Broadly speaking, the major obstacles to conducting clinical trials in the United States identified through this research include: high financial cost, the lengthy time frames, difficulties in recruitment and retention of participants, insufficiencies in the clinical research workforce, drug sponsor-imposed barriers; regulatory and administrative barriers, the disconnect between clinical research and medical care, and barriers related to the globalization of clinical research. We discuss each of these in further detail below.
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4.1 High Financial Cost
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The largest barrier to conducting clinical research—and the one into which most other barriers feed—is the high cost. Studies estimate that it now costs somewhere between $161 million and $2 billion to bring a new drug to market (DiMasi, Hansen, & Grabowski, 2003; Adams & Brantner, 2006; Morgan, Grootendorst, Lexchin, Cunningham, & Greyson, 2011). One particularly well-known and often-cited paper by DiMasi, Hansen, & Grabowski (2003) arrives at a total pre-approval cost estimate of $802 million in 2000 dollars to develop a single drug (inflated to 2012 dollars, this estimate is $1.07 billion) (DiMasi, Hansen, & Grabowski, 2003; U.S. Bureau of Labor Statistics, 2012). More recent estimates of drug development costs are around $1.3 billion to $1.7 billion (Collier, 2009). It is important to note that the DiMasi, Hansen, & Grabowski (2003) estimate and many others in the literature represent fully capitalized costs and are inclusive of failures.
The DiMasi, Hansen, & Grabowski (2003) research on this topic is sponsored by the Tufts Center for the Study of Drug Development (CSDD) and has been the subject of much debate among researchers. Light & Warburton (2005) contend that the $802 million figure is far too high due to “problems with the data and sampling,” specifically small sample size, differences in cost allocation methods over time and across companies, upward biases in industry-reported costs, the types of drugs included, and failure to adjust for government subsidies or tax deductions/credits. Light and Warburton (2005) are also critical of the authors’ use of proprietary and confidential data which precludes independent verification (Light & Warburton, 2005). DiMasi et al. (2003) address these concerns in replies, stating that the accuracy of their results is bolstered by cross-checks against other sources and validation by the U.S. Office of Technology Assessment (DiMasi, Hansen, & Grabowski, 2005). Adams & Brantner (2006) also sought to replicate the findings of DiMasi, et al. (2003) using publicly available data. They arrived at a cost estimate of $868 million, suggesting that $802 million might actually be an underestimate. The authors caution, however, that estimated costs vary widely, depending on drug type, therapeutic area, regulatory policies, and strategic decision-making by drug sponsors. Thus, policymakers should be careful about using a single number to characterize drug development costs (Adams & Brantner, 2006).
Although experts debate the accuracy of various cost estimates, there is widespread agreement that clinical trial costs are substantial and rising. According to a 2007 article, the average cost of developing a drug had risen at a rate 7.4 percent higher than inflation over the past two decades, mostly due to rising clinical trial costs (Collier, 2009). Costs also tend to increase as a drug progresses through each phase of the pipeline, and, as the Institute of Medicine (IOM) notes, Phase 3 clinical trials have become “extraordinarily expensive” (English, Lebovitz, & Giffin, 2010). DiMasi, Hansen, & Grabowski (2003) report that the mean costs per investigational drug entering a phase are $15.2 million for Phase 1, $23.5 million for Phase 2, and $86.3 million for Phase 3. Using publicly available data and a larger sample size than DiMasi, et al., (2003), Adams & Brantner (2010) estimate the average expenditure per drug in human clinical trials at around $27 million per year, with $17 million per year on drugs in Phase 1, $34 million per year on drugs in Phase 2, and $27 million per year on drugs in Phase 3 of the trials. Note that DiMasi, et al. (2003) present costs for the average drug over the entire length of each phase, while Adams & Brantner (2010) present expenditures for one year. Multiplying the latter by average phase durations yields estimates of $24 million, $86 million, and $61 million for Phases 1, 2, and 3, respectively (Adams & Brantner, Spending on new drug development, 2010).
