Authored by Randy C Dockens, PhD; Clinical Pharmacology Scientific Operations,
Susan Lubin, RN, MA; Clinical Pharmacology Medical Operations,
Kristian Hubbard, BA; Central Clinical Services Grant Management &
Raja Haddadin, BS, MBA; Pharmaceutical Development


During Phase 1 development, there are several challenges to the timely delivery of an optimal drug product formulation for the start of Phase 3 clinical trials. Any delay to the start of a Phase 3 clinical program causes a significant delay in patients receiving needed drug treatment. In addition, immense development and clinical resources are invested to produce the desired formulation with the appropriate targeted safety and exposure attributes. This involves unrestrained formulation, analytical, bioanalytical, clinical, and manufacturing commitments to accumulate knowledge and eliminate risks while advancing the drug product to Phase 3 utilization. Once Phase 3 starts, changes to the formulation composition or properties creates significant risks or unknowns which must be mitigated to garner sufficient safety and efficacy data on the final to-be-marketed formulation. This, in turn, could potentially lead to delays and/or lengthening the Phase 3 development program.

Bristol-Myers Squibb has developed a co-location strategy to help ensure such a delay is not realized in our drug product development process. Co-location means both the development work and the clinical in vivo testing of prototype formulations are done by the same Contract Research Organization (CRO) at the same physical location. There are significant advantages to this strategy: (1) an abridged formulation development timeline by having a centralized location for the transfer of methods, and the requirement for less product stability data to support the short transit time between manufacture and dosing (hours or days vs. weeks or months) which eliminates many logistical headaches; (2) the option to customize and quickly manufacture clinical material for dosing, and (3) the most optimal formulation can rapidly integrate into the beginning of the Phase 3 program to decrease the chances of delays in the drug product approval resulting from needed bioequivalence studies during the conduct of the Phase 3 program.

Choosing an optimal partner for a co-location strategy is important. Forethought is needed in order to determine how complicated formulation designs and their execution may likely be, so engage a CRO who has the expertise, experience, and capacity for delivering both the drug product and the clinical results on time and with high quality. A Sponsor company really needs to understand not only what products it is currently making, but also what is forecasted in the future. It is imperative the Sponsor partners with a CRO that is dedicated to the Sponsor’s vision. In addition, whomever the Sponsor partners with must be able to provide rapid turnaround of physiochemical properties and PK data of evaluated prototype formulations. This foundation is critical to facilitate quick decisions on what changes are needed for the next dosing arm, if any, and to know if one has reached the optimal formulation to commence scale up processes for Phase 3 development.

There are other factors one needs to also pay close attention to when deciding to implement such a strategy. The optimal CRO should be strongly diversified. For example, protocols for such studies are not trivial. The chosen CRO should have ample experience in protocol development of such studies to deliver quality protocols which can be executed efficiently without needing amendments to complete the study. It is also important the CRO already has vetted such adaptive trial designs with their corresponding regional Regulatory Agency to allow for study approval in as short a time as possible. Answering Regulatory questions can take a significant amount of time and cause study delays which in the end impacts the start of the Phase 3 program. Being sure the regional’s Regulatory Agency is familiar with these types of protocol designs is essential to an efficient and effective completion of the clinical trial.

The next component to consider is how does such a strategy fit into one’s current outsourcing model. The CRO chosen for a co-location strategy may not be a preferred vendor the Sponsor has already chosen. Doing these types of studies requires a unique skill set which not every CRO can conduct successfully. However, at the same time, a Sponsor does not want to further complicate its existing outsourcing model. Of course, one way is to bring this new CRO into the Sponsor’s list of preferred providers. Yet, that would mean one needs to do further due diligence as well as be sure the CRO follows the Sponsor’s entire lists of established procedures, guidelines, and quality assurance checks, which can take a lot of time and effort on both sides. The other way is to have one of the preferred CROS work with this new CRO to leverage established processes and the operational model without having to change anything too radically in the Sponsor’s current processes. The CRO chosen for the co-location strategy can write the protocol since they have the expertise for the contracted study type. Yet, the Sponsor can also utilize the expertise of the already established preferred CRO to handle the clinical management portion of the co-location strategy. That way, all of the standardization already worked out for tables, figures, listings, and clinical study report design can synergistically still occur with the existing CRO without the co-location CRO having to be involved with those particular aspects.

Finally, measurement of the financial impact should occur across the involved functional areas. The impact of each functional category should be measured in multiple ways. First, a possible trade-off may occur across the functional groups experiencing a varying degree of financial impact which may offset the cost for an overall financial gain. Secondly, efficiencies may be gained by a functional area with a reduction in cycle time and/or efforts by internal resources providing an indirect reduction in costs. Transparency between each functional group provides a full spectrum of the advantages gained for each functional area and thereby the overall gain for the entire study.

The above framework offers drug product design efficiency for Phase 3 application, shortens time to achieving the start of Phase 3, intelligently utilizes the expertise of each CRO, allows the least perturbing of an established outsourcing process, and most importantly of all, allows the drug of interest to get approved and to the desired patient population in the shortest period of time possible.