From Cradle to Grave

All experimental compounds tested in humans during clinical development are under stringent control to ensure that these drugs are administered only to eligible patients participating in approved study protocols. To that end, regulatory agencies worldwide mandate that all investigational products manufactured for clinical trials must have cradle-to-grave tracking for accountability, reconciliation, and destruction.^1,2

The life cycle of an investigational product (IP) is complex, transitioning from a manufacturing environment during production to a clinical environment during experimentation. Each of these situations has a unique body of governing regulations, Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP), respectively. The IP also reverts back to GMP when accounted, reconciled, stored, and packed for destruction as waste, creating an additional transfer between environments.^3,4,5

Sponsors must be able to document and demonstrate to regulatory authorities that they are in complete control of the drug supply chain at all times and can account for the whereabouts of all manufactured investigational products, whether consumed or destroyed. Currently, the administrative burden of accounting for and reconciling clinical supplies rests largely on the investigative sites, monitors, and depots, who generally perform these tasks manually and without the benefit of a central tool that tracks clinical material from manufacture to dispensation and return.⁶

Sponsors can reduce this burden and streamline the process start-to-finish by planning up front for the consideration of closeout activities and budget requirements. A plan that also includes the collection of data through a centralized, interactive database can help sponsors minimize errors, stay within budget, and more efficiently reconcile all IPs at study closeout per regulatory requirements.

Startup considerations

The need for rigorous control over IP progress through the manufacturing and clinical trial processes is apparent for controlled substances—those drugs with high potential for abuse, including narcotics, stimulants, and hallucinogens. However, in reality, every investigational product requires a clear and documented plan for accountability and reconciliation, not just those that can create physical or psychological dependencies.

In many instances, the timeline to launch the study and dose the first patient is very tight. Typically there are delays each step of the way, such as when batches fail analytical testing, protocols need to be finalized, and the labeling and packaging vendors impose their own requirements for lead time. The study start date is almost never extended to compensate for these delays. The narrow focus on study startup activities often does not include consideration of endgame activities, which can result in significant unexpected costs if a procedure for an IP has not already been addressed and incorporated into the study budget.

Early planning can help studies close out more quickly and efficiently and also bring hidden costs to light for inclusion in the overall study budget. Failure to account for closeout activities up front can result in the need to subcontract out the reconciliation tasks with potential budget overrun.

Figure 1 illustrates the potential paths of an IP through its life cycle and the types of information captured at each step during transit. This information is typically recorded by different users in different formats (supply logs, dispensation logs, and spreadsheet files) as the IP travels through the supply chain. The manufacturer, packager, warehouse, depot, and site may all account for and reconcile the IP as the study drug flows through their respective locations but typically do not reconcile their data with each other. The study sponsor, however, must ultimately be able to trace and document the drug's path through each functional area and resolve any discrepancies in the accounting process.

Figure 1. Potential paths of progress for an investigational product through its life cycle, from manufacturing to destruction.

Sponsors need to be aware of their own unique business practices regarding how to handle the remaining IP at the end of a trial and be mindful of the demands created on resources and budget in order to comply with regulatory requirements. While it is possible to backtrack and collect existing IP data after the fact, proactive planning can minimize the time and effort required to gather and clean the information for accurate accounting and reconciliation.

Mapping a prestudy plan

There are important questions that ideally should be answered prior to study startup. These include the following:

Who will manage the accountability/reconciliation of IPs? Defined roles and responsibilities for these tasks help make the process more efficient at the time of reconciliation. Assigning a resource proactively during the planning phase rather than reactively when the need arises ensures the task will be completed and according to regulatory requirements.

What levels/details should be documented? Regulatory agencies globally require documentation of and accounting for all IPs produced, but the requirements can vary depending on the country in which regulatory approval is being sought. Sites must abide by local authorities and sponsors must abide by the local regulations where the drug application is being filed.

