changes, it really can be easier than one may think to make impactful improvements. Our experience shows that assumptions, planning, and communication are behind many drug shortages. Here’s where our Trident IRT team sees some of the most common problems.

Manufacturing & Shipping
Many manufacturing and shipping issues can be prevented during planning. Planning smart from the start can help avoid delays and associated issues when you do these two things:

• Ensure the distribution center is able to keep up with demand. Say for instance you planned on “X” number of shipments per month and the depot can only meet half that, balancing site expectations and supplies will be difficult, if not impossible.
• Allow for sufficient lead time to correct manufacturing and supply availability issues (e.g. comparators and ancillary supplies). Otherwise you may find yourself with ready and willing sites, but not the necessary supplies.

Communication
A little communication, especially across functions, goes a long way. During planning, be sure to discuss important topics like these with the rest of the study team:

• Amount of supplies to be packaged
• Timing of packaging
• Timing of shipping

It’s important that all team members are aware of timelines and expectations from the beginning so that resources can be assigned accordingly.

Consumption vs. Double Blind
Keep in mind that drug supplies for all treatment arms must be on site during the randomization period. This is especially critical in double-blind randomized trials when it may be hard to predict what supplies will be needed and at what time. It’s also an important consideration when designing how randomization will work in your trial. It is much easier to change the randomization method early in the study development process as opposed to after systems are being built and/or after drug packaging is underway.

Timing of Supplies
Be careful not to send too much supply too early. Over-reliance on enrollment assumptions may cause too much supply to be sent to sites/countries right from the get-go, and this can have a domino effect on the rest of the study.

Enrollment Rates vs. Expectations
Sometimes what’s believed to be the best-case scenario—enrollment exceeding expectations—can actually lead to the worst-case scenario—insufficient availability of supplies. Keep an eye on enrollment. If the expectation is 20 subjects per month but twice or triple that enroll, inadequate drug supply may prevent enrollment.

Labeling
Be careful not to limit your drug supply options down the road when making decisions regarding local vs. global labeling. Keep in mind that overly restrictive labeling can prevent shipping of supplies between countries/locations if and when needed.

Data Review Frequency
No one likes to be seen as operating in a reactive vs. proactive mode, yet that’s what it may look like if data review is performed too infrequently. Watch out for things like:

• Supply monitoring and enrollment tracking performed too infrequently
• Resupply expectations not kept updated to reflect actuals during enrollment
• Supplies replaced at locations although unneeded, impacting expiry and/or re-labeling

When it comes to the frequency of review, you’ll have to decide what’s right for your study. The important thing is to be willing to adjust expectations as the trial progresses.

Logging Assignments in IRT
Beware of how fast things can get messy if sites begin to pull supplies from shelves without logging assignments into the IRT. This situation most commonly occurs with open-label or bulk drug studies. It can quickly lead to inaccurate inventory resupply predictions and other drug accountability issues so don’t allow not logging assignments in the IRT to be tolerated.

Other Planning Details
Be sure to nail down all of the planning details surrounding activities such as:

• Re-test dates
• Obtaining approvals (allow time for re-labelling and system updating)

It’s important to know timeframes surrounding re-labeling and/or new packaging runs upfront in case there are additional supplies and/or supply testing needs to be accommodated.

Accounting for Damaged Supplies
While it is impossible to foresee things like incidents and accidents resulting in damaged supplies, study teams may be spared from added pains by taking into consideration potential loss that could occur due to:

• Temperature control
• Unexpected damage that may occur during shipping

A Solution Using Predictive Technology
As evidenced above, avoiding drug shortages takes significant upfront planning with a great deal of tasks to be completed prior to study start. Early in the protocol planning process, it is ideal to include a supply planning and forecasting tool to provide supply chain managers information to help avert delays, supply related compliance issues, and other obstacles that can sometimes lead to supply issues and subject loss.

However, tools can be implemented during the trial design phase to help address these challenges. Certain assumptions are made based on information about the study protocol, projected enrollment, location of trial sites, and other information supplied by the clinical and supply management teams. Forecasting tools then provide an initial prediction of trial supply needs taking into account a variety of ‘what-if’ scenarios to project unpredicted demand.

After trial launch, supply managers can import live data and re-run the original simulations. This provides an opportunity to adjust resupply settings and controllable variables to optimize supply utilization. As trial conditions change and more data about sites, population, utilization, costs and other elements are collected and fed into the simulation, projections can be updated and refined. But projections are just that, projections. So once the actuals are available, you are able to generate real-world forecasts and even identify serious issues that may have otherwise been overlooked, such as drug supply shortages. Real-time data can help you to plan around critical points in the trial and ensure subjects are dosed in time with the protocol design.

Predictive clinical trial supply management tools can make it possible to avoid many of the drug shortages discussed here.
Together with early planning, such tools can also make the difference in whether a trial gets delayed, flounders for lack of supplies, or is a success. 

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John Burns is the senior IRT project manager at BioClinica.