If you have been pondering whether to employ a multi-regional strategy in your clinical development program, you are not alone. Despite the growing prevalence of global clinical trials and global registration strategies in the past two decades and the increase in the number of firms who specialize in conducting these trials, there are still a depressingly large number of ways that the unsuspecting sponsor can get it wrong and see their clinical development plans spin hopelessly off the rails. Here are a few points to consider in planning your next multi-regional project.
Choose Your Regions
First, you should identify how you want to deploy your resources and why. Do you intend to register your medicinal product in multiple regions? Are you pursuing countries because they have patients with the disease you are studying and you need the numbers to shorten your enrollment timeline? In that case are you seeing one or more countries of regions as part of a "rescue" scenario, where you want the country or region designated as rescue to contribute to the back end of your enrollment period? Knowing the answers to these questions can help you choose countries and regions that can contribute meaningfully to your ultimate dataset, rather than simply stacking it with bodies.
As an ethical sponsor, you should also strongly consider the ethics of conducting a clinical trial in a country or region where there is no intention of registering the product. Some health authoritiessuch as Israel or Argentina will not allow clinical trials to be performed in their country absent a registration plan, or at minimum will require some sort of reciprocity commitment by the sponsor, e.g., to provide the subjects with continuation therapy for some period of time.
Before you narrow down your list of countries, find out all you can about the differences or similarities of medical practice in your therapeutic area in each region. Many countries have patients with the disease you want to study but it is also important to note how and when they are diagnosed, i.e., at what stage of disease does diagnosis typically occur; and what is the standard of care, i.e., what would their physician normally prescribe as first line therapy. Differences in these points can affect the usability of the resulting data. For example, there are many patients in India with Type 2 diabetes, but initial diagnosis tends to be at a later stage in their disease and they also tend to be leaner than their US counterparts, which may alter the first line choice of therapy and result in different response curves than in other regions.
Develop a Vendor Strategy
At the same time as you are determining your regional or country strategy, you should also be evaluating potential clinical services vendors. Options include:
- large multinational one-size-fits-all CROs;
- niche vendors based in each country or region or your study;
Large multi-national CROs can offer many advantages to sponsors including presence in most countries, large staffs, and financial resources to offer flexibility in pricing and risk sharing. Some smaller sponsors have observed dissatisfaction with a large CRO, such as having one team come to the bid defense, and another team actually performing the study conduct. There is a developing trend among larger CROs to employ strategies to guard against this mismatch perception such as using high-level executives asa sponsoror key account representative, and committing to keeping key team members on the project.
Niche providers in the regions or countries of interest have advantages in that they are true experts in their locales, with long-standing relationships with both investigators and regulators. These relationships in turn can be very effective for performing feasibility or for anticipating queries from the reviewing bodies. The drawback for the sponsor in multi-regional projects is the amount of time and management required to project manage the various contracts and teams in each region. Some of these smaller vendors have created a solution for this problem by forming their own alliances and partnerships. An example of this is Topstone Research in Canada, who together with EastHORN (for the Central and East European countries and Pharmaceutical Solutions Limited in Australia and New Zealand), have formed a multi-regional partnership of local experts capable of operating under a single set of SOPs and a single invoice.
Fact or Myth
Finally, it is important to separate fact from myth as you evaluate your vendors and countries or regions. The most commonly advertised attraction to conducting exUS studies is the promise of reduced cost, time, or both. Many CROs claim that they can provide patients for 40-50% less than US or EU per patient costs, but make sure you are comparing the same things. If you have chosen a country with a 6-8 month regulatory and ethics start-up timeline (think Argentina or Brazil), meaning you cannot begin to enroll those patients for 2-3 quarters, you have to factor in the costs of that delay to your overall study timeline, and that 40-50% margin starts to shrink to something much smaller.
Many countries also require less documentation, particularly in CMC or preclinical information to approve a clinical trial application. In Australia for example, a protocol, investigator's brochure, informed consent form and a few other documents are all you need to submit an application for a phase 1 study.
Other countries require more, especially those countries that require a full investigation medicinal product dossier and Qualified Person (QP) release. All countries require translation only of the patient-facing documents, such as informed consents and diaries, and some countries require translation of all documents, such as China.
Having a strategy for region, country and vendor identification can go a long way towards helping sponsors conduct successful multi-regional clinical trials. Know your purpose, decide how to implement it, and then sift through the barrage of information you will receive to separate fact from advertising to give yourself the best possible chance at successful conduct of your trial.