Regulations are often created in response to a negative event befalling a trial participant or a study as a whole (Kramer, Smith, & Califf, 2012). While these regulations are intended to improve safety or other facets of the clinical research process, many times they are not subsequently evaluated to determine whether they actually achieve those purposes or are simply creating additional obstacles.
Furthermore, U.S. regulations pertaining to clinical research were written when the clinical trials enterprise was smaller in terms of the number of active trials and before multicenter trials became common (in the 1980s-1990s) (Kramer, Smith, & Califf, 2012). This section addresses several subcategories of regulatory and administrative barriers.
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4.5.1 Regulations Protecting Human Research Subjects and Their Privacy
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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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4.5.2 Safety Reporting Requirements for Investigational New Drugs (INDs) and Biologics (21 CFR 312)
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In the course of clinical investigations conducted under investigational new drug (IND) applications, information regarding adverse events must be communicated among investigators, sponsors, IRBs, and FDA in safety reports. There are a number of terms that are used to categorize adverse events and thereby determine which must be reported. The most up-to-date definitions of these terms from 21 CFR 312.32(a) are provided below:
- Adverse event: “[A]ny untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”
- Life-threatening adverse event or life-threatening suspected adverse reaction: “An adverse event or suspected adverse reaction is considered ‘life-threatening’ if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.”
- Serious adverse event or serious suspected adverse reaction: “An adverse event or suspected adverse reaction is considered ‘serious’ if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.”
- Suspected adverse reaction: “[A]ny adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”
- Unexpected adverse event or unexpected suspected adverse reaction: “An adverse event or suspected adverse reaction is considered ‘unexpected’ if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.”
In the past, the FDA, IRBs, and clinical investigators in multicenter trials have been flooded with expedited reports of serious adverse events (SAEs), making it difficult to determine which were true signals of significant safety events and which were simply “noise.” This high-volume reporting occurred largely as a result of the FDA’s previous safety reporting requirements, which were insufficiently specific with regard to the threshold for determining whether an adverse event was reportable (Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011), combined with cautious over-reporting on the part of sponsors (see Section 4.6). These reports did not provide enough context—such as aggregate data by treatment group—to allow for interpretation of the events and evaluation of their causal relationship with drug therapy. For example, it is impossible to determine whether a single reported case of myocardial infarction is causally related to drug exposure in a study population comprised of elderly patients (Kramer, Smith, & Califf, 2012; Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011).
A new FDA safety reporting regulation (effective March 2011) seeks to remedy these problems by clarifying the roles and responsibilities of sponsors and clinical investigators in the safety reporting process (Kramer, Smith, & Califf, 2012; Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011). The new regulation requires that clinical investigators continue to report all serious adverse events to the sponsor, regardless of whether they are considered to be drug-related. The sponsor, in turn, is required under 21 CFR 312.32(c) to submit an expedited IND safety report to the FDA and all participating investigators within 15 days when any of the following criteria are met: (1) there has been a suspected adverse reaction that is both serious and unexpected (as defined above); (2) there are findings from other studies or animal or in vitro studies that suggest that exposure to the drug results in a significant risk to humans; or (3) there has been a “clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.” The crux of the new rule is that sponsors should send expedited reports only for those events that the sponsor believes are causally linked to exposure to the investigational agent, rather than sending expedited reports for all events that either the sponsor or the investigator believes are even possibly linked to exposure to the investigation agent.
In contrast to the previous regulations, which permitted either the sponsor or the investigator to make causality determinations, assessment of which events are likely caused by the drug is now solely the responsibility of the sponsor, who has more complete information than the individual investigators. Additionally, more guidance is provided to help sponsors evaluate causality for adverse events and what types of reactions need to be reported. The new requirements are thus intended to reduce the excessive volumes of events being reported to FDA, investigators, and IRBs and more clearly identify which events actually have important patient safety implications (Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011).
Still, it is too early to tell how sponsors will adapt to the change and to what extent the changes will succeed in their intended purpose (Kramer, Smith, & Califf, 2012). Despite the revisions that were made in the spring of 2011 (to 21 CFR parts 312 and 320), some remaining issues were raised by industry and IRB representatives at the public FDA hearing held in April, 2012. For one thing, there may be inconsistent reporting requirements. Investigators are required (under 21 CFR parts 56.108(b)(1), 312.53(d)(1)(vii), and 312.66) to report promptly “to the IRB…all unanticipated problems involving risks to human subjects or others”; however, investigators might interpret an event to be “anticipated” (and therefore not required to be submitted) on one occasion, and then might interpret the same event to be “unanticipated” at another time (Public Hearing, 2012). Another speaker expressed concern that 21 CFR part 56 is still interpreted by sponsors and investigators as requiring every investigator to send every IND safety report to the IRB, and IRBs have trouble interpreting safety data received in a “piecemeal” fashion. The speaker asked that FDA clarify sponsors’ reporting obligations. Individual investigators are also burdened by the need to act as middle men between sponsors and the IRB, which, the speaker argued, is inefficient and unnecessary (U.S. Food and Drug Administration, 2012).
