Legal advisors have traditionally encouraged sponsors to be conservative in their reporting of unexpected SAEs (at least prior to March 2011, when a new drug safety reporting regulation was implemented). In selecting barriers to analyze in the context of the clinical trial decision-making model developed, we considered whether each proposed strategy could be alleviated by policies, whether the appropriate policies could be implemented or encouraged by FDA, and whether there was evidence in the literature that could be used to quantify the potential impacts of those policies on clinical trial costs. Use of lower-cost facilities and/or in-home testing can reduce per-trial costs by up to $0.8 million (16 percent) in Phase 1, $4.3 million (22 percent) in Phase 2, and $9.1 million (17 percent) in Phase 3, depending on therapeutic area. In the detailed descriptions of each strategy below (Table 3), we discuss the impacts on model parameters that we were able to quantify using published estimates and also list any other parameters that are likely to be impacted but for which we do not have a basis to estimate the magnitude of effect. Cost analysis and efficacy of recruitment strategies used in a - Trials Systematic review on costs and resource use of randomized - PubMed The clinical investigator career track is unattractive to researchers. Furthermore, with regard to post-market data collection, several respondents noted that FDA is justifiably worried about the problematic history of pharmaceutical company promises about post-marketing clinical trials, as some companies have drawn out the process of designing post-market clinical trials for many years. Even though FDA has released draft guidance (in August 2011) on risk-based monitoring approaches (U.S. Food and Drug Administration, 2011c), it is likely that some companies will still continue doing what they have done traditionally because it has proven successful in the past. 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). The model uses a real annual discount rate of 15 percent based on input from interviews conducted with drug sponsors as default, and we were able to obtain some of the other data needed from the available clinical research literature. 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). 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. 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. Notes: Adoption rate of 50% in 2007-2008 has been used to adjust the percentages/effects reported in the literature. 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. The user may choose to leave these fields blank or specify that the default values be used, in which case these fields are populated with the values from the interviews and literature, as described below. An additional cleaning step was necessary to reconcile some minor discrepancies between the data obtained from the literature and the data received from Medidata. The following sections describe the data sources used (Section 2.1) in constructing the model, the conceptual framework (Section 2.2), the operational model (Section 2.3), and the model parameters (Section 2.4) in further detail. Overall, the factors that contribute the most to costs across all trial phases include. The ranges for the number of trials for each phase were decided upon based on discussions with the U.S. Department of Health and Human Services (HHS) and the U.S. Food and Drug Administration (FDA) (we asked FDA for an estimate of the number of trials used to support efficacy for NME NDAs and were provided with a range of roughly one to nine trials for Phases 2 and 3). The simplified clinical decision-making model incorporates the following considerations: 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. In the model, we compute the expected net present value at the decision point by working backwards through the tree. For example, a significant group of barriers to clinical trials are administrative. A related issue is the failure of academic medical curricula at the graduate and undergraduate levels to encourage fundamental principles of clinical research. Morrison, B. W., Cochran, C. J., White, J. G., Harley, J., Kleppinger, C. F., Liu, A., . To take into account both extremes and all possibilities in between, we assumed that the phase length in years across all trials associated with a given phase is the average of these two measures (the maximum trial length specified and the total of all lengths specified). Retrieved September 24, 2012, from Medidata Solutions Worldwide, News & Events: http://www.mdsol.com/press/medidatasolutions-selected-to-support-us-gove Medidata Solutions. (2008, May 1). To reflect this anticipated increase in stability, the drug sponsor may determine that it is more appropriate to use a lower discount rate than otherwise expected. (2012, February 17). Drug Information Journal, 44,745 756. Engage sponsors in discussions on the topic of data and site monitoring to ensure that they are aware of the FDA guidance stating that 100% source data verification is not required, Notes: Adoption rates by phase and therapeutic area used to adjust effects. Drug Information Journal,44, 477483. The length of study for phase 4 clinical trials can be the same as that for a phase 3 clinical trial or even longer. India is ready for your clinical trials. Are you? | Credevo Articles If these factors remain unaddressed, more sites can be expected to permanently close their doors to clinical research (Getz K. A., 2010a). DiMasi, J. . Retrieved December 15, 2011, from Applied Clinical Trials Online: http://www.actmagazine.com/appliedclinicaltrials/article/articleDetail.j Getz, K. A. 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. This estimate includes patient out-of-pocket costs of $16.22 billion and patient time costs of $4.87 billion. Results: On average, 4,012 hours (range, 1,512 to 13,319 hours) were required for a government-sponsored trial, and 3,998 hours (range: 1735 to 15,699) were required for a pharmaceutical industry-sponsored trial involving 20 subjects with 17 office visits, or approximately 200 hours per subject. Invisible Barriers to Clinical Trials: The Impact of Structural, Infrastructural, and Procedural Barriers to Opening Oncology Clinical Trials. According to the CSDD study, it cost an average of $453,932 to implement each individual protocol amendment. We developed the operational model in Microsoft Excel for ease of use and sharing, with a user interface coded in Visual Basic. Phase 1 studies are designed to assess how well patients tolerate the new drug under investigation and to determine the maximum tolerated dose (MTD) recommended for phase 2 trials. The drug can later be withdrawn from the market if there are concerns. The figure reflects the time value effect and computes the cumulative present value of returns from each path using the 15 percent cost of capital as the sponsorsinternal rate of discount. Phase 4 post-marketing studies, as described earlier, do not appear in Figure 2 as part of the decision tree because they do not play a role in determining which branch or outcome node a new drug ends up on in the same way that Phase 1, 2, and 3 trials do. Investigators are required (under 21 CFR parts 56.108(b)(1), 312.53(d)(1)(vii), and 312.66) to report promptly to the IRBall 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). Sources: Tantsyura, et al., 2010; Medidata, Encourage sponsors to make wider use of mobile technologies, centrally available data to evaluate site performance, electronic data capture (EDC), and other efficiency-improving options. In situations where drug sponsors are uncertain as to which events must be reported, they are inclined to err on the side of over-reporting rather than under-reporting. 