When it comes to IMP supply for investigator-initiated studies (IIS), there are numerous obstacles that must be overcome by sponsors and CROs alike. One person with a wealth of experience dealing with IIS is clinical supply specialist Peter Orosz.
Orosz is a trained pharmacist who has worked within the clinical trial supplies unit of Boehringer Ingelheim for the past 20 years. In being responsible for IMP supply chain management within oncology therapeutic, Orosz has uncovered the keys to success in the delivery of IIS.
In this Industry Viewpoint, he sits down with CTA Editor Henry Kerali to share vital considerations sponsors should factor.
Henry Kerali: What are some of the unique challenges behind investigator-initiated studies and IMPs?
Peter Orosz: In contrast to studies sponsored by pharma companies or the manufacturer directly, clinical trial processes are often not that well-established for IIS. Even if a process map is defined, manufacturers face the situation that nearly each IIS has a different sponsor/investigator, meaning the interface is new.
Therefore, expectations and process knowledge, in terms of smooth management of IMPs, have to be aligned. This is challenging for both parties, largely because many factors need to be agreed, such as the packaging design of products to be delivered, the label approval process, and the prerequisites needed for the regulatory compliance.
HK: Can you provide a sense of the regulatory barriers associated with IIS?
PO: Additionally for IIS, a Clinical Trial Authorization (CTA) must be submitted. One such part is the so-called Investigational Medicinal Product Dossier (IMPD), which covers product specifications. If marketed products are used as an IMP in the IIS, the sponsor/investigator can refer to the Summary of Product Characteristics (SPC) of the authorized product.
Alternatively, if non-authorized products are used, the sponsor can obtain a “Cross-reference-letter” by the manufacturer referencing to an existing IMPD available from the Health Authorities. With a cross-reference-letter, it is avoided that any confidential product specification information be handed out to investigators.
HK: What approaches should trial sponsors adopt to circumvent these hurdles?
PO: A better understanding of the regulations on the part of the sponsors would greatly help reduce the hurdles in this area. In my opinion, it’s important to understand the dependency of the final IMP release by Qualified Person on the CTA and Ethics approval, as well as on compliance of the IMP with all submitted documents.
HK: When it comes to the distribution of IMPs, what are the sponsor’s options?
PO: The sponsor has to clarify whether the depot(s) should run under their or the manufacturer’s responsibility. Typically, this is documented in the Sponsor-Manufacturer Quality Assurance Agreement.
Furthermore, terms related to shipping responsibilities must be clarified in the same agreement. It’s imperative, therefore, the sponsor, or its contracted distribution partner, has the knowledge to carry out the shipments in accordance with current Good Distribution Practices, including the appropriate temperature monitoring measures.
The process for initiating a shipment from depot to site has to be agreed if the manufacturer is responsible for distribution activities. This should include responsibilities for tracking site and depot stock levels. Crucially, sponsors must ensure resupplies are ordered on time.
HK: What advice and key considerations would you give to industry professionals for IIS?
PO: It’s important manufacturers setup a clear process map, including all internal interfaces, such as: Medical affairs → Clinical Supplies Unit → Quality Unit → Regulatory Affairs. Additionally, well-structured templates should be established for ordering supplies, establishing the sponsor-manufacturer contract, and for putting in place the Quality Assurance Agreement.
Thereafter, I would recommend to hold a kick-off meeting between the sponsor representative and the manufacturer to introduce the IMP process, timelines, as well as roles and responsibilities. When defining internal timelines and milestones, the manufacturer must include the IIS approval process and a milestone to start packaging and labeling activities. From personal experience, if IMP preparation starts too early in the process, a huge risk is incurred of losing the medication before the study even begins.