Examination of Clinical Trial Costs and Barriers for Drug Development. 4.5.1 Regulations Protecting Human Research Subjects and Their Privacy


Ethical / Institutional Review Board Approval (21 Code of Federal Regulations (CFR) 56)

The ethical review process suffers from a lack of clarity regarding the roles and responsibilities of various oversight bodies and what is expected of investigators (English, Lebovitz, & Giffin, 2010). IRBs have expanded their scope of responsibility in recent years, undertaking new tasks such as review of investigators’ conflicts of interest, protection of patient health information, assessment of trial design, and risk management. As a result of this “mission creep,” trials require more approvals from different people within a single IRB, yet there are no indications that safety is improved by the expansion of responsibility (Kramer, Smith, & Califf, 2012).

In addition to the increased bureaucracy and associated delays, the IRB review process for multisite trials (which usually require approvals by multiple IRBs) is also plagued by problems of coordination and consistency (English, Lebovitz, & Giffin, 2010). IRB definitions and standards (e.g., for reportable adverse events, or for what qualifies as equipoise) vary by geographic location, resulting in inconsistencies, delays, and other complications. Lost time and redundancies result when multiple local IRBs must review the same protocols and adverse events instead of a single IRB doing so, and dividing authority among multiple IRBs may weaken any individual board’s ability to demand important changes to protocols. Moreover, important issues flagged by one IRB may not ever be communicated to the other IRBs (Kramer, Smith, & Califf, 2012).

To alleviate some of these problems, FDA recommended in 2006 that one central IRB be used for multicenter trials (U.S. Food and Drug Administration, 2006b); however, many drug sponsors have not made this a requirement and some sites are still unwilling to work with central IRBs. On April 23, 2012, FDA held a public hearing to obtain input from stakeholders on FDA's scope and direction in modernizing the regulations, policies, and practices that apply to the conduct of clinical trials of FDAregulated products, and IRBs were a topic of much discussion. According to speakers at the public hearing, institutions often express concern that they will remain liable, even if reviews are delegated to central IRBs, and therefore prefer to use their own (local) IRB rather than to delegate to a central IRB. Academic institutions have a reputation for being particularly reluctant to defer to central IRBs (reasons for this are discussed in Section 4.8) (U.S. Food and Drug Administration, 2012).

Informed Consent (21 CFR 50)

The process of obtaining informed consent, while important, is burdensome and time-consuming, both for researchers and trial participants. Sponsors are required to educate clinical trial participants as to the purpose of the study, its duration, necessary procedures, potential risks and benefits, and their rights before they can enter the trial. As part of this process, the research team must produce carefully worded documents, discuss the documents and the trial process with each individual patient, get the required patient signatures, and track the paperwork (English, Lebovitz, & Giffin, 2010).

Patients must fill out and sign the numerous forms before they can participate, which can be overwhelming, especially when combined with the U.S. Health Insurance Portability and Accountability Act (HIPAA) forms, monitoring, and compliance (English, Lebovitz, & Giffin, 2010). A recent study of 124 informed consent documents used in multinational, U.S. government-sponsored human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) trials found the median length of the forms to be 22 pages (27 pages for adult forms)(Kass, Chaisson, Taylor, & Lohse, 2011). The authors also noted that, despite the forms’ length, key concepts such as randomization were often inadequately explained, and higher-level reading comprehension skills (at least a ninth-grade level) were needed to understand the documents. The lengthy and confusing forms can be especially problematic for patients with language or disability barriers (U.S. Food and Drug Administration, 2012).

Development of technological solutions is underway, though it is still in its early stages. One option discussed at the April 2012 FDA hearing was to replace paper forms with wireless tablets, which have the potential to facilitate document security and management, as well as to provide information in multiple languages or in audio/video format, which might be more accessible to children and patients with disabilities. However, simply moving excessively long and complicated forms from paper to a tablet screen will not address the need to fundamentally streamline the informed consent process and improve both efficiency and understanding (U.S. Food and Drug Administration, 2012).

Patient Privacy: U.S. Health Insurance Portability and Accountability Act (HIPAA) (45 CFR Part 160 and Subparts A and E of Part 164)

HIPAA requires patients’ authorization to use their health information for research (may be combined with informed consent). There are severe penalties for violating HIPAA, so IRBs strictly enforce compliance. However, one consequence of HIPAA and other privacy laws is that, when patients drop out, site investigators are reluctant to attempt to contact them or seek their medical records to followup on major outcomes/study endpoints. This in turn reduces statistical power and can lead to uncertain study results. It has been suggested that informed consent documents include a statement alerting participants that, should they drop out of the study, the investigators will seek their authorization to track their major outcomes (Kramer, Smith, & Califf, 2012).

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