While the reasons for these high costs are manifold, a few key macro-level trends stand out. One contributing factor is the productivity of the drug industry in past years. High levels of investment in research and development have yielded so many drugs that companies are now finding it difficult to develop truly innovative pharmaceuticals. As a result, most new drugs are actually just variations of existing drugs, intended to be only incrementally more effective or safer than those already on the market. Detection of such small, incremental improvements requires studies with large numbers of patients (Collier, 2009), and with greater numbers of participants comes greater expenditure on recruitment efforts, data collection, compliance with administrative requirements, and other trial components.
In addition, there has been a shift in the biopharmaceutical industry toward chronic and degenerative disease research, which, given the aging of a large segment of the population, has the potential to secure steady and sizeable revenue streams for companies who can capture a share of these markets (Collier, 2009; DiMasi, Hansen, & Grabowski, 2003). On the other hand, however, clinical trials for these chronic conditions (such as arthritis, dementia, and cardiac diseases) tend to involve complex and expensive testing, large numbers of patients, and long timeframes, as extended drug exposure is required in order to identify potential long-term effects. Multiplying these long-term data requirements by large numbers of patients yields enormous volumes of data that must be collected, processed, analyzed, and reported, all at great cost to the sponsor.
Another significant trend contributing to higher clinical trial costs is the increased use of health care cost containment strategies, such as tiered formularies and cost-effectiveness data requirements, in the United States and other countries. In response to these measures, drug sponsors might choose to devote more of their clinical research budgets to trials that compare their drug to a competitor drug, as opposed to trials that compare their drug to a placebo. As discussed above, this can lead to increased expenses, as larger trial sizes are needed to demonstrate statistical significance in comparisons of multiple drugs (DiMasi, Hansen, & Grabowski, 2003).
Other cost drivers, which are discussed in more detail in subsequent sections, include increasingly complex clinical trial protocols, conservative approaches to data and site monitoring, and delays caused by differing interpretations of requirements by different parties involved in multicenter trials (Collier, 2009).
The increasing cost of clinical research has significant implications for public health, as it affects drug companies’ willingness to undertake clinical trials. Many companies are taking their trial operations—and their research dollars—to other countries, such as India and China, where trial costs can be up to 60 percent lower (Collier, 2009). Some researchers argue that rising clinical trial costs have made the industry as a whole more risk averse; with such large sums of money at stake, sponsors are less willing to take chances on novel drugs (Collier, 2009). Clinical research centers are also more closely scrutinizing the types of clinical trials they will take on, out of concern that certain projects will fail to be profitable and put them in a deficit (e.g., due to complicated protocols or low per-patient grant amounts) (Collier, 2009; Getz K. A., 2010a).
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4.2 Lengthy Timelines
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Closely related to the cost of clinical trials is the length of time it takes to complete them, which has also increased in recent years. Between 2000 and 2005, pharmaceutical companies experienced a three percent median increase in development cycle times and a nearly 11 percent increase in regulatory cycle times (Getz K. A., 2006). Though the most recent data released by FDA in the fiscal year (FY) 2011 Prescription Drug User Fee Act (PDUFA) Performance Report indicate that median times to approval for priority and standard applications have decreased by a few months since FY 2008 (U.S. Food and Drug Administration, 2012), 12 the drug development process as a whole is still lengthy. DiMasi, Hansen, & Grabowski (2003) calculated that the average length of time from the start of clinical testing to marketing is 90.3 months (7.5 years), and the entire process, from discovery to registration with the FDA, takes 10 to 15 years for a typical drug (English, Lebovitz, & Giffin, 2010).
Lengthy timelines directly contribute to lower revenues over the course of a drug’s lifecycle, increasing the financial burden of drug development. For instance, long trials mean large human labor costs, as investigators and staff must be compensated for many hours. Long development times also reduce the time a drug has under patent protection, thereby opening the door for generic competitors and reducing the amount of revenue that can be earned. Additionally, the potential for study results to impact medical practice may be reduced over time as changes in clinical practice or the standard of care might make the new drug obsolete (English, Lebovitz, & Giffin, 2010). The timing of investments and returns also factors into the total cost of drug development. As DiMasi, Hansen, & Grabowski (2003) explain:
Once a timeline is established and out-of-pocket costs are allocated over that timeline, the expenditures must be capitalized at an appropriate discount rate. The discount rate should be the expected return that investors forego during development when they invest in pharmaceutical R&D instead of an equally risky portfolio of financial securities. Empirically, such a discount rate can be determined by examining stock market returns and debt-equity ratios for a representative sample of pharmaceutical firms over a relevant period. The resulting discount rate is an average company cost-of-capital (DiMasi, Hansen, & Grabowski, 2003).