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4.5.3 Regulations for Multiple Jurisdictions
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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).
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4.5.4 Conservative Regulatory Climate
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Nearly all of the company representatives and experts interviewed commented on what they perceived as a particularly risk-averse regulatory climate of recent years. Many framed the problem as a disproportionate weighting of risk in the risk-benefit equation, with FDA now appearing hesitant to take on even small amounts of risk, regardless of the potential benefit to patients. Those with several years of experience in the industry observed that this conservatism is part of a cyclical pattern governed by political, Congressional, and media pressure following adverse outcomes.
In describing this perceived regulatory conservatism, many company representatives expressed frustration with FDA’s safety data demands for certain indications. For example, multiple interviewees said that many companies can no longer afford to develop drugs for diabetes because of new cardiovascular risk guidelines. In 2008, in light of published findings that the approved drug Avandia increased the risk of heart attacks, FDA issued guidance requiring that all diabetes drugs undergo a cardiovascular risk assessment lasting at least two years (Harris, 2010). Similar requirements are being considered for obesity drugs in the United States (Pollack, 2012).
While interviewees supported the goal of improving patient safety, they also encouraged consideration of the disincentives created by the new rule. They explained that it takes months to test whether a diabetes drug works to help control blood sugar levels, but it takes years and thousands of patients to determine cardiovascular risk, making clinical trials in this therapeutic class prohibitively expensive. Such barriers discourage investment by venture capitalists, and can drive sponsors to other (non-U.S.) markets or lead them to stop pursuing drugs in these classes altogether, thereby drying up the pipeline at a time when high obesity rates in the United States necessitate more treatment options (Pollack, 2012).
Drug company representatives also warn that safety requirements calling for large programs and large volumes of data can produce unexpected safety signals as a result of multiple comparisons and detection bias. Some feel that FDA is requiring too much investigation of safety pre-approval and could instead allow for more of this work to be shifted to post-marketing studies, while reserving the authority to pull the drugs off the market if these are not completed satisfactorily. Sponsors further argue that at the time of approval, FDA could simply make all information available to clinicians and their patients so that they can make their own decisions.
FDA’s exploratory IND guidance was offered by a CRO representative as another example of regulatory risk aversion. Often, in the early stages of research, there are many potential molecules a sponsor is interested in, and some human data is needed before the sponsor can decide which to pursue. FDA’s exploratory IND rule says that sponsors do not have to have all the toxicity data that they would normally need before getting started, but they can only use 1/100th of a dose in human patients (U.S. Food and Drug Administration, 2006a). The interviewee argued that 1/100th of a dose is not informative, and therefore the rule was of little practical use.
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4.5.5 Lack of Clear Regulatory Pathways and Guidance for Some Therapeutic Areas
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Sometimes, not having a clear idea of what FDA requires is the fault of companies, who might avoid meeting with FDA early in the process, perhaps out of fear of hearing bad news that must then be shared with their investors. However, industry representatives assert that, in many cases, much of the responsibility for failed communication and unclear expectations rests with FDA.
While the regulatory pathways for some therapeutic areas, such as oncology and cardiovascular disease, are well-established, the requirements remain much less clear for other, more “cutting edge” areas, like central nervous system disorders, metabolic diseases, and biosimilars, for which there is little in the way of precedent. In disease areas where guidelines are nonexistent, old, or otherwise lacking, sponsors find it difficult to understand what FDA expects of them before beginning their studies, and the process can result in lengthy back-and-forth discussions and negotiations with reviewers. Such a situation is both inefficient (as each individual company must take the time to seek out information or negotiate the requirements on its own) and unpredictable (as reviewers may change their minds over time).
According to one CRO representative, some drugs fall between the cracks of other regulatory pathways because they are intended to treat diseases that are exceptionally rare or sporadic. While the orphan drug pathway is appropriate for conditions affecting fewer than 200,000 patients, there are some conditions affecting only a few hundred patients that might be effectively treated with a new drug. The barriers to developing a drug for such conditions are substantial; from a regulatory perspective, it is similar to developing a drug for millions of patients, despite the fact that enrollment and other aspects of the process are much more difficult. The interviewee noted that, while there were cases in which FDA had been flexible and helped an important treatment to reach patients (e.g., Botulism Immune Globulin, or “BabyBIG”), there have been other instances where drugs have been dropped because the regulatory barriers were not adjusted. By existing rules, it seems infeasible to sponsors to test a treatment for Escherichia coli (E. coli), for example, as not enough patients can be found who become ill with hemolytic uremia to test the drug. While FDA’s Animal Rule allows sponsors to demonstrate effectiveness in animals, it has only been used a few times (e.g., anthrax).
