The logistics provider is often the last partner to be consulted when setting up a clinical trial, which can have a detrimental effect, in particular when conducting clinical research of controlled substances. Alex Klim, product manager, Clinical Trials Logistics at DHL Supply Chain, explains why involving the logistics partner at the design phase of a clinical trial can provide a competitive advantage.
Stakeholders involved in controlled substance or narcotics clinical trials will know that these studies can be the most challenging and complex types of clinical research: from the sponsor and the clinical research organisation (CRO) to the packagers, logistics companies and investigators, everyone understands that obtaining approvals and ensuring drug availability in order to conduct the research is often problematic. Delays and challenges in the supply chain not only slow down advances in clinical research and impact the benefit to patients, but can also be very costly to the sponsor. Inefficiency leads to inflated expenditure, insufficient clinical data, and delays can result in rival products being released to the market first.
Traditional practices
When deciding which countries to select for a clinical trial, site feasibility, patient recruitment, key opinion leader endorsement, clinical trial approval times and investigator site relationships are more often than not at the forefront of the design discussions. Once the clinical trial sponsor has agreed these with the CRO, a list of countries and sites is produced so that work on site initiation can begin. It is often only after this point that the interactive voice recognition system (IVRS) provider and logistics company are brought into the discussions and are asked to agree the lead-times for shipping into each country. Inevitably, shipments are expected to commence as soon as possible.
Challenges of supply
Different drugs under research can present unique challenges in consideration of their distribution. Controlled substances are naturally one of the more challenging due to the security considerations associated with their frequently more dangerous or addictive nature. These drugs are classified in five schedules according to different levels of control.
Complexity is further increased because different countries have different rules and regulations regarding the importation or exportation of these substances when conducting a clinical study. The EU has recognised in general the need to harmonise the regulatory landscape to facilitate more clinical research taking place in Europe within the member states. As a result the following clinical trial legislation has been implemented over the past six years:
- 2001/20/EC (GCP)
- 2003/94/EC (GMP)
- EUDRALEX Vol 4.
- Article 13 (Manufacture and Import of IMP)
- Annex 13 (Manufacture of IMP)
- Annex 16 (QP Cert and Batch Release)
This regulatory harmonisation has made an impact. For example, all clinical trials supplies being imported to France previously had to be shipped to an in-country warehouse to undergo checks before they could be moved on to the investigator site conducting the research. This added extra time and further unnecessary handling in the supply chain, along with the extra costs of an in-country warehouse. With the passing of the harmonisation in member state country regulation, drugs can be shipped from a central stockholding location within the EU directly to an investigator site. This enables a 24-48-hour turn-around time, from an order being placed on the IVRS through to delivery to site, which in turn enables supply chain companies to do what is logistically efficient by reducing transit times and the number of people that handle a drug.
The issue, however, with controlled drugs is that, rather than a health authority regulating trials and their supplies, member state countries have separate ‘narcotics authorities’ that have not been subject to regulatory harmonisation (see Table 1, above).
Therefore there are narcotics rules within the EU with regard to pre-notification of a shipment, import and export permissions, ‘safe custody’ of the product, and the destruction of unwanted medication, which vary from country to country. All are important factors that a logistics company has to be aware of, but that are not always considered at the design phase of the clinical trial.
Balancing act
Despite many EU member states having different rules when importing, exporting and storing controlled drugs during a clinical trial, there is one regulation that is currently quite consistent – the need for an in-country depot. This often consists of making someone in-country responsible and accountable for all deliveries of controlled substances to a hospital or pharmacy. Finding the right warehouse while trying to maintain standard operating procedures across all the depots within the clinical trial can be demanding.
Globally, one can always find a specialist clinical trials supplies (CTS) organisation that can store, pick and distribute materials during a clinical trial. These CTS providers are used to deliver ‘fine pick’ operations where individually serialised medication packs must be identified during blinded or double-blinded studies, and go through a number of checks to ensure picking accuracy. However, there are only a few with the expertise or infrastructure to store and distribute controlled drugs (as well as having knowledge of the unique demands of the clinical supply chain).
This expertise may be found among wholesalers that have all the required licensing and comply with infrastructure and security regulations. Their experience lies in the need to supply pharmacies and doctors with prescribed medicines on a much larger scale than a clinical trial, with far more standardised products (for example, not blinded or needing the same degrees of cold chain control).
Selecting between the two within each country can be a difficult choice, and often requires on-site training to up-skill a non-CTS company’s capability while trying to maintain standard operating procedures across all the countries involved in the same clinical trial, so as to provide a service consistency that does not put the supply chain at risk. A logistics company needs to take a lead role in the supply chain to address any inconsistencies through training and clearly defined responsibility matrices.
Planning and visibility
With inventory having to be stored in a warehouse in each country involved in a clinical trial, and the often quite extensive exportation and importation requirements that differ from country to country, careful planning and accurate information is vital to maintaining the network to ensure adequate availability of supply (not stocking out).
As the slightest error in the import or export documentation or process can result in lengthy delays in customs, careful inventory management, delivered through integrated reporting tools, is required to plan and mitigate against the risk of the right medication packs not being available for a patient visit.
This is never more evident than at the start of a clinical trial when sites need to have drugs ready for first patient-in dates, and a careful back-scheduling of applications, permits, training and contracts must be undertaken so that site initiation dates can be met. With so many logistical issues to be dealt with before the drugs can move out of the central warehouse, logistics companies must be factored into the chain of communication at the earliest possible opportunity.
Involving the logistics provider
In conclusion, the earlier a logistics company is brought into the planning of a clinical trial, the higher the likelihood of meeting key planned research milestones.
One recent example involved a large EU-controlled drugs clinical trial (under DHL’s supply chain management). Italy was under consideration and patient recruitment had already commenced, but with the heavy administrative burden required for each import it was unrealistic to meet the required initiation date. It was therefore decided not to initiate Italy and instead to recruit extra patients in Poland. This decision, driven to alleviate a supply chain constraint, helped the controlled substance gain marketing approval nine months before its competitor product (trialling in Italy).