Where should IPs be destroyed? Typically, IPs must be destroyed by a licensed incineration facility that can issue a certificate verifying destruction. For noncontrolled substances, sponsors also have the option of having the sites destroy unused drugs themselves. However, many sponsors elect not to go this route due to the risk of the drug being diverted and ending up on the street, creating legal and liability issues. Processes must be defined for returned IPs to travel from the warehouse to the destruction facility and these agreements established prior to the accumulation of IPs.

When should all IPs be destroyed? Again, it is important for sponsors to engage their shipping and destruction vendors early on to understand the lead times required and the costs associated with freight and transport. Often, transport runs to the destruction facilities must be scheduled a month in advance to ensure that a full load is being delivered.

Process considerations

Determining how to approach the accountability and reconciliation process will depend on local regulatory requirements, each sponsor's unique business practice, and preferences of the study manager. Nearly all of the aspects described below are best discussed early in the planning process rather than dealing with the situation as it arises toward the end of the study. Neglecting to address these issues at the time of planning and prior to final budget approval can result in inefficient closeout, delays in destruction, and additional storage and transportation fees incurred for unreconciled IP.

Site reconciliation vs warehouse reconciliation. Having both the site and the warehouse perform reconciliation on the same IP invariably leads to discrepancies. Site reconciliation is usually more accurate, more efficient, and less costly. That's because sites, for the most part, deal with smaller quantities at any given time and can reconcile the IP as it is returned. GCP guidelines require that sites account for both used and unused drugs at the time of study closeout, and sponsors can leverage this requirement for site-level accountability as part of the overall accountability process. Since site reconciliation is done before the IP is shipped back to the warehouse, the site knows exactly how much study drug was consumed during the study.

Contract warehouses can also perform accountability and reconciliation, but will often charge an additional hourly fee or per-receipt fee to receive, count, report, and prepare IPs for destruction. Many also charge a per-pallet, per-month fee for storage, starting with the first receipt of a clinical return. Warehouses also may not have resources immediately available to perform ongoing reconciliation as the returns arrive. Shipments may begin to accumulate before reconciliation is performed, and the accumulation can then translate into additional storage fees passed on to the sponsor.

Warehouses do not operate under GCP; consequently, their reconciliation activities are often performed with unregulated documentation procedures (often using simple spreadsheet programs) that also require reconciliation. The tracking spreadsheets are neither validated nor controlled, and must be printed and signed to be used as data for the audit trail in compliance with 21 CFR Part 11 (the FDA's requirement for electronic record keeping and maintaining an audit trail around investigational products). Further, warehouses can often only track kit numbers because they do not have access to study data from the sites, and thus cannot map kit numbers to patient numbers. This gap becomes the responsibility of the sponsor to fill, reconciling warehouse spreadsheets with the site accountability records to track assignments and returns at the level of the medication kit.

Redistribution of supplies. It is common that not all IPs allocated to a site are consumed due to poor recruitment or low enrollment. To maximize the use of available study drugs, sponsors often redeploy supplies to other sites with true demand. This practice can help prolong the supply of study drugs, but can also introduce uncertainty and complexity in accountability due to the difficulty of tracking all the locations where the IP has been and the route taken. While redistribution is a fairly common practice, regulatory agencies typically discourage site-to-site and site-to-warehouse-to-site shipments because storage cannot be confirmed once the initial shipment leaves the warehouse, and these subsequent shipments may not have QA inspection and release processes.

Disposal procedure for sites. In the event that the sites are authorized to destroy returned IPs, what documentation is required? What is the disposal procedure?

Many sponsors elect not to have sites destroy IPs directly due to the risk of the drug being diverted from a controlled environment. Having the sites return drugs to the warehouse serves as an internal check to ensure that all drugs stay within the sponsor's control. Once the IP concludes its life cycle in the realm of the site, it transitions out of GCP and back to GMP. When returned goods are approved for destruction, they are then packed and treated as waste.

