In addition to the federal regulations listed above, there are also state and local regulations to comply with, and the requirements may be different for each location in multi-site trials. Companies conducting trials at sites in the European Union (EU) (or other countries) are also regulated by the European Commission/EU Clinical Trials Directive (or other national regulatory authorities) (Kramer, Smith, & Califf, 2012), which may have varying guidance and regulations. The abundance of regulations at various levels and the lack of harmonization among these add a great deal of complexity to the process of conducting clinical trials (Kramer & Schulman, 2011). In interviews, sponsors listed the following areas as being particularly problematic: reporting of results, format for applications, guidance on endpoints, registration requirements, guidelines for clinical programs, biosimilars legislation, and adverse events reporting. For example, the United States and Europe differ as to who bears responsibility for ascertaining the cause of unexpected serious adverse events (SAEs). Under the new U.S. regulation, the drug sponsor is responsible for determining causality; in Europe, either the sponsor or the investigator may do so (as stated in the ICH guidelines) (Kramer, Smith, & Califf, 2012; Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011).
Most industry representatives interviewed agreed that, while the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH-GCP) guidelines (discussed in Section 4.9) and other harmonization efforts have proven helpful, the problem of differing practices and requirements across jurisdictions is far from being solved. The EU Voluntary Harmonisation Procedure (VHP) illustrates this point. In incorporating the 2001 EU Clinical Trials Directive into national laws and regulations, divergent practices emerged across member states with regard to application dates, timelines for review of clinical trial applications, content/format/language requirements, distribution of responsibilities between authorities and ethics committees, and workload among authorities (Clinical Trials Facilitation Groups (CTFG), 2010).
To address these issues, the Clinical Trials Facilitation Group (CTFG) established the Voluntary Harmonisation Procedure, which allows clinical trial applicants to electronically submit a single set of materials to one coordinator and obtain trial approval across multiple EU states at once, instead of making submissions to each country separately (Buchholzer, 2011; Krafft, Bélorgey, & Szalay, 2012). Since its introduction in 2009, the VHP has been increasingly utilized; over 140 applications had been received as of February 2012, approximately a third of which came from U.S. sponsors and most of which received a positive opinion (Krafft, Bélorgey, & Szalay, 2012). Still, despite near-universal adoption of the VHP across EU member states, many sponsors and CROs remain hesitant to use it (possibly because it is a new and unfamiliar process, and drug companies tend to adhere to traditional practices with proven track records) (Buchholzer, 2011). Furthermore, the VHP does not extend to countries beyond the EU, nor does it address harmonization concerns regarding aspects of clinical trials other than the application process.
Apart from studies spanning multiple geographic locations, lack of harmonization can also be a barrier for research that falls under the purview of multiple federal agencies. In particular, oncology research may be subject to the requirements and guidance of not only FDA, but also the Office for Human Research Protections (OHRP), the National Institutes of Health (NIH), and the Office for Civil Rights (OCR), depending on the study (U.S. Food and Drug Administration, 2012). Though efforts have been made by FDA and OHRP to harmonize guidances, some differences remain among agencies in privacy requirements, government access to records, safety reporting requirements, terminology, and conflict of interest disclosure (U.S. Food and Drug Administration, 2012). For example, while HHS lowered the monetary threshold at which significant financial interests require disclosure from $10,000 to $5,000 in 2011(National Institutes of Health, 2011), FDA’s reporting threshold is $25,000 (U.S. Food and Drug Administration, 2011b). Such inconsistencies cause confusion among investigators and make it difficult to keep abreast of the various requirements (U.S. Food and Drug Administration, 2012).