Cost of clinical trial

Department of Health and Human Services , containing Table 1 below. Per-patient pivotal trial costs were calculated by Thomas J. Moore et al.

The cost of a clinical trial depends on several factors, such as study size number of patients , locations number of countries , number of clinical sites, therapeutic area, drug type, and the specific tests and procedures needed per protocol, among other aspects. The study size number of patients to be recruited is closely related to the study phase.

Early-phase phase 1 trials require few patients in average while international phase 3 studies may involve hundreds of subjects even thousands. Furthermore, academic non-commercial and industry-led commercial trials should be distinguished.

Academic, not-for-profit sponsors may conduct trials without commercial interest, counting on less financial resources to cover trial activities.

On the other hand, commercial sponsors have higher budgets to execute their drug development programs. Therefore, the clinical trial cost question does not have a single price answer. It really depends on the type, size, territory, and complexity of the research. This article describes the general cost sections typically included in a Clinical Research Organization CRO quotation, including the total price of each section.

If you want to see the actual cost breakdown of the budget described in this article, you can get the fully detailed quotation here including the price of every single line item. You can also obtain a full quotation for a phase 1 or phase 2 trial in this same page. CROs may structure their budgets in different ways, proposing different rates. Nevertheless, clinical trial quotations normally include the following cost sections:.

In the following paragraphs these cost items are further explained and valued. D2 alone in second line of advanced tumors. A total of patients would be recruited in 25 European sites, located in two countries Spain and a second EU member state not specified. The proposed CRO management strategy consists of central management services provided for all countries, from the CRO headquarters located in Spain, and the use of senior Clinical Research Associates CRAs operating in the second European country for specific local tasks mainly start-up, regulatory, and monitoring.

This section comprises the preparation, collection and analysis of feasibility questionnaires, as well as onsite selection visits, in order to verify the capabilities of each hospital. Each selection visit includes time dedicated to scheduling, preparation, travel, the visit itself, post-visit report, and follow-up tasks. These tasks involve contract negotiation and execution with each hospital and site payment management amounts paid by the Sponsor to the hospitals for each patient enrolled.

Each visit involves time dedicated to scheduling, preparation, travel, the visit itself, the post-visit report, and follow-up. This support consists of daily communication with sites via e-mail and telephone, responding to site inquiries, reviewing site performance, and escalating any issues to the Clinical Project Manager or Sponsor. CRAs must also notify sites about any updated documents during the course of the study, ensuring that research teams have the latest versions of the study documents e.

Monitoring activities firstly require the development of a monitoring plan. Then, onsite monitoring visits are conducted by CRAs during recruitment and follow-up, in order to verify source clinical data and other aspects, according to plan.

Each onsite monitoring visit includes time devoted to scheduling, preparation, travel, the visit itself, post-visit report, and follow-up. A reasonable monitoring strategy can be one onsite monitoring visit per site every 2 months. In addition, suspected unexpected serious adverse reactions SUSARs must be reported to regulatory authorities and other parties according to legislation. The CRO can provide a Medical Monitor for the trial, but this is not always the case since such role may also be played by staff of the pharma or biotech company.

For instance, the CRO may or may not be involved in helping with drug manufacturing and importation aspects. The model framework is also amenable to accommodate the changing cost of capital evaluations of the sponsor. For example, in the example scenario described above, it is possible that an NME will be approved for a secondary indication as well as a primary indication.

If the drug is used to treat multiple conditions, it may be the case that the sales and expected returns will be more stable than they would be if the drug were only approved for a single indication. 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.

For example, a significant group of barriers to clinical trials are administrative. All of these barriers result in increasing the cost of clinical trials, hence reducing the eNPV of drug development from the point of view of the drug sponsor. In the above model, alleviation of such barriers could be captured in the form of reduced clinical trial costs and possibly reduced duration. Some Phase 2 studies are similar to subsequent Phase 3 studies.

The time between Phase 2 and Phase 3 can be decreased by viewing the Phase 2 study as a segment of the Phase 3 study.

Even though this reduces the time to submission, it might also decrease the amount of information that can be gained relative to a complete and detailed Phase 2 program.