The authors estimated that half of the total average cost of bringing a new drug to market—which they estimated at $802 million—was attributable to opportunity costs associated with foregone investments over the drug development period ($403 million) (DiMasi, Hansen, & Grabowski, 2003).
There are a number of factors contributing to the length of clinical trials, and several of these are also discussed in other sections. For one, industry’s focus on treatments for chronic diseases (see Section 4.1) creates a need for long trials to demonstrate safety for drugs that are meant to be taken over an extended term. As discussed in the following sections, long trials face additional challenges with patient and investigator retention, which can in turn cause costly holdups (Weisfeld, English, & Claiborne, 2011). Numerous administrative and regulatory barriers also create delays that protract the clinical trial approval process in the United States (see Section 4.5 for more details). Additionally, the “one-off” ad hoc nature of trial organization contributes to long trial initiation timeframes, as investigators, staff, study sites, and other resources are retained for the purposes of a single trial and then disbanded. In the absence of a consistent trial infrastructure, each clinical trial requires that these resources be assembled anew, a process that can take years (Eisenberg, Kaufmann, Sigal, & Woodcock, 2011; English, Lebovitz, & Giffin, 2010).
Although various technological advances and opportunities for centralized coordination have the potential to shorten drug development timelines, the clinical trial business model has not yet evolved in such a way that would take full advantage of them (Kramer & Schulman, 2011). For example, electronic data capture (EDC) improves efficiency by replacing paper forms and manual data queries with electronic forms and checks; however, not all companies have adopted EDC as a replacement for paper records (Neuer, Warnock, & Slezinger, 2010), and other efficiency gains made possible by this technology—for instance, in patient screening and recruitment—have not yet been realized (Kramer & Schulman, 2011). Site monitoring is another example; according to a recent survey of 65 organizations, 83 percent reported using centrally available data to evaluate site performance, but only 12 percent of respondents actually made frequent use of centralized monitoring to replace time-consuming on-site visits (Morrison, et al., 2011). A third example is the unwillingness of some research sites (academic institutions, most notably) to defer to central IRBs to allow for streamlining of the ethics review process.
According to the literature and the interviews with drug company representatives, this industrywide inertia is rooted in a desire to avoid perceived regulatory risk. That is, companies, investigators, and reviewers continue to take actions that add time and cost but are not value-added, simply because those actions have proven successful in the past (Kramer & Schulman, 2011). Getz (2006) reported that some companies, including Bayer, Astra-Zeneca, Allergan, Boehringer-Ingelheim, and Merck, have found ways to achieve speed advantages (development cycles shortened by up to 17 months and regulatory cycles shortened by up to 3 months) relative to average performers. According to the author, these advantages can be attributed at least in part to terminating projects sooner, collaborating more actively with global regulatory agencies, using information technology and electronic data management technologies consistently and widely, and using CROs more (Getz, 2006). Additionally, partnerships and networks, such as the Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC), have succeeded in increasing efficiency by bringing resources together and allowing multiple trials to be conducted without building the infrastructure up from scratch each time. Still, adoption of these models and practices is the exception rather than the standard.
12 See also Brooks, C. (2012). According to this report, analysis of 4,300 global clinical trials across multiple therapeutic areas indicates the trend toward longer trial durations has reversed and clinical trials are now being completed in less time.
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4.3 Difficulties in Recruiting and Retaining Participants
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In interviews, expert consultants and representatives from pharmaceutical and biotechnology companies and CROs cited patient recruitment as one of the most significant barriers to conducting clinical trials in the United States. Failure to recruit sufficient numbers of patients can result in costly delays or even cancellation of the entire trial (Weisfeld, English, & Claiborne, 2011).