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). Which of these government actions you enumerated above would have the greatest impact/potential to promote more clinical research in the short term? Developing a new drug is a costly endeavor and the ever-increasing cost of clinical research is often cited as one of the main reasons for the slowdown in FDA application filings. To quantify the impact of this strategy, we used data reported in a 2008 article by Kenneth Getz, which found that [e]nrollment rates for volunteers who met the rising number of protocol eligibility criteria dropped from 75 percent to 59 percent between the 19992002 and 20032006 time periods []. Given the differences in resources and requirements across review divisions, we attempted to gauge what types of improvements in efficiency were viewed as being achievable by FDA itself. Since applications are received and filed throughout a calendar year, the filed applications in a given calendar year do not necessarily correspond to an approval in the same calendar year. By Pam Belluck. Sometimes additional studies are conducted following FDA approval, during general use of the drug by medical practitioners. For the counts/non-cost data elements (Number of Site Management Months; Number of Project Management Months, and Number of Site Monitoring Days), Medidata used phase-specific factors to create tables of derived values. In many cases the trial might be for something that is not yet . Thus, guesstimates of ranges of hours/dollars/percentages are sufficient. If so, how significant of a problem is this? http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm, http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm256525.pdf, http://www.fda.gov/downloads/Drugs//Guidances/UCM269919.pdf. http://www.pharmalot.com/2011/06/pfizer-and-a-clinical-trial-in-a-boxfor http://csdd.tufts.edu/files/uploads/september-october_impact_report_pres http://csdd.tufts.edu/files/uploads/nov-dec_2012_ir_summary.pdf, http://www.hhs.gov/news/press/2012pres/02/20120217a.html. According to a report by the Indian Council of Medical Research (ICMR), the number of registered clinical trials in India increased from 141 in 2005 to a peak of 539 in 2010, before declining to 183 in 2018. There are severe penalties for violating HIPAA, so IRBs enforce compliance. This also means that research findings are less likely to be adopted by such physicians in their regular practice (English, Lebovitz, & Giffin, 2010). How Much Do Phase 1 Clinical Trials Cost in the United States? - LinkedIn Other respondents felt data collectionor at least data collection costscould be reined in through various means. Implementing the Voluntary Harmonization Procedure for Accelerated Clinical Trial Approval. Patient enrollment cycle times increased for protocols conducted in the latter time period (Getz K. A., 2008). We should point out that, U.S. Department of Health and Human Services, Collaborations, Committees, and Advisory Groups, Examination of Clinical Trial Costs and Barriers for Drug Development, Biomedical Research, Science, & Technology, Long-Term Services & Supports, Long-Term Care, Prescription Drugs & Other Medical Products, Physician-Focused Payment Model Technical Advisory Committee (PTAC), Office of the Secretary Patient-Centered Outcomes Research Trust Fund (OS-PCORTF), Health and Human Services (HHS) Data Council, http://www.atkearney.com/index.php/Publications/make-your-move.html, http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-, http://www.cuttingedgeinfo.com/2011/outsourcing-phase-ii-drug-development/. 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). The process of obtaining informed consent, while important, is burdensome and time-consuming, both for researchers and trial participants. Expected savings across most therapeutic areas and phases is in the order of $0.0 to $0.1 million. Delays can be caused by differing interpretations of regulations by the various parties involved in multicenter trials. 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). 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. Washington, D.C.: The National Academies Press. The savings that could potentially be realized range from $0.1 million (dermatology and endocrine) to $0.8 million (immunomodulation and respiratory system) in Phase 1. Tardiff, B. As can be observed from Table 1, Phase 2 costs are lower than Phase 3 costs for all but three therapeutic areas: gastrointestinal, hematology, and immunomodulation. Global Public Policy Issues: GlaxoSmithKlines Position: Clinical Trials in the Developing World. Criteria for Distinguishing Effectiveness From Efficacy Trials in Systematic Reviews. Introduction: Drugs are Different. Thus, we used the derived means and variances for these fields to fill in missing values across all therapeutic areas. While the reasons for these high costs are manifold, a few key macro-level trends stand out. If it is more convenient for patients to fulfill trial requirements, they may be more willing to participate in studies. 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). One of the studys authors, Kenneth Getz, believes protocol amendments will continue to be prevalent, as the mean number of amendments was found to be positively and significantly correlated with the increasing number of procedures per protocol, study length, and number of investigative sites involved in each clinical trial (Tufts CSDD, 2011). Fifth, the regulatory environment in wealthy countries, including the United States, has become increasingly burdensome to drug sponsors (Glickman, et al., 2009). Source: Neuer, Warnock, & Slezinger, 2010. Table 4 below provides estimates of expected reductions in per-study costs by phase and overall due to EHR adoption in clinical research across the different therapeutic areas. In support of this claim, there is evidence to suggest that the rate of attrition among U.S. investigators is increasing. Washington, D.C.: Institute of Medicine of the National Academies. 2 According to a technical review prepared for the Agency for Healthcare Research and Quality (AHRQ), the distinction between efficacy and effectiveness trials is defined as follows: Efficacy trials (explanatory trials) determine whether an intervention produces the expected result under ideal circumstances.