The sponsor companies must be more vigilant and thorough in their planning and oversight of trials conducted by vendors. A proper estimation of clinical trial cost could help both large and small pharmaceutical companies in planning their outsourcing of trials.
Hence, it is imperative that procurement teams develop a clear understanding of the various cost drivers and parameters of the cost of a clinical trial. This article discusses the major cost drivers and tries to present a qualitative picture of trial cost components. The cost of a clinical trial can be calculated in terms of the cost incurred for analyzing each patient at each site during the study.
To estimate the overall cost, many parameters must be considered. The following table captures a sample of the various cost components involved in a clinical trial. Procurement teams must adopt a detailed approach while estimating the cost per components. Involvement of stakeholders from all departments is vital.
Due to the complex regulatory environment, it is easily possible to go wrong on certain cost parameters if operational teams are not consulted. For example, estimating the cost of data management is very tricky.
Currently, regulatory authorities are focused on integrity of data. Each data point costs a lot and may or may not be influenced by following factors:. Clinical trial cost varies with the therapeutic area as well. Such data points can help in estimating and benchmarking clinical trial costs. For example, clinical trial requirements of cell therapies are more stringent and cost-intensive than those of common drug therapies.
A good understanding of the various intricacies involved in the cost of a clinical trial helps procurement and finance teams in budgeting and efficient execution of the whole process. Procurement must understand the criticality of the study and the respective study requirements. The researchers examined trials, covering 59 different drugs—some of which were tested in multiple trials for multiple disorders. For each trial, the team calculated the likely trial cost with standard cost-estimation software used by contract research organizations and others in the pharmaceutical industry.
The scientists also looked at how trial costs varied depending on the type of clinical trial. Costs were also higher for trials comparing a new drug to an existing standard rather than a placebo. Costs tended to be higher when a trial lasted longer or enrolled more patients.
Our study suggests that therapeutic area as well as number and types of clinical procedures involved are the key drivers of costs in Phase 1 through Phase 4 studies. Figure 5 presents an overview of the different types of costs constituting each phase and their magnitudes.
The denoted error bars represent one standard deviation below and above the mean value. Excluding site overhead costs and costs for sponsors to monitor the study, the top cost drivers of clinical trial expenditures across all study phases are Clinical Procedure 15 to 22 percent , Administrative Staff 11 to 29 percent , Site Monitoring nine to 14 percent , Site Retention nine to 16 percent , and Central Laboratory four to 12 percent costs see Table 2 above.
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. The largest barrier to conducting clinical research—and the one into which most other barriers feed—is the high cost. Bureau of Labor Statistics, DiMasi et al. The authors caution, however, that estimated costs vary widely, depending on drug type, therapeutic area, regulatory policies, and strategic decision-making by drug sponsors. Although experts debate the accuracy of various cost estimates, there is widespread agreement that clinical trial costs are substantial and rising.
According to a article, the average cost of developing a drug had risen at a rate 7. Using publicly available data and a larger sample size than DiMasi, et al.
Note that DiMasi, et al. 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, , and with greater numbers of participants comes greater expenditure on recruitment efforts, data collection, compliance with administrative requirements, and other trial components. 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.
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, 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, 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, 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.
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 and , pharmaceutical companies experienced a three percent median increase in development cycle times and a nearly 11 percent increase in regulatory cycle times Getz K.
Food and Drug Administration, , 12 the drug development process as a whole is still lengthy. 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.
The timing of investments and returns also factors into the total cost of drug development. 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. 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.
There are a number of factors contributing to the length of clinical trials, and several of these are also discussed in other sections. Numerous administrative and regulatory barriers also create delays that protract the clinical trial approval process in the United States see Section 4.
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.
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. Getz 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, 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. According to this report, analysis of 4, 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.
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. 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. 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. Patient retention is a common problem in studies involving long-term endpoints e.
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. 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.
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. Media attention to cases with negative outcomes e. Aside from the uncertainties involved, participating in clinical research may simply be inconvenient or overly burdensome to patients.
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.
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. 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.
In support of this claim, there is evidence to suggest that the rate of attrition among U. 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. 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. The outlook for resources at the investigative site level is similarly bleak. Many veteran sites in the U.
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. Recruitment is also very difficult in the United States see Section 4.
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 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. If these factors remain unaddressed, more sites can be expected to permanently close their doors to clinical research Getz K. 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. This section addresses several subcategories of regulatory and administrative barriers. IRB definitions and standards e. Food and Drug Administration, b ; however, many drug sponsors have not made this a requirement and some sites are still unwilling to work with central IRBs.
On April 23, , 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. Food and Drug Administration, 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.