Patient recruitment difficulties are caused by a number of factors, some of which are fairly universal across clinical trials, while others arise due to characteristics of a particular disease or trial. One obvious factor is study size; as discussed previously, trends toward comparative and chronic disease studies contribute to a need for larger numbers of participants. Another common problem is finding willing individuals to participate in clinical trials. Most company representatives also expressed frustration over competition among drug companies for the same patient pools, explaining that multiple large companies often find themselves targeting the same big markets at the same time. For example, many sponsors are interested in pursuing anti-inflammatory drugs because the road to regulatory approval is clear and well-established for these drugs. These companies then compete to enroll patients with a few specific diseases (e.g., asthma, multiple sclerosis, and chronic obstructive pulmonary disease) on which they would like to test their drug. On the other hand, for smaller markets, recruitment might be hindered by the simple fact that patients are few and far between. Many smaller companies focus on developing drugs for orphan diseases, for which the potential pool of patients is, by definition, limited.
There are several factors specific to certain disease areas or trial types that can make it especially difficult to recruit and retain patients in sufficient numbers. For some diseases (such as certain cancers), problems of access arise because patients are located mostly in remote areas, far from the clinical trial sites that are selected based on where investigators are (English, Lebovitz, & Giffin, 2010). Patient retention is a common problem in studies involving long-term endpoints (e.g., multiple sclerosis), lengthier treatments, or negative side effects that cause patients to become fatigued or sick and drop out. Additionally, some trials have narrow patient eligibility criteria that intentionally disqualify many potential participants who have the targeted disease but do not meet other inclusion criteria (English, Lebovitz, & Giffin, 2010). The goal in excluding these patients is to conduct a pure experiment that is free from the confounding influences of comorbid illnesses, concomitant medications, and other such factors (Kramer, Smith, & Califf, 2012). Enrollment restrictions such as these may simplify the trial itself but make recruitment more difficult.
Even if there were an abundance of readily available, ideally suited patients, participation in clinical trials would still be greatly hindered by public attitudes, incentives, and lack of knowledge. Both physicians and their patients are often unaware of clinical trial options, and often times it is only patients of higher socioeconomic status who have the resources, knowledge, and motivation to seek information about a disease, including clinical trials (English, Lebovitz, & Giffin, 2010). Furthermore, physicians may not be able to determine whether standard treatment or a trial is the better option for their patients. To some extent, these problems arise from the separation between the realms of scientific research and clinical care in the United States and the lack of engagement among physicians in the clinical research process (discussed in greater detail in Section 4.7) (Bonham, Califf, Gallin, & Lauer, 2011).
For their part, patients who are aware of clinical trial options might be hesitant to participate for a number of reasons. Fear is a major deterrent; patients understand that taking part in clinical research is good for public health but feel uncertain as to whether it is the best option for their own personal health. Many people are ill-at-ease with the idea of serving as “guinea pigs” and possibly suffering unexpected side effects, while others might assume the new drug is likely to be effective and worry instead about being assigned to a no-treatment or placebo group (Mills, et al., 2006; Welton, Vickers, Cooper, Meade, & Marteau, 1999). A related issue is discomfort with randomization and the idea that choice of treatment will be based on chance rather than the decision of a doctor or the patients themselves (Jenkins & Fallowfield, 2000). Media attention to cases with negative outcomes (e.g., serious side effects or deaths) has also fostered distrust of industry-sponsored trials, and many patients believe that industry will put its own interests ahead of theirs (Weisfeld, English, & Claiborne, 2011; English, Lebovitz, & Giffin, 2010). Awareness of deceptive, exploitative, and racist past practices in experiments, such as the Tuskegee syphilis study, continues to fuel this distrust, particularly among some minorities and cultures within the United States (Weisfeld, English, & Claiborne, 2011; Shavers, Lynch, & Burmeister, 2000).
Aside from the uncertainties involved, participating in clinical research may simply be inconvenient or overly burdensome to patients. By signing up for a trial, patients might subject themselves to interruptions in care, physical and emotional stress caused by leaving their regular provider, time and travel costs, (including transportation to the study site and lost income), and large volumes of confusing paperwork associated with the informed consent process (English, Lebovitz, & Giffin, 2010). Finally, language and literacy barriers may also deter some from participating (Weisfeld, English, & Claiborne, 2011).