For therapeutic areas where guidance is lacking, FDA often takes a long time to issue and update guidances. While FDA has undertaken some positive initiatives recently (e.g., starting to issue new guidances, including draft guidance for biosimilars; examining guidances for skin and pneumonia; considering guidances for unmet need pathogens; and considering new approval pathways for pathogens that would require more restrictive labeling and be for more limited populations), these processes can be very slow from industry’s perspective.
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4.5.6 Barriers Related to the Review Process
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The expert consultants and drug company and CRO representatives interviewed acknowledged the difficulty of FDA’s position, as the Agency faces conflicting pressures from Congress and industry and must balance the need for scientific evidence with the need for timely access to the new drug. Most respondents commented that FDA is consistently understaffed and underfunded, and the resources it does have at its disposal are stretched too thin.
Nonetheless, there were some specific concerns shared by the interviewees regarding the regulatory review process at FDA. One issue that was frequently mentioned was the perceived concentration of too much responsibility and power in the hands of individual reviewers. When most of the burden of decision-making is borne by a single reviewer, that reviewer will bear full responsibility if something goes wrong; thus, he or she might be more risk averse than a group of individuals across whom responsibility is spread evenly. Anecdotal evidence suggests that junior reviewers might be particularly risk averse, while veteran reviewers might be inflexible. Additionally, turnover among reviewers becomes problematic, as it can take quite a long time to get a new reviewer up to speed. Such a system makes company representatives feel that their outcomes are subject to the whims of the individual reviewer and his or her personal feelings about a particular drug or company. Consequently, some respondents expressed a preference for the European regulatory review system, which involves multiple academic experts to reach a scientific consensus. While the FDA does use an advisory board, the interviewees felt that it is involved too late in the process, and its authority is too weak to overrule the reviewer’s decision.
Another common grievance among interview respondents was the difficulty of getting timely feedback from FDA. Though a recent New England Journal of Medicine article found that FDA reviewed applications involving novel therapeutics faster, on average, than the European Medicines Agency (EMA) or Health Canada (Downing, et al., 2012), many sponsors interviewed by ERG felt that there was still room for improvement in the efficiency and predictability of communication. There is a perception in the industry that FDA is becoming more bureaucratic and seeking to formalize all processes--making communication increasingly cumbersome. Rather than being able to contact the relevant FDA reviewers directly, companies say they must first go through project managers, fill out written requests, and complete other intermediate steps. While investigational new drug (IND) timelines are considered acceptable (feedback is received within 30 days), receiving feedback in the post-IND or review periods can take a long time.
A final oft-repeated refrain among industry representatives is the lack of consistency among reviewers and divisions within FDA’s Center for Drug Evaluation and Research (CDER). Respondents believed there to be appreciable variability across divisions at FDA in responsiveness, scientific expertise, flexibility, and openness to meetings. For example, it was mentioned that the Division of Cardio-Renal Drug Products has a reputation for being particularly innovative and flexible relative to other divisions, while Metabolism and Endocrinology Products and Pulmonary, Allergy, and Rheumatology Products are perceived as divisions where drugs are more likely to be delayed. Interviewees indicated that there are good scientists at FDA, but they are scattered across different departments, and the overall scientific caliber of reviewers could be improved to ensure better consistency.
A newly published study by Tufts CSDD explores the issue of consistency among the various FDA drug review divisions using data on new molecular entity (NME) New Drug Applications (NDAs) and “new” Biologic License Applications (BLAs) from the period between 2006 and 2010 (Milne & Kaitin, 2012). The authors outline the various factors that contribute to disparities in regulatory experiences on both the industry side (including therapeutic area, technology turnover, investment levels, and experience/expertise of the sponsor) and FDA side (including staffing levels, organizational changes, workload fluctuations, leadership, advisory committee dynamics, and political pressures). According to the study, there are substantial differences among divisions in terms of staff, workload, approval times, rates of clinical holds ordered on commercial INDs, the percentage of products for which an advisory committee meeting is held, NDA approval rates, and other measures. Confirming what was said in our interviews with industry representatives, the Metabolism & Endocrinology and Respiratory/Rheumatology divisions were indeed found to have exceptionally high rates of clinical holds relative to other divisions.
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