Given the increasing pressure to make development programs more enticing to investors and partners, many innovators consider conducting clinical trials outside the United States. Doing so can enable them to reach value inflection points or to secure capital required to move R&D forward (e.g., demonstrating clinical proof of concept) especially in a time when capital is difficult to secure for early programs. In this installment of our ongoing column, we will review the considerations for early clinical trials that are conducted outside the United States. While this data can certainly add value in certain instances, it is important to align the designs of such studies with your target product profile (TPP) that we have discussed in prior columns, and consider the ability to rely on the data for decision-making and perceptions. Further, it is critical to set appropriate objectives for data acquired from ex-U.S. clinical trials to ensure it meets your goals and that conducting them is the right decision for your project and stage.

When to Pursue an ex-U.S. Trial

When conducting clinical investigation outside the United States, remember that the goal is not to avoid the U.S. Food and Drug Administration or requirements it has for initiating a trial. Requirements for proper clinical conduct (GCP), toxicology, chemistry and manufacturing controls are meant to provide reliability of data for the developers and safety to patients. Ultimately the ex-U.S. data will still be submitted to the FDA, and it is important that the agency agrees that it will be supportive and reliable data.

Given that the goal of development is to provide a product the best chances for success, each component of the development program must add value by advancing the program toward financing, regulatory approval, partnering/acquisition or demonstrating safety/efficacy of the respective drug/device to help inform, design or define the TPP. The conduct of smaller ex-U.S. proof-of- concept (POC) studies should be aligned with one of these. A global regulatory strategy to reduce lag time between U.S. approval and other regions such as Europe and Japan, and integration of clinical sites or parallel studies in other regions to that path, is another topic of its own.

With that said, pursuit of clinical POC at ex-U.S. sites can allow innovators/entrepreneurs to:

 • Access patient populations that are difficult to recruit in the United States. This includes rare disease, needing patients naïve to treatment, and when access to standard of care may impact recruiting. For example, a placebo control trial may not be ethical to conduct in the United Sates in certain cases; however given differences in access to care or accepted standard of care, it may be possible in other regions. In these cases, the ex-U.S. studies may expand beyond small POC, into the full Phase II and III trials.

 • Gain insights that will guide decision-making and optimization of the product. Oftentimes we see ex-U.S. datasets that are significantly smaller than is common here, are non-randomized or lack other necessary features and controls of clinical trials designed to support a new drug application or premarket approval application. The strategy and future insights to be gained from these potential studies (and their value) should be interpreted on a case-by-case basis.

For devices, it is always helpful to take into account the different regulatory standards for safety and efficacy by different regions of the global market. Advancing safety considerations as well as potential surgical techniques for more significant-risk products can be very helpful when done in concert with FDA consultation through the Pre-Submission process. For example, as we look at new classes of surgically implanted devices such as MIGS (micro-incision glaucoma surgery) and intraocular pressure measuring devices such as Implandata Ophthalmic Products GMBH (Hannover, Germany) PRO-IOP monitoring, the development cycle includes several rounds of POC work. Companies like Implandata have taken the approach of demonstrating safety and surgical technique on a small scale. This can be very helpful before turning the focus to efficacy endpoints and final-product designs. If this work can be done efficiently and allow for CE marking in Europe based on quality controls and safety, the companies can work to expand their approval base and allow the investment community to see progress toward milestones of global commercialization, and then focus on assessing efficacy for FDA. 

It is paramount to engage potential partners or investors early in order to determine what are the relevant questions that will support value inflection and drive decision-making, in order to establish the most appropriate design and approach. For example, small POC data may not help if the key third parties you are targeting will discount the data because the supplies are not from GMP suppliers; if there is not a placebo or appropriate control; if the proper time points for assessments are not met because a clinical site did not have the right processes in place; or if proper monitoring and oversight were not in place. 