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4.4 Increasing Competition for Qualified Investigators and Sites
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In addition to patient recruitment, difficulty finding investigators and sites was one of the issues most frequently raised by industry representatives in discussions with ERG. According to some, the problem is not a lack of researchers overall but rather a lack of highly qualified researchers who are consistently able to enroll high-quality patients in sufficient numbers. As a result, sponsors compete with each other for these top investigators, creating the impression that there is a shortage even though less well-qualified investigators might be available.
Whether and how sponsors experience this competition is based, to some degree, on their companies’ size and disease specialties. Many of the larger CROs have strategic partnerships with large drug companies, which provide the CROs with a consistent revenue stream. In exchange, the drug companies get priority access to staff, data management resources, and investigators. This allocation of resources to big drug companies further intensifies resource competition for small companies. Companies pursuing drugs in the same therapeutic areas at the same time will also face more competition, not only for patients, as discussed in the Section 4.3, but also for investigators and sites. For highly specialized treatment areas such as anti-fungals, sponsors may have a very limited universe of qualified investigators to choose from in the first place.
Other experts frame the problem somewhat differently, asserting that this barrier stems not simply from competition for top investigators but also from an actual overall shortage of biostatisticians and clinical informaticists across academic medicine, industry, and government (Bonham, Califf, Gallin, & Lauer, 2011). In support of this claim, there is evidence to suggest that the rate of attrition among U.S. investigators is increasing. The proportion of clinical investigators who are from North America has been falling since 1997, while the proportions of investigators from Western Europe and the rest of the world have been increasing (English, Lebovitz, & Giffin, 2010).
There is reason to believe that this trend will persist and the pool of investigators in this country will continue to shrink. It is very challenging to conduct clinical trials and establish a successful career as a clinical investigator in the U.S (English, Lebovitz, & Giffin, 2010); 45 percent of first-time investigators quit the field after their first clinical trial (Califf, Filerman, Murray, & Rosenblatt, 2011), and there is little motivation for new investigators to replace them. The clinical investigator track is, in many ways, less appealing than other options available to researchers, who would prefer to publish results more easily and avoid the hassles of getting a clinical trial protocol approved. Furthermore, conducting clinical trials does not earn researchers much respect among academics, and academic institutions often provide little support in the design and initiation of trials. Although community physicians and practitioners represent a large pool of potential investigators, they are generally uninvolved in the clinical trial process (for reasons discussed in Section 4.7) (English, Lebovitz, & Giffin, 2010). In this shrinking pool of resources, competition for resources will likely continue to intensify as increasing numbers of trials are conducted in orphan/low-prevalence diseases.
The outlook for resources at the investigative site level is similarly bleak. Many veteran sites in the U.S. have been struggling financially in recent years, forcing some to shift resources to more profitable enterprises or even cease their clinical research activities altogether (Getz K. A., 2010a). While some of this financial hardship can be attributed to the global economic downturn—the number of new trials being initiated declined, and many trials have been delayed or terminated—much of it is due to industry practices. For one thing, protocols have grown increasingly complex (in terms of the number of procedures and amendments and amount of effort required to execute them), to the point of becoming unmanageable (discussed in more detail in Section 4.6). Recruitment is also very difficult in the United States (see Section 4.3), which increasingly drives sponsors to sites overseas. Furthermore, sponsors and CROs are responding to the unpredictability of site performance with a practice called “hedging,” in which trials are spread across larger numbers of sites, each with smaller numbers of patients, an economically unfavorable arrangement for many sites. Finally, sites face serious cash flow problems. In general, sponsors try to defer payment to later in the study; it takes an average of approximately 120 days for sites to receive payment from sponsors and CROs for work that they have already completed. Many experienced investigative sites need to borrow money in order to stay afloat, with the average U.S.-based site carrying a debt of $400,000. If these factors remain unaddressed, more sites can be expected to permanently close their doors to clinical research (Getz K. A., 2010a).
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4.5 Regulatory and Administrative Barriers
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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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4.6 Drug Sponsor-imposed Barriers
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Drug sponsors face a number of barriers to conducting clinical research that are outside their control. However, there are also a number of barriers that drug sponsors voluntarily impose upon themselves, adding further cost and delay to the process unnecessarily. While some of these avoidable costs and delays are incurred as a result of insufficient early planning or inefficiencies in company practices, the majority of them stem from a desire to avoid failure at all costs (Kramer & Schulman, 2011).
