BIO Statement to the Presidential Commission for the Study of Bioethical Issues: Principles Regarding Ethical Performance of International Clinical Trials

Given by
Russell M. Medford, MD, PhD
President and CEO, Salutria Pharmaceuticals, LLC
BIO Board Standing Committee on Bioethics Co-Chair

Madam Chairwoman and Members of the Commission:

Good morning.  My name is Russell Medford, and I am the CEO and President of Salutria Pharmaceuticals, LLC, a biotechnology company based in Alpharetta, Georgia, and Co-Chair of the Biotechnology Industry Organization's Board Standing Committee on Bioethics. 

BIO is a trade association based in Washington, DC, that represents over 1,100 life science companies around the world.  BIO members are performing important research to develop treatments and cures for a variety of diseases such as diabetes, heart disease, and various cancers.  In fact, this research has already led to the development of over 250 drugs and biologics with hundreds more in clinical testing.

We appreciate the opportunity to submit comments to you today on the topic of international clinical trials.  BIO commends the Commission for studying this important topic.  Our comments will address some of the recommendations in the draft report, "Research Across Borders," and will present our views on other important topics.  We have also provided the Commission with a written statement on October 28 containing information about industry best practices, including BIO's Statement of Ethical Principles and BIO's Principles on Clinical Trials. 

BIO has long supported responsible and ethical testing, protection of individual privacy and genetic information, and regulatory systems that best serve humanity and advance research into new treatments for patients, regardless of where research is conducted.  Toward that end, BIO supports appropriate oversight of clinical trials and medical research, whether conducted in the United States or elsewhere in the world.  BIO has long argued that performing important research and protecting research subjects are mutually attainable goals.

BIO believes that decisions regarding whether and how to use medical products and technologies must always be made with profound respect for the rights of patients.  In our view, appropriate regulation of biotechnology should be solidly rooted in values such as autonomy, privacy, beneficence, social justice, and intellectual freedom.

BIO's Statement of Ethical Principles provided in our written comments outlines our commitment to encourage discussion of the ethical and social implications of scientific development in biotechnology research.  As our companies develop promising new technology to benefit humankind, this technology may raise ethical questions.  Therefore, we must examine, discuss, and address the ethical issues related to conducting global clinical trials.

There are several reasons commercial drug sponsors may wish to conduct research outside of the United States.  For example, when searching for potential patients and investigators, sponsors are able to reach a much larger population by conducting research both inside and outside of the country.  Finding a sufficient number of clinical sites and reaching recruitment and enrollment targets remains a challenge for sponsors domestically, especially when studying products for rare diseases.  Companies are able to recruit and conduct clinical trials at a much faster rate when not limited to one or a few countries. 

Another reason to perform clinical trials around the world is that companies may wish to study diseases found predominantly in those countries or elsewhere outside of the United States.  Furthermore, global trials may increase patient data regarding race and ethnicity, thereby expanding the knowledge of racial, ethnic, and genetic variations in disease and patient care.  

In addition, at a time when average per-patient clinical trial costs are rising at significant rates in the United States in the midst of a global economic downturn, companies can realize cost savings by conducting clinical trials overseas.  While it is true that the average cost per-patient of a clinical trial conducted abroad is less, this is due to the fact that, on average, healthcare costs outside of the United States tend to be lower.  As a result, clinical trial costs abroad also tend to be lower.

Recent press coverage has raised concerns about how clinical trials are being performed in other countries, particularly in the developing world.  Even prior to these reports, some have asserted that sponsors conduct clinical trials abroad to avoid red tape ˗ or to avoid the scrutiny of strict regulatory bodies, such as the FDA.  However, research done by companies with the intent of seeking FDA approval and access to the U.S. market must still meet FDA standards regardless of where that research is conducted.  FDA regulations require trial sponsors to undertake several quality assurance and audit activities.  Because failure to abide by these rules could delay or disqualify a product's chances of getting marketing approval, companies develop numerous processes to ensure compliance.

Such processes include:

• standard operating procedures, technical operations policies, and training programs for staff.
• pharmacovigilance conducted by experts (oftentimes hundreds of individuals in one company) who collect, analyze, follow-up, and distribute safety-related information from new drug trials.
• establishment of data and safety monitoring boards to impartially evaluate safety as studies progress.
• regular sponsor monitoring of clinical trial sites to ensure quality, compliance, and safety of research participants.  
• and quality assurance units that audit operations associated with clinical research to ensure adherence of company personnel to regulations, guidelines, and internal and external procedures, policies, and programs.  

Still, there are examples of unethical clinical trials performed around the world.  These instances tarnish the reputation of all researchers and their work.  For that reason, BIO members take seriously the ethical issues they and other research organizations confront when conducting overseas clinical trials.  

Some of these issues include:  

Inducement -- A fundamental bioethics principle is that subjects can only participate in research after providing voluntary informed consent.  This is required by law in the United States and many other countries.  It is also embedded in the World Medical Association's Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects.  However, in some countries, potential research subjects are of low income, and the opportunities to receive medical care are few.  Companies planning research abroad must be sure to determine whether providing access to medical care through participation in a trial creates an undue inducement for subjects to participate.  Prior to commencing a study, companies should also address whether research participants or other citizens will be provided the product after the trial has concluded.