Patients must fill out and sign the numerous forms before they can participate, which can be overwhelming, especially when combined with the U.
A recent study of informed consent documents used in multinational, U. The lengthy and confusing forms can be especially problematic for patients with language or disability barriers U. Development of technological solutions is underway, though it is still in its early stages.
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. Patient Privacy: U. This in turn reduces statistical power and can lead to uncertain study results. 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 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.
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 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. Despite the revisions that were made in the spring of to 21 CFR parts and , some remaining issues were raised by industry and IRB representatives at the public FDA hearing held in April, For one thing, there may be inconsistent reporting requirements.
Investigators are required under 21 CFR parts 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. 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.
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. Since its introduction in , the VHP has been increasingly utilized; over applications had been received as of February , approximately a third of which came from U. 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, 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. 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.
Food and Drug Administration, b. Such inconsistencies cause confusion among investigators and make it difficult to keep abreast of the various requirements U. 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.
For example, multiple interviewees said that many companies can no longer afford to develop drugs for diabetes because of new cardiovascular risk guidelines. In , 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, Similar requirements are being considered for obesity drugs in the United States Pollack, 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. 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. 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.
Food and Drug Administration, a. 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.
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 , 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. By existing rules, it seems infeasible to sponsors to test a treatment for Escherichia coli E. 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.
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. Another common grievance among interview respondents was the difficulty of getting timely feedback from FDA. 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. 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. 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.
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. Risk aversion leads companies to take unnecessary steps at various points throughout the clinical trial process.
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. Contract negotiation and internal review are two major administrative areas where drug companies suffer from inefficiencies of their own creation.
The IOM and the National Cancer Institute NCI have tried to generate standard contract terms so that the trickiest parts of contracts between sponsors and contractors and clinical sites would not need to be renegotiated from scratch every time; however, these have gone largely unused by drug companies.
For example, in the past, Bristol-Myers Squibb needed 8 months and 34 internal review cycles to develop and activate a new protocol. In trying to create a pure scientific experiment and thereby maximize likelihood of drug approval, sponsors may restrict enrollment using restrictive eligibility criteria that may exclude, for example, patients on other medications or with comorbidities. Aside from hampering recruitment, the restrictions on participant eligibility also raise scientific concerns, as the new drug might not be adequately studied on relevant patient populations, such as people with common comorbidities.
This issue is discussed further Section 4. Clinical trial protocols, which outline the trial methodology, are becoming increasingly complex, involving more assessments, exploratory endpoints, biomarkers, biopsies, etc.
A study of over 10, industry-sponsored clinical trials found that the quantity and frequency of trial-related procedures e. A case report form CRF is a tool used by investigators to collect data for each participant throughout the trial.
More complex CRFs including many data points can significantly increase trial monitoring and other costs e. According to experts and industry representatives interviewed, sponsors almost always capture more data than they eventually use in their FDA submissions, and sometimes this extra data even confounds study results.
Though the percentage of data collected that ultimately goes unused varies by trial, interviewees estimated that it is anywhere from 10 to 30 percent, and a recent study by Kenneth Getz and others at Tufts CSDD found that The reasons given by interviewees for collecting this extra data were many and varied.
Researchers tend to be overly inclusive, as they are scientifically-minded individuals who want to be able to answer the main question and test other theories, as well. Some of the extra data are needed when the clinical value of some endpoints is uncertain. Some data are collected in part to satisfy payers and providers e. Some of the individuals interviewed expressed the opinion that collection of extra data is unavoidable due to the nature of the process; clinical trials represent research under uncertain conditions, and at the time when they are making data collection decisions, study designers do not know for sure what they will need.
Some also argued that the data being collected are not actually superfluous because there is always need for the data on file, not because FDA is mandating it, but because it is supportive and reasonable to collect. Other respondents felt data collection—or at least data collection costs—could be reined in through various means. For example, some of the data can be collected at lower-cost facilities, such as local clinics and pharmacies, reducing the need for infrastructure and overhead.
Companies can also be more practical in their planning and streamline their studies by minimizing the number of research questions they seek to answer in a single trial.
Some respondents also called for more flexibility on the part of FDA; for example, drugs can be approved without mortality data with the requirement that post-marketing data be collected to demonstrate safety. The drug can later be withdrawn from the market if there are concerns. Still, there are hurdles to implementing some of these ideas.
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. Clinical trial protocols often need to be amended after they have been finalized and approved, a process which can be costly and time-consuming, but also preventable.
Using data provided by 17 midsized and large pharmaceutical and biotechnology companies, a recent study conducted by Tufts CSDD analyzed the types, frequency, causes, and costs of nearly 3, protocol amendments from 3, protocols.