Risk aversion leads companies to take unnecessary steps at various points throughout the clinical trial process. As one drug company representative explained, there is a “bad feedback loop”; clinical trials are so costly that companies will spend millions more to achieve small reductions in the risk of failure. Legal advisors are major drivers of these strategies, which are designed to ensure regulatory compliance and minimize liability (Kramer, Smith, & Califf, 2012). In trial design, each assumption is made conservatively, and the study ends up being overpowered. At larger companies especially, statisticians and others are insulated from the cost consequences of their recommendations, so there is less accountability; no one objects because no one wants to be responsible for failure.
The rest of this section discusses, in greater detail, the various barriers that drug sponsors impose upon themselves in their administrative, study design, data and site monitoring, and serious adverse event reporting practices.
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4.7 Disconnect Between Clinical Research and Medical CARE
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Janet Woodcock, director of CDER, identified the separation between clinical research and clinical practice in the United States as one of the most serious problems with the current clinical research enterprise (English, Lebovitz, & Giffin, 2010). The problem is a multi-faceted one that also serves to reinforce many of the barriers discussed in other sections, such as shortages of investigators and patients, high costs, and lengthy timelines.
One aspect of this problem is the lack of involvement of community physicians in the clinical research process (English, Lebovitz, & Giffin, 2010). Most U.S. health systems and clinical practice sites do not include research as part of their mission (Kramer, Smith, & Califf, 2012); thus, there are fewer physician referrals of patients to clinical research studies and fewer investigators available to conduct the research than there might be otherwise. This also means that research findings are less likely to be adopted by such physicians in their regular practice (English, Lebovitz, & Giffin, 2010). Many health care professionals do not receive training in research methods (Bonham, Califf, Gallin, & Lauer, 2011) and have difficulty understanding research results and therefore applying them (Kramer, Smith, & Califf, 2012) (discussed in greater detail in Section 4.8).
Apart from issues of mission and training, there exist some disincentives for clinicians to participate in research. The U.S. system is one that encourages physicians to focus on efficiency and profitability, and discourages clinical research for being risky, time-consuming, and costly (Kramer, Smith, & Califf, 2012). Furthermore, although participation in pharmaceutical industry-sponsored clinical trials can be an attractive way for physicians to supplement their incomes (Ashar, Miller, Getz, & Powe, 2004), there is a great deal of scrutiny of doctors who work with pharmaceutical companies, due in part to media attention to conflict of interest cases. Any gifts or other “freebies” doctors receive from drug companies must be reported according to the Physician Payment Sunshine provision under the Patient Protection and Affordable Care Act, and several states have additional rules governing physicianindustry relations (Milne C. , 2012). While these safeguards against conflicts of interest are important, they have the unfortunate side effect of contributing to what some industry representatives described as a prevailing attitude of suspicion toward physician involvement in industry-sponsored clinical research. Such an atmosphere can dampen the appeal of the financial incentives provided by pharmaceutical companies and discourage physicians from participating in trials.
The separation between clinical research and clinical care in the United States also produces data collection inefficiencies, as some of the data that are routinely collected in the course of clinical trials overlap with data collected for the purposes of clinical care. Integration of clinical care and clinical research datasets would eliminate redundancies in data collection, help researchers to identify potential study participants, and offer other efficiency gains. However, at present, such integration is hindered by the lack of standard nomenclature and blend of incompatible paper and electronic data collection systems used in clinical care/billing and clinical research (Kramer, Smith, & Califf, 2012; Califf & Muhlbaier, 2003).
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4.8 Barriers at Academic Institutions
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There are cases in which drug sponsors might find it appealing or necessary to use academic institutions as trial sites. For instance, sponsors might seek to employ key opinion leaders who are affiliated with a particular institution, or they may be studying a very specialized disease area for which patients can only be found in sufficient numbers at certain universities, medical schools, or other academic sites. Despite these benefits, many aspects of academic institutions are not conducive to efficient and successful clinical research.
