Planning for Challenges of Global Clinical Trials

Leah R. Kendall, Epstein Becker & Green P.C.

Pharmaceutical and medical device companies are increasingly recognizing that international clinical studies offer important advantages to studies undertaken in the United States, but they are also recognizing that international studies present numerous complex legal challenges.  In terms of advantages, studies conducted abroad can be a source of drug-naïve patients, which can be rare in the United States, and they can help to provide a large number of patients as well.  Global studies can also help foster sponsors’ relationships with different clinical sites and investigators and with global thought leaders.  Moreover, conducting research abroad allows companies that sponsor research to lay the groundwork for regulatory approvals in markets outside of the United States.

To ensure that they reap the potential benefits of international studies, however, sponsors should be prepared to address challenges that may arise while structuring and managing international clinical studies.  This article highlights key challenges and preparatory steps that a sponsor should consider from a health care regulatory perspective when venturing into the realm of global clinical trials.

Potential Challenges

Sponsors should be prepared to face several health care regulatory challenges with respect to clinical studies conducted partially or entirely outside the United States:

-         Legal Agreements.  One potential challenge is the development of an efficient contracting process that protects the sponsor and that is consistent throughout the globe.  For example, if a sponsor has 50 or 100 study sites in multiple countries, how does the sponsor minimize risk exposure?  Further, if the sponsor is a global company, how can it work with its local affiliates to leverage internal resources, while also ensuring that legal agreements are sufficiently protective?

Regarding the content for site and investigator contracts, each country may have its own legal requirements that impact the clinical study agreement.  For example, certain countries have legal requirements for insurance or for indemnification, while other countries have requirements on the number of agreements that a sponsor might need.  Additionally, if the sponsor plans to use study data to support a marketing submission in the U.S., it needs to know what legal controls are required in order to ensure that the U.S. Food and Drug Administration (FDA) will accept the study data.

Additionally, sponsors often use contract research organizations (CROs) to help conduct, monitor, and manage research.  CRO expertise and manpower potentially can be invaluable – especially in global studies.  That said, companies sometimes struggle with how contractually to ensure a CRO’s performance. 

-         Working with CROs.  Sponsors may also struggle with using and managing CROs effectively.  An international clinical trial can exacerbate this struggle, because sponsors may use multiple CROs or multiple affiliates of a CRO.  In this regard, sponsors may find it challenging to monitor and measure the various aspects of a CRO’s performance, particularly on a global scale.

-         Effective Monitoring and Site Access.  Sponsors may be concerned about whether they will have access to well-qualified monitors abroad – through either a CRO or the sponsor’s internal resources.  Moreover, even if a sponsor has excellent monitors, the sponsor can still encounter basic practical challenges in terms of transportation, adequate site facilities, language barriers and translation issues that can impede monitoring the study, thereby leading to serious compliance problems.

-         Payment Issues.  Budgetary issues – including third-party reimbursement – can encompass payments and costs surrounding research-related activities, routine care, and injuries to study subjects that may arise during or after the study.  Needless to say, these can be extraordinarily complex issues.

Careful and diligent planning is critical to meeting challenges like these – and for being prepared to surmount the unexpected but inevitable problems that will arise during the course of a study.  Below are some suggestions for sponsors to consider as they plan for studies conducted abroad.

Overcoming the Challenges

While each sponsor’s situation is unique, there are some universal considerations that are useful for sponsors to consider as they plan for international studies.  Sponsors should think carefully about the oversight and management of their trials.  Internally, who is going to champion the process?  Who is going to be responsible for keeping track of all the moving pieces and ensuring that it all comes together?  While somewhat obvious, it bears mentioning that excellent project management skills are needed to keep sight of the big picture and all the moving pieces.  Substantive knowledge is important, but equally important is having a detail-oriented and responsive person or team to manage the clinical trials process.

Sponsors should also consider who will handle the contracting process internally – and how they will do it.  For example, will internal legal counsel manage it at a high level, or will they draft and negotiate contracts on their own?  If outside counsel is involved, what responsibilities will they assume?  In this regard, there are a wide range of possibilities – from negotiating directly with sites, to drafting contract templates, to providing discrete areas of expertise. 

The actual substance of the agreements is another matter.  While the intricacies of legal provisions are beyond the scope of this article, thinking about acceptable provisions within clinical trial agreements before the agreements are negotiated or even drafted will often save the sponsor time and money in the long run.  Among the provisions to consider are indemnification, payment for study subject injuries, insurance, publication, intellectual property, monitoring, confidentiality, governing law and venue.  Further, assuming that the sponsor’s goal is FDA approval, it should think about FDA data acceptance issues and the legal requirements with which a site must comply. 

Just as with clinical trial agreements, a sponsor should also consider the provisions it will require in its contracts with CROs.  In this regard, a sponsor is often concerned about how to ensure a CRO performs according to the sponsor’s expectations.  One way to accomplish this is to contractually require the CRO to meet certain performance metrics. Sometimes these metrics are tied to financial penalties if the CRO fails to meet them.  Drafting a clear, comprehensive, and well thought-out statement of work is also critical to obtaining a high level of performance.  For example, a statement of work should balance the authority and responsibility given to a CRO with close and careful supervision by the sponsor.  A sponsor must always remember that it, not the CRO, is ultimately responsible for the data and marketing submission. 

Sponsors should also conduct due diligence when engaging external resources to help them with tasks such as the contracting process or monitoring.  For example, a potential contractor should be able to back up its marketing statements with references and examples of representative expertise.  Sponsors also should not underestimate the power of networking – consider asking contacts at other companies for recommendations on resources. 

In addition to due diligence on external contractors, performing due diligence on both potential sites and investigators can also be important for a sponsor’s success in international clinical studies.  In terms of legal requirements, a critical consideration is whether the clinical sites and investigators are compliant with Good Clinical Practices (GCPs), including the International Conference on Harmonization (ICH) standards and guidelines.  Assuming that the relevant sites and investigators are in compliance with GCPs, a sponsor should further consider a country’s local requirements and legal infrastructure.  For example, one basic question is whether the country has a reputable and solid infrastructure where a dispute can be resolved in an expeditious and fair manner.  Other legal considerations include insurance requirements, intellectual property rights and patent protection, and jurisdictional issues related to the country’s courts and legal system. 

Another important question is whether the standard of medical care in the country is compatible with the study design.  Companies should also consider any potential cultural or ethical barriers.  For example, in developing countries, the trial participants and even the study sites may believe that the sponsor is providing medical care and may not fully appreciate the experimental nature of the trial.  However, every sponsor’s situation is unique and disadvantages may be outweighed by advantage; for example, sponsors will also want to take into account where they or their CROs already have strong relationships with clinical sites and investigators.  Prior success is often one of the best predictors of future success.

A final suggestion is that sponsors should consider “Plan B” for the unavoidable setbacks as the study gets underway.  What happens, for example, if one or more sites just simply do not move forward with their legal agreements and other required regulatory documents -- what is the plan if certain sites just don’t come to fruition?  Or what if there are major compliance – even data integrity -- issues? 

In summary, undertaking a clinical study with international sites can be a daunting task.  However, by being proactive, diligent and thoughtful during the initial planning process, sponsors can help to ensure their study is a success. 

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Leah R. Kendall is an Associate in the Health Care and Life Sciences practice group at Epstein Becker & Green, P.C.  Leah regularly helps clients navigate the legal, practical, and ethical challenges pertaining to clinical research.  You may reach Leah at lkendall@ebglaw.com or 202-861-4197.