Informed Consent -- As noted, U.S. law and the Declaration of Helsinki require that a participant understand the risks and benefits of participating in a research project.  This is a bedrock principle of the regulatory system in the United States and throughout the world.  BIO agrees with the Commission's report that individual voluntary informed consent is always required regardless of where a trial takes place.  Companies must make sure research subjects provide this consent and develop strategies to address situations where potential research participants have limited literacy, limited fluency in widely spoken languages, or different cultural values. 

Independent Oversight -- U.S. law requires independent oversight (by an Institutional Review Board) of any clinical trial involving human beings.  This is meant to protect research participants and help ensure that the study is done appropriately.  In some countries, however, this infrastructure does not exist and IRB review is not available.  In those cases, companies strive to have a U.S. IRB review the proposed study protocol.  If that option isn't available, companies must ensure that the study is reviewed by another appropriate independent oversight board.

In addition, BIO offers the following comments concerning three specific recommendations outlined in the draft "Research Across Borders" report:

Ethics Training for Investigators -- The Commission recommends that funders of human subjects research should support ethics training for investigators and others, including IRB members.  The rationale for this recommendation is that researchers and others involved in human subjects research must be adequately educated and qualified to assess risks to the health and well-being of participants.  While training and education of research concepts and regulatory matters is critical, funding for these activities should come from sources besides sponsors.  Professional associations, research institutions, or government programs are more appropriate and logical choices.  Moreover, BIO also recommends establishment of a multi-stakeholder group comprised of representatives of investigators, commercial sponsors, research institutions, and others to develop best practices.  All stakeholders would financially contribute to the group.

Equivalent Protections -- The Commission calls for clarification of how the doctrine of "equivalent protections" can be applied.  U.S. law has long permitted U.S. agencies conducting or supporting research in foreign countries with different procedural requirements to substitute the foreign standards for U.S. rules so long as “protections that are at least equivalent” to U.S. rules.  The Commission found that U.S. agencies have rarely, if ever, exercised this authority and have failed to delineate criteria by which to determine equivalent protections.  BIO agrees with the Commission that without additional clarity, this standard is too vague and difficult to apply.  Sponsors shouldn't be held to this standard without more federal guidance.  Moreover, we urge the U.S. Department of Health and Human Services to seek the input of clinical trial sponsors when developing this guidance.  

Compensation for Injured Clinical Trial Participants -- The Commission recommends creation of a no-fault compensation system for individuals injured in clinical trials.  The panel says the U.S. government should consider creating a fund for compensating individuals who are harmed in research, and consider modeling it after the Vaccine Injury Compensation Trust Fund, which provides funding for the National Vaccine Injury Compensation Program (NVICP) to compensate vaccine-related injury or death claims for covered vaccines.  

According to the Commission, justification for such a fund rests on the notion that research -- like immunization programs -- is a socially collaborative project for the social good.  According to the Commission, if someone is injured in the course of research in which they have served the social good, they should be compensated to pay for those injuries.  Moreover, under the Commission's proposal, the presence of such a fund should not eliminate the right to litigate.

BIO has significant concerns with this proposal.  The Commission is correct that the NVICP (and others like it in other countries) has been successful.  However, the NVICP was created to compensate injured citizens quickly and fairly; but to do so outside of the tort system.  In fact, one of the key rationales for the program was that vaccine manufacturers were being sued and therefore disincentivized from developing vaccines.  The law creating the program bars virtually all lawsuits against manufacturers.  So long as the injuries sustained were presumed to be unavoidable and the manufacturers complied with FDA requirements for product labeling (directions for use and sufficient warnings), plaintiffs can bring suit only after going through the program and rejecting the damages awarded.  These principles must be part of any no-fault compensation program.

In addition, the rationale for the NVICP was that, even if manufacturers followed best practice, some injuries would result from vaccines.  Moreover, the injuries could be categorized for each vaccine such that an administrative body could quickly and fairly determine appropriate compensation.  More analysis is needed before we can be sure these principles apply to clinical trials. 

Furthermore, a new compensation system may duplicate or undermine alternative solutions that already exist.  In the private sector, sponsors are required to obtain clinical trial insurance to pay for medical expenses for injured trial participants.  We recommend that a clinical trial insurance approach be explored as a solution for public sector and academic research.

There are many reasons that clinical trials are being performed around the world.  Since this trend is likely to continue, BIO is pleased the Commission is examining the ethical issues related to global clinical trials.  It is critical that all stakeholders work collaboratively to ensure that patients in trials are protected wherever the trial is performed. 

BIO looks forward to working with this Commission -- as well as regulators, researchers, and others -- to develop appropriate ethical frameworks that protect patients while facilitating important research.  Thank you for the opportunity to speak to you today.  I am happy to answer any questions.