Academic institutions have a reputation for taking their ethical and regulatory oversight responsibilities to extremes and creating bureaucratic entanglements that add months to clinical trial timelines (Kramer, Smith, & Califf, 2012; Dilts & Sandler, 2006). A recent study found that the number of steps necessary to open a clinical trial at academic centers was over 110, in contrast to fewer than 60 steps at non-academic centers. The number of approval signatures needed ranged from 11 to 27, compared to a maximum of 11 at non-academic centers (Dilts & Sandler, 2006). For multi-site trials, sponsors and CROs must negotiate contracts individually with each participating institution, and, in a study of 218 trials at academic institutions, the mean time taken for grants and contracts approval was 100 days (which is even longer than IRB review takes, at 69 days) (Kramer, Smith, & Califf, 2012; Dilts & Sandler, 2006).
Though it does not take up as much time as the grants and contract approval process, obtaining ethical approval is another source of frustration for drug sponsors working with academic institutions. As discussed in Section 4.5, use of central IRBs can greatly improve the efficiency of this process; however, academic institutions are often unwilling to defer to these central IRBs. While one pharmaceutical company representative was optimistic that this reluctance was beginning to fade for the sake of staying competitive with other sites, there are other factors that might be difficult to overcome. For one thing, academic institutions have already invested in developing their own internal IRBs (as well as the electronic systems required for protocol submissions to those IRBs), so officials at those institutions will likely be hesitant to let those investments go to waste and lose financial support to a central IRB (Kramer & Schulman, 2011). Another interviewee explained that academic institutions are concerned about relinquishing their responsibility without also being relieved of some of their liability.
Aside from the regulatory and administrative roadblocks, many academic medical centers undervalue or fail to provide incentives for clinical research. There is a perception that clinical research is less intellectually rigorous than basic research. Moreover, many academic institutions do not inculcate in their students, trainees, and faculty a sense of professional obligation to generate new medical knowledge as part of clinical practice. As a result, faculty engaged in clinical research struggle for resources in the academic setting and face special challenges in achieving academic promotion and tenure. Students observing their struggle are less likely to choose the clinical research career path (Kramer, Smith, & Califf, 2012).
A related issue is the failure of academic medical curricula at the graduate and undergraduate levels to encourage fundamental principles of clinical research. Even training designed for investigators neglects research principles in favor of an emphasis on strict compliance with standard operating procedures (Kramer, Smith, & Califf, 2012). Those studying to be physicians are not adequately trained in advanced statistical methods to interpret clinical trial results (even at the level at which they are reported in medical journals), impairing their ability to use such results to inform their clinical care and practice evidence-based medicine (Kramer, Smith, & Califf, 2012; Horton & Switzer, 2005). For example, in a survey of 367 residents from 11 programs, only 37.4 percent knew how to interpret an adjusted odds ratio from a multivariate regression analysis. Seventy-five percent of survey respondents said they did not understand all the statistics they saw in journal articles, but the vast majority felt it was important to be familiar with the concepts in order to understand the literature (Kramer, Smith, & Califf, 2012; Windish, Huot, & Green, 2007).
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4.9 Barriers Related to the Globalization of Clinical Research
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Another significant barrier to conducting clinical trials in the United States is competition from sites in other countries; indeed, the clinical research footprint is shifting overseas. The number of active, FDA-regulated investigators based outside the United States has grown by 15 percent each year since 2002, while the number of U.S.-based investigators has fallen by 5.5 percent annually (Getz K. A., 2007). A recent study of industry-sponsored Phase 3 clinical trials for the 20 largest U.S.-based pharmaceutical companies found that approximately one third of the trials are being conducted entirely outside the United States and that over half of all study sites are located in other countries. The number of non-U.S. countries being used as trial sites more than doubled between 1995 and 2005, while the proportion of trials conducted in the United States and Western Europe decreased (Glickman, et al., 2009).
There are a number of factors driving this geographical shift. First, significant cost savings are possible, particularly in developing countries (Bailey, Cruickshank, & Sharma; Glickman, et al., 2009). One pharmaceutical company representative reported that a top-tier academic medical center in India charges around $1,500 to $2,000 per case report, which is less than a tenth of the cost at a second-tier center in the United States (Glickman, et al., 2009). Human labor accounts for much of the cost of clinical research, and salaries for physicians, nurses, and study coordinators in developing countries are lower than they are in the United States and other high-income countries (World Health Organization, 2006). Payment to clinical trial sites is also lower elsewhere than it is in the United States, and U.S.- based clinical trials are not as cost-effective (in terms of cost per patient visit) as trials based in other countries (English, Lebovitz, & Giffin, 2010).
