Stefan Dürr

	From 1977-when the FDA began routine clinical trial audits-to 1990 insufficient drug accountability records were found in 25% of audited sites. From 1994 to 2010 FDA investigators found inadequate drug accountability records in about 15% of sites audited in the U.S. and 20% in Europe. 

	FDA trial site audits are designed to evaluate the conduct of research and ensure patients’ rights, safety, and welfare have been protected. During an audit, the FDA investigates six areas to determine whether a site is in compliance with federal drug accountability regulations:

		Who is authorized to administer or dispense the investigational drug?

		Has the investigational drug been supplied to any unauthorized person?

		Can the records for investigational drug inventory be reconciled, i.e., the quantities shipped, received, used, and returned or destroyed?

		Can drug shipments, dispersals, and returns be verified?

		Is the drug stored in the manner mandated by the protocol?

		Does the storage of drugs with the potential of abuse meet the federal regulations for controlled substances?

	If a sponsor or CRO can’t answer these questions and prove compliance, consequences can be severe and far-reaching. A failed site audit can lead to costly delays, non-approval of the investigational drug, and/or criminal liability. Sites with inadequate drug accountability management may inadvertently increase safety risks for patients. For example, site staff might disperse the wrong dose or the wrong drug to patients. Insufficient drug accountability records may make it difficult for site staff to determine if a patient is treatment compliant or has returned all unused trial drug.

	Unfortunately, most sites still use paper records to manage drug accountability. Paper is hard to administer and puts a burden on site staff and monitors. Paper also creates opportunities for illicit activity by staff.

	Sponsors and CROs can prevent these problems and ensure trial site comply with federal regulations by adding electronic drug accountability to an existing IRT (Interactive Response Technology) system. Electronic drug accountability is proven to increase patients’ safety, save time and money, and ensure data validity.

	IRT systems have been used on thousands of clinical trials for a myriad of tasks from patient randomization to drug supply management and allocation. IRT helps enable drug accountability because it tracks drug dispensing units by warehouse, depot, and site location as well as by batch, bulk lot, packaging step, label group, and patient allocation.

	All trials can benefit from using IRT for electronic drug accountability management because IRT is designed with safeguards that reduce the risk of human error. It can automatically timestamp dispensing information; automatically flag entries that do not adhere to protocol; enforce compliance by mandating staff to write summary statements for potential protocol deviations; and, create an audit trail with electronic signatures that helps preserve the integrity of the trial data. IRT also allows for remote, site-level monitoring of drug accountability logs.

	These capabilities and the built-in safeguards make electronic drug accountability a more accurate and efficient method than paper. For example, IRT links records, which eliminates time-consuming collating of files at the end of the trial. This timesaving feature is also cost-effective because it reduces the need for costly site visits by the clinical trial monitor, which can account for up to 35% of the overall cost of a Phase III trial.

	IRT centralizes information and reports it in a uniform format that is always available for review. This is a vitally important feature for trials investigating drugs with the potential for abuse. For this type of trial, the FDA mandates sponsors provide all information including case report forms and final outcomes on all instances of drug diversion, discrepancies in inventory of the clinical supplies of the study drug, and noncompliance and protocol violations. Complying with this federal mandate requires a substantial increase in the administrative burden on clinical site staff when paper-based methods for drug accountability are used. The availability of centralized trial information provided by an IRT system is invaluable for this and other tasks including reconciling inventories of investigational drug supplies at study termination.

	A centralized accountability system allows sponsors to easily track trial drugs from manufacture to shipping, use, return, and/or destruction. IRT also provides site-level, real-time tracking of investigational drug supplies. This reduces the possibility of drug diversion or inappropriate drug assignment by clinical staff as well as patient non-compliance.

	Organizations should plan for some resistance to change before undertaking the switch from a paper to electronic drug accountability system. High-level stakeholders should develop an implementation plan for the change and write standard operating procedures for adoption and use of electronic drug accountability. The new procedures should ensure electronic accountability can fully replace paper when implemented. If done correctly, electronic drug accountability combined with an IRT system will help ensure sponsors and CROs can answer those critical six questions regulators ask during audits.

Stefan Düerr, Senior Director of Client Delivery and Head of Drug Supply Center of Excellence 

Articles

During an audit, the FDA investigates six areas to determine whether a site is in compliance with federal drug accountability regulations-can sponsors answer them?


Sponsors—Can You Answer 6 Questions Regulators ask During Audits?

	From preventing drug overages to ensuring patients receive the right medication, managing clinical trial supply is no easy task. However, it’s an important one for sponsors to consider carefully because the right strategy can help save a lot of money and reduce unnecessary spending.