The study found that nearly 60 percent of all trial protocols require amendments, a third of which are avoidable through better initial planning and participant recruitment. Across all phases, 43 percent of amendments occur before any patients are enrolled, with amendments more likely to occur in Phase 1.
The median time to resolve a protocol problem is 65 days 65 days multiplied by 2. It does not include the cost of internal time dedicated to implementing each amendment, costs or fees associated with protocol language translation, and costs associated with resubmission to the local authority, nor were any indirect costs e. The most common causes of amendments were found to be availability of new safety information In general, protocols with longer treatment durations had a higher incidence of amendments.
Among therapeutic areas, cardiovascular and gastrointestinal protocols had the highest incidence of amendments and changes per amendment Getz, et al. Industry sponsors generally do not involve site investigators in the protocol design process. A CRO representative interviewed provided examples: for instance, a protocol could require that magnetic resonance imaging MRI and a series of neurocognitive tests be performed within three days of each other at a site that does not have sufficient access to an MRI machine; or, a protocol might require a series of labs that are highly specialized and cannot be done by the site in house.
Better planning and conferring with site investigators during the protocol design phase can help trials to avoid hitting foreseeable logistical snags such as these. Data from 3, protocols were collected across various therapeutic areas, yielding information on 3, amendments containing 19, total protocol modifications. Only implemented amendments—that is, amendments approved both internally and by the ethics committee— were counted and analyzed in this study.
Data and site monitoring costs are another key barrier that is largely self-imposed by sponsors. In general, industry-sponsored trials are monitored by individuals who visit sites at intervals defined by their company standard operating procedure SOP or study-specific monitoring plan. It is common practice in the industry to conduct site visits frequently every weeks , and source data verification SDV —the process of ensuring that the reported trial data are complete and consistent with study subject source records—consumes quite a bit of time during these visits Usher, ; Tantsyura, et al.
One particularly costly practice is percent SDV. FDA regulations do not require study monitors to check every single source data point at every investigative site, but risk aversion and a conservative interpretation of the regulations has resulted in percent SDV becoming the industry standard Korieth, Eighty-two percent of pharmaceutical industry sponsors reported always verifying CRF data against source data.
Because the cost of SDV depends on the size of the study and the complexity of the protocol, the overall trend toward larger, more complex studies is making it increasingly expensive and logistically difficult to check every data point at every site Korieth, There are a number of possible explanations for this. First, resources are often expended to verify data that is largely or completely irrelevant to study outcomes, such as vital signs or other health information that is not central to the study.
Second, it is not likely that drugs will fail to get approval because of SDV issues; there are much more critical areas of concern, such as protocol violations. Third, percent SDV does not even ensure percent accuracy; for a human manually looking for errors, the error rate is 15 percent meaning the process is only 85 percent accurate Korieth, ; Society for Clinical Data Management, Fourth, this approach may lead to the detection of some types of errors e.
Given its enormous costs and the lack of evidence supporting the value of percent SDV, some industry representatives recommend a shift to partial or risk-based monitoring approaches; however, there are key barriers that must first be overcome.
The pervasive risk-aversion in the industry is perhaps the biggest obstacle to the adoption of more efficient monitoring practices. There are not yet wellestablished processes or controls for partial or risk-based monitoring, and drug companies are hesitant to change their practices without FDA guidance on what is acceptable. Food and Drug Administration, c , it is likely that some companies will still continue doing what they have done traditionally because it has proven successful in the past.
There are also practical hurdles; the most commonly used EDC and electronic clinical trial systems were designed to support percent SDV, so technology vendors must change their systems so that they permit partial SDV before such approaches can be widely adopted by industry Korieth, If these barriers can be overcome, the savings for drug sponsors would be enormous.
A study published in the Drug Information Journal found that sponsors could save up to The Phase 2 savings are estimated at For a cardiology study, the Phase 2 and Phase 3 savings are estimated at These cost reductions are a function of reduced per-page review time and reduced number of site visits by monitors, which mean fewer hours spent by monitors on-site and reduced travel expenses Tantsyura, et al.
It is also worth noting that several sponsors have yet to make the transition from paper-based studies to use of EDC technologies. It also eliminates inefficiencies arising from transcription of data from paper to electronic format U. 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.
Possible areas of ambiguity or excess burden related to the safety reporting regulations themselves are discussed in Section 4. 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. Most U. Apart from issues of mission and training, there exist some disincentives for clinicians to participate in research.
The U. 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.
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. A recent study found that the number of steps necessary to open a clinical trial at academic centers was over , in contrast to fewer than 60 steps at non-academic centers.
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. 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.
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. A related issue is the failure of academic medical curricula at the graduate and undergraduate levels to encourage fundamental principles of clinical research.
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