Second, shorter timelines, due largely to faster recruitment, are also possible outside the United States. Countries such as China, India, and Russia have large potential patient pools that can help accelerate the otherwise time-consuming recruitment process (Bailey, Cruickshank, & Sharma; Glickman, et al., 2009). One industry representative said participants could be found in India in approximately half the time it takes to recruit in the West (Rai, 2005). For some diseases, such as malaria, sufficient numbers of patients can only be found in other countries (GlaxoSmithKline, 2011). Ultimately, U.S. investigators enroll only two-thirds as many patients as investigators elsewhere (English, Lebovitz, & Giffin, 2010).
Third, conducting trials in other countries allows drug sponsors to access more commercial markets for the drug they are testing. Increasingly, foreign regulatory agencies are demanding that drugs be tested on their own populations before they will allow the drug to be registered in their country; thus, sponsors conduct trials in those countries to fulfill those demands (Schmidt, 2001).
Fourth, conduct standards and intellectual property protection have improved in foreign countries, making these sites more attractive than they have been in the past. A key driver of this improvement has been the widespread adoption of the ICH Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH-GCP) guidelines (Bailey, Cruickshank, & Sharma; Glickman, et al., 2009; Schmidt, 2001; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 1996). The ICH-GCP guidelines establish a set of universal principles to which all clinical trials should adhere, including requirements to follow ethical standards, ensure scientific soundness, preserve the rights and safety of trial subjects, and maintain confidentiality of records, among others (Kramer, Smith, & Califf, 2012).
Fifth, the regulatory environment in wealthy countries, including the United States, has become increasingly burdensome to drug sponsors (Glickman, et al., 2009). More detailed discussion of regulatory barriers can be found in Section 4.5.
Given the factors listed above, it is easy to understand why drug sponsors might decide to shift part or all of their clinical research operations overseas. However, in doing so, they create a new set of potential scientific, ethical, and practical problems. From the standpoint of U.S. clinical care, there is concern that results from trials conducted in other countries may not be generalizable to the U.S. population. Indicators of standards of care for a particular site or country often are not reported, so it is difficult to tell whether different places are really comparable (Glickman, et al., 2009). Furthermore, some diseases may go untreated or undertreated in developing countries, making it easier to find trial participants whose outcomes will not be complicated by prior medications. Such patient populations are not representative of the types of people who would be using the drug in higher income countries, more specifically, patients for whom previous treatments have failed (Glickman, et al., 2009). Finally, geographically dispersed populations may have genetic differences that cause them to respond differently to drugs. Thus, a U.S. patient might have a different reaction to a drug compared to a patient from Asia or Eastern Europe, for example. These genetic differences are often not accounted for in study design or reporting of results (Glickman, et al., 2009).
Aside from the scientific concerns, conducting trials in other countries can also be ethically challenging. This is especially true in developing countries, where research involving human subjects is complicated by factors such as lack of education, poverty, and low health care standards. Participants may not fully understand the trial process or their role, or they may feel compelled to participate by the promise of financial compensation or access to health care that might otherwise be outside their reach (Glickman, et al., 2009). Beyond the generalizability concerns discussed above, it is also ethically questionable to conduct trials in places that are not intended to be major markets for the drug being studied (Glickman, et al., 2009). Lastly, there is a lack of transparency with regard to clinical research in many developing countries. The International Committee of Medical Journal Editors created the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication” (International Committee of Medical Journal Editors, 2010), but investigators in developing countries tend to be less well-versed in these guidelines and less experienced, which can be a barrier to obtaining trial data and publishing results (Glickman, et al., 2009).
Practically speaking, conducting trials at multiple sites across different countries magnifies the barriers associated with multicenter trials, including lack of harmonization among regulations across multiple jurisdictions and difficulties in enforcing consistency in protocol across multiple trial sites. Further discussion of these types of barriers can be found in the previous sections.
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