	The pharma market is growing, which means there is a lot of opportunity in the industry. In fact, revenue numbers exceeded the one trillion-dollar milestone in 2015 per the 

International Trade Commission’s 2016 Top Markets Report on Pharmaceuticals

. A good portion of that revenue is put into research, so developments are happening in the clinical trial space.

	Despite these advancements, we waste a lot of these investments due to problems with clinical supply management. Our research team at Cenduit recently reviewed 200 clinical studies that have wrapped up over the last two years to gain more insight on this issue. Out of those studies, 62% of the material packaged and released was not even used. Basically, two thirds of supplies never actually made it to a patient.

	When it comes to assessing the costs associated with clinical trials, one of the biggest factors to consider is drug expenses. This includes everything from production, to packaging and handling, and storage. For these actions, there are fixed and variable costs that must be examined closely.  

	As an example, let’s consider a trial that has a thousand patients getting three kits each. That’s 3,000 kits that must be produced. But there are other costs that need to be considered, particularly the need to produce an overage because we don't know where those 1,000 patients are going to be at all times. Buffers will be required to make sure sites don't run out of drugs.

	To calculate overages accurately, clinical trial managers must look at what is driving supply needs and costs-which is not as simple as settling on a comfortable number and checking off the box. If you have many dispensing visits, for example, that might mean you can better forecast site needs and would require less of an overage. If you have a high number of sites with many depots; however, you might need a higher overage, especially if you will be replacing the drug more often due to limited shelf life of the drug.

	Sometimes patients can be screened before drug shipments are initiated, which typically increases the possibility that the drug is going to be used. However, much of that depends on the study design. Very often, the time of the first shipment to a patient is unknown and this itself serves as a buffer stock. In general, the overall buffer stocks at sites need to be carefully watched to ensure these are always well below the total overage.

	The key to striking a balance in the management of all these variables, to anticipate drug needs and expenses, is getting accurate information up front. Getting reliable data will help you calculate recruitment rates, patients screened, and number of patients that need to be randomized. The more information you have in your system on patients, the better off you will be.

	This is all important because the potential savings on overages are huge. As an example, consider a global study with 100 sites. Say you have 1,000 patients who will need monthly kits for one year, which equals 12,000 must-have kits. If the drug costs $100 per kit and upon close examination you’ve discovered that a 50 percent overage will be sufficient, rather than the 200 percent overage you originally forecasted, that means you’re saving 1.8 million dollars!

	Shipping costs can also be a major drain on resources if not effectively assessed. A useful factor to consider in reducing shipping costs is the resupply interval, which refers to the average time between two shipments to a site. Essentially, you can save money if you’re able to increase that interval and ship less often.

	Another aspect to consider in reducing shipping costs is the just-in-time margin. If you want to decrease the amount of shipments, you want to make sure that you trigger the resupply shipment only shortly before there is a stock-is-out risk. You want this timing to be right because you don’t want a shipment that just sits at site for a long period without being used. We've seen studies where the resupply settings trigger drug shipments that go unused even until a next shipment arrives on site, which is inefficient and wasteful.

	The key here is to find a way to send more drugs per shipment without increasing buffer stocks at sites and sending the shipments as late as possible, but early enough to ensure no patient is ever without drugs.

	It’s a delicate balance, but the potential savings are huge. Let’s say you have 100 sites in a three-year study and shipping costs of $500 per shipment. If you can increase the 30-day resupply interval to 60 days using some of the strategies discussed, cost savings are almost a million dollars! That’s quite a lot of money when you think about it from this perspective.   

	It has been said that computers are fast, reliable and stupid. We need to make them more intelligent through solutions that help to streamline processes and make things more efficient. This is where the latest Interactive Response Technology (IRT) platforms come into play.

	Today, IRT has developed into modern, configurable systems. With enhanced development and delivery methodology, these systems can generate faster builds, improve system quality and simplify clinical trial processes. These developments over the past several years have certainly brought many benefits to Randomization and Trial Supply Management (RTSM) delivered on IRT. Interestingly, though, while some eClinical technologies, such as Electronic Data Capture (EDC), are readily brought in house by biopharma companies and Contract Research Organizations (CROs), IRT is rarely “tech transferred” by comparison. Instead, pharma companies generally seek IRT vendor relationships to ensure high-quality builds that meet their needs and avoid the potential pitfalls associated with RTSM.

	The speed and agility benefits being realized by configurable systems can be likened to creating a faster car with better handling. Yet even the best high-performance car needs a skilled driver-a driver who can navigate effectively, anticipate, and avoid risky situations and at the same time, make sure that all passengers are comfortable throughout the ride. Likewise, even with an effective, modern platform, tapping into the experience of an IRT specialist is essential to get the best performance out of your system.