Shipping the remaining IP from the site to the warehouse or depot. Again, return activities are often not considered when the study budget is being developed and can lead to cost overruns during close out. There are additional charges for hazardous material, regulated waste, medical waste, and any other materials that require special handling and transport, which the sponsor should be aware of early on in the process to avoid surprises. Sponsors should also engage in proactive consultation with the waste management vendor, as not all materials can be destroyed locally and the vendor can advise as to transport requirements and freight charges. Insufficient planning can lead to delays due to the need for monthly scheduling of transport runs, which can in turn translate into additional storage time and costs at the warehouse.

Streamlining data collection

As described previously, packagers, warehouses, and sites all touch IP as it flows through each location and all use different tools to account for and reconcile materials that they handle. However, because these processes are piecemeal and largely manual, there is no easy way for the sponsor to follow the progress from one environment to the next.

One way to streamline the data collection of the accountability and reconciliation process is to incorporate the IP return function into a centralized database such as an interactive voice response (IVR) system, which is already being used to track IP release through clinical distribution and dispensation to patients. An IVR system can significantly minimize the administrative burden on the site when used for randomizations and drug assignments, and with proactive planning the system can also be leveraged to facilitate site accountability of returned IPs. In addition to investigative sites, warehouses and depots that are already familiar with the IVR system can also use the tool to enter what IP a patient has returned and even capture the date the IP was destroyed.

The IVR system houses all the data that would otherwise be captured separately by the sites and warehouses in a single database, which the sponsor can access easily. Most commercially available IVR systems are fully validated and developed in compliance with 21 CFR 11, eliminating the sponsor's need to piece together disparate data sources in a way that is acceptable to regulatory authorities. As some data is still captured through handwritten documentation, using an IVR system also eliminates the need for data entry and verification required for transcription into an electronic tracking file.

Importantly, an IVR system does not eliminate the need to count unconsumed medication, but it can consolidate all information from release to destruction in one system. The entire reconciliation can be easily accessed at any time through IVR-generated reports either by request or on a scheduled basis. An IVR system can also help consolidate cost and reduce or eliminate the per-hour fees associated with warehouse reconciliation and per-receipt return fees. This approach can reduce many hours of reconciling various reports and documents manually, which also reduces costs.

Conclusion

Investing in proactive study planning with early consideration of endgame activities can save time and reduce the risk of cost overruns. Although it is often difficult to establish concrete plans while a protocol is still being developed, thoughtful planning and consideration in conjunction with the clinical study manager and clinical supply manager can prevent the surprises of unforeseen tasks and hidden costs.

Leveraging readily available tools such as IVR systems not only during the study but also after the last patient out can streamline many labor intensive activities and minimize errors. By addressing these processes during the planning phase, a study is more likely to stay within budget and close out activities will include the all-important final disposition of IPs.

Monica English* is a senior project associate and Amy Ma, PhD, is a manager with Covance IVRS, 210 Carnegie Center, Princeton, NJ 08540, (609) 452-8550, email: monica.english@covance.com.

*To whom all correspondence should be addressed.

References

1. European Commission, Enterprise Directorate General. Volume 4, Good Manufacturing Practices, Annex 13: Manufacture of Investigational Medicinal Products (EC, Brussels, July 2003).

2. Code of Federal Regulations, Title 21, Volume 5, Part 312, Investigational New Drug Application, Part 59, Disposition of Unused Supply of Investigational Drug (2006).

3. Code of Federal Regulations, Title 21, Part 210, Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs (2006).

4. Code of Federal Regulations, Title 21, Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, Section 150, Distribution Procedures; Section 196, Distribution Records; Section 204, Returned Drug Products (2006).

5. The Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscellaneous Amendments) Regulations 2005 (2005).

6. N. Dowlman, M. Kwak, R. Wood, G. Nicholls, "Managing the Drug Supply Chain with eProcesses," Applied Clinical Trials, 15 (7), 40–45 (2006).