 • Potentially lower costs. The gap between clinical trial costs in the United States compared to other regions has narrowed in recent years in most cases. Many times, the anticipated slightly reduced costs of an ex-U.S. POC program may be swallowed up by the need for repeat testing, based on how the FDA, investors and partners interpret and use the results. Again, we emphasize the importance of engaging the FDA early. We have seen projects started ex-U.S. come back only to start again under the investigational new drug or investigational device exemption phases of FDA review. 

An Ex-U.S. Success Story

While the costs of proper controls and monitoring per Good Clinical Practice compliance would not necessarily be lower, clinical investigator costs can still certainly be reduced, at times. In addition, how a company is financed may also impact the strategy for utilizing an ex-U.S. POC trial.

For example, when a company is internally financed, then the objectives can be set to advance the understanding for the TPP, building early data sets, etc. The goal is to verify safety and efficacy and “fail early” if that’s going to be the outcome. Recognizing that this may potentially impact future partners’ and investors’ perceptions related to quality and reliability of the results, the goal is to have this data inform future, more formal U.S.-based studies under IND/IDE. If other potential investors/partners are involved, confirmation should be obtained on how such data will be used and perceived. 

Allegro Ophthalmics has successfully used this approach. Allegro is developing ALG-1001, the first in a new class of drugs called integrin peptide therapy for the treatment of retinovascular diseases. Of course, only after determining that the drug was safe and effective in animals, Allegro began its international human clinical program with a primary endpoint of safety in the target population and a secondary endpoint of initial efficacy. They made the decision to conduct early human studies outside the United States because of efficiencies in recruitment time and expense (specifically around cost of the clinical investigators), without compromising the quality of clinical data. In an effort to ensure the highest-quality results, Allegro leveraged long-standing existing relationships with reputable ex-U.S. clinical sites with which the company had prior experience, and engaged its own scientific advisory board, an independent retinal reading center, and third-party clinical research oirganizations to monitor and evaluate the study.

The approach succeeded: A subsequent 2013 collaboration with Senju Pharmaceutical for Japan and a successful FDA IND filing in both vitreomacular traction and wet AMD demonstrate success in reaching their objectives with this strategy. Allegro acquired clinical Phase II data in less than four years from discovery, and answered important questions that added value to the ALG-1001 development program and enabled design of larger trials in the United States to be conducted under an IND designation. 

While details are beyond the scope of this particular column, for certain products, we would point out that there may be differences, for example, in requirements for toxicology to support early clinical trials. 

Assessing external expectations (those of the FDA, investors and potential partners) for studies conducted outside of the United States is integral to maximizing the value of these trials. Ascertaining whether investors/potential partners will view clinical POC in an ex-U.S. trial as a value inflection point before planning or conducting ex-U.S. trials should be a precursor to any development work. Again, we emphasize that proper study design and controls (GCP) must still be followed to support reliability of the data. 

There is little value in conducting studies that do not demonstrate safety/efficacy in well-designed trials or with proper controls, ending with data that can’t be interpreted. We have seen some external parties (investors and partners) be open to well-controlled and executed ex-U.S. trials, whereas others are suspicious of it and don’t give the data full value. The key is to set expectations on how that data will be viewed and used.

Managing internal expectations on timelines and the ability to conduct your trial ex-U.S. is also paramount. In the interest of establishing and preserving reputations and protecting their population, many regional regulatory authorities are strict. In some cases there have been more complications and longer submission timelines to prevent companies from simply attempting to use local citizens as the sole research subjects in studies.

While you can plan for a 30-day review by the FDA of an IND and IDE, review timelines can be unpredictable in emerging countries. We recently saw more than a year review of a submission in one country due to structural volatility. In another, multiple delays arose due to political changes followed by changes to local regulations, which caused additional delays with re-submissions, and rework of documents and procedures in the middle of a study. While a local institutional review board may approve a project, there may be critical elements missing on the toxicology, manufacturing and controls that can create issues when you do file in that region for approval, or with the FDA. This relates to so-called “IRB shopping” to find, for example, an IRB that will approve an IND as “non-significant risk” to allow proceeding with a trial, when the FDA may take a more conservative stance, creating review issues later.