Maintaining optimal supply chain performance 

	A faulty clinical supply chain is perhaps the most common pitfall in IRT setup and maintenance. This is because every trial has its own unique design and requirements. The main goals of an effective supply strategy include ensuring that every patient gets their medication on time and minimizing any waste due to over-supplying sites.

	These two goals are obviously at odds with each other and require balancing many factors. Some of the key considerations include:

		The countries, regions, depots and sites where it will be used

		Regulatory requirements for shipping drug to each region

		Minimizing shipping costs, planning the volume and frequency of shipments to avoid stock-outs at depots and sites

		Frequency of patient visits, varying patient recruitment patterns and managing expiry dates

	IRT specialists have a great deal of experience in balancing these types of factors to ensure that every patient gets the right drug at every dosing visit, while simultaneously making sure that the number of costly shipments is minimized. It is not simply a matter of plugging in a few parameters in a “set-it-and-forget-it” manner. It requires ongoing vigilance, the ability to anticipate and foresee potential risks and when necessary, taking appropriate actions to keep the supply chain on track.

	Another issue that affects the supply chain is accurately forecasting drug requirements. Many sponsors today use forecasting methods or systems that are detached from the actual IRT system to estimate the amount of drug required to run a study. This means that the baseline forecast is often out of sync with the IRT algorithms for identifying the need to ship more drug to a depot or site, how much drug will be sent with each shipment, whether any drug pack type should be sent and so on. Then as the study progresses, the additional forecasts may become further detached from the actual supply chain if the real-world information from the IRT system is not regularly fed into the predictive models.

	Once again, IRT subject matter experts can provide the insights and advice necessary, not only for baseline forecasting, but also for ongoing modeling of the supply chain using real-world data directly from the system. Further, vendors who are deeply integrated with international supply companies that specialize in global logistics can provide sound advice on setting up and optimizing your supply chain. They can also offer effective forecasting solutions and advice on using these to ensure success.

	Drug accountability and returns management (DARM) is an important component in a cohesive supply strategy, but many clinical trial sites today still use an ancient, manual process with paper records. This type of accountability system is difficult to administer and burdensome for busy site staff, as well as clinical trial monitors. Manual accountability systems can also create opportunities for illicit activity by staff as well as patients, such as drug diversion for future use or sale and disregard for randomization assignments.

	The good news is that advances in technology have rendered paper-based drug accountability records obsolete. Electronic drug accountability, a function that can be added to an existing IRT system, can help ensure gaps left by legacy paper trails. These solutions provide the capability to:

		Ensure that all entries adhere to the protocol

		Monitor drug accountability logs remotely

		Resolve queries to rapidly clear up potential issues

		Customize the system to meet your unique trial needs

		Increase the safety of patients in clinical trials

	IRT is an ideal system for management of drug accountability because it was designed with safeguards that reduce the risk of human error. It automatically time-stamps dispensing information, automatically flags entries that do not adhere to protocol, enforces compliance by mandating that staff write summary statements for potential protocol deviations, and creates an audit trail with electronic signatures that helps preserve the integrity of the trial data. IRT also allows for remote, site-level monitoring of drug accountability logs. Finally, to meet the unique needs of every trial, some vendors offer a fully customizable IRT.

	Returning to the analogy of a high-performance car, it is critical to have the right “driver” to navigate effectively and to skillfully negotiate risky situations. It is also vital to have an experienced “pit crew” to maintain your investment and make sure it continues to function optimally and at the highest levels. Along the same lines, combining an advanced IRT platform with an experienced service team can provide many advantages, including:

		A truly optimized supply chain that ensures every patient gets the right medication at every visit

		Saving money and avoiding overages that leads to expensive wastes

		Maintaining overall study health for critical factors such as treatment balance

		Avoiding major risks that impact trials, such as unintentional unblinding

		Effective planning that results in getting the most out of your IRT configuration

	To maximize efficient supply management, IRT should be involved from the very beginning of a trial and integrated with other supply planning and simulation tools. This can help ensure the accurate forecasting of material needs and that there is no disconnect between the supply strategy used to compute overage and the supply strategy implemented in IRT.

, Senior Director of Project Management, Cenduit

Managing clinical trial supply is not easy for the pharmaceutical industry between drug overages and right medical distribution. However, this is an important topic for sponsors to consider because the right strategy can help save money and reduce unnecessary spending.


Stefan Dürr

Articles

Sponsors—Can You Answer 6 Questions Regulators ask During Audits?

Meeting the Clinical Supply Challenge with IRT