In general, adaptive designs suffer from this criticism. Although the decision tree analysis format is invaluable in characterizing a range of clinical trial formulation possibilities, the modeling can become extremely complex as the number of event and decision nodes increases. Thus, while the operational model developed allows the user to enter customized cost scenarios in a certain therapeutic area, it does not allow for changes in the number of decision or event nodes.

The model is structured such that the user makes all selections through a guided user form, which enables the user to input project-specific values while the underlying worksheets and cost aggregation formula are protected from editing. The model also allows for a blend of default and custom values as may be desired by the user. Further details on the uses and features of the model can be found in Appendix C. 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.

Phase durations were one such parameter. The two studies, however, provide different success rate estimates—for example, DiMasi, et al. The differences in the two studies can be attributable to the fact that they were drawing from different pools of data.

DiMasi, et al. The BioMedTracker study covered 4, drugs from biotechnology and pharmaceutical companies of all sizes.

As the BioMedTracker study was more recent and included more drugs and a broader range of companies, we opted to use the success probabilities reported by BioMedTracker in our model. These success probabilities were broken down by clinical trial phase and, for Phase 2 and Phase 3, by therapeutic area as well.

For Phase 1, we used 67 percent for all therapeutic areas. All probabilities used in the model were for lead indications. The custom tabulation received from Medidata contained means and variances for a wide range of clinical trial cost elements, including study-level costs such as IRB approvals and source data verification SDV costs , patient-level costs such as recruitment and clinical procedure costs , and sitelevel costs such as monitoring and project management.

Number of planned patients per site and number of sites per study were also provided. A complete list of these data elements can be found in Appendix B, along with more detailed descriptions of each field, unit specifications, and sources. The data are from and later and have not been adjusted for inflation by Medidata.

As the data points represent averages across this range of time and cannot be assigned specific years, we were unable to adjust them for inflation, which is one of the study limitations.

Medidata provided means and variances of costs by trial phase Phases 1 through 4 , geographic region U. For the purposes of this analysis, we focused on the data points specific to U. The therapeutic areas for which Medidata provided data were: anti-Infective, cardiovascular, central nervous system, dermatology, devices and diagnostics 7 , endocrine, gastrointestinal, genitourinary System, hematology, immunomodulation, oncology, ophthalmology, pain and anesthesia, pharmacokinetics 8 , and respiratory system.

To the extent possible, we attempted to match the success probabilities by therapeutic area from BioMedTracker to the therapeutic area categories used by Medidata. Among the devices included in this category are stents, implants, joint replacements, inhalers, and blood sugar monitoring devices. These studies look at the mechanisms of absorption and distribution of a drug candidate as well as the rate at which a drug action begins and the duration of this effect.

We worked closely with Medidata to determine the appropriate methodology for aggregating the itemized costs that characterize the overall cost of a clinical trial. To obtain totals for each individual trial within a given phase, we grouped the cost components into per-study costs, per-patient costs, and per-site costs, where:.

We first added site overhead as a percentage of the sum of the above per-study costs roughly 20 to 27 percent of the above per-study costs as estimated by Medidata. Still missing from this total are costs for sponsors to run the study and other costs not captured elsewhere.

We applied the cost aggregation methodology outlined above to all trials within Phases 1, 2, 3, and 4. In the operational model developed, if the user specifies that the study will include more than one trial per phase, the cost totals for each trial are summed to get an overall total cost for the phase. Adding the lengths of time associated with each trial within a phase was somewhat more complex, as there are a range of possibilities.

One possibility is that all trials within a given phase are completed concurrently, in which case the total length of time for the phase would be equal to the maximum length of time needed to complete any individual trial within that phase. For example, if there were two Phase 2 trials, and one took 1.

At the other extreme end of the spectrum, the trials within a phase might be completed sequentially with no overlap, in which case the lengths of time specified would need to be summed to arrive at the total phase length. In the previous example, this would mean that the total length of Phase 2 is 1.

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. It should be noted that if only one trial is specified for a given phase in the operational model, this average will simply be equal to the length given for that trial. The operational model discounts the total costs for each phase back to Year 0 before Phase 1 trials are started using the real annual discount rate 15 percent for the default scenario.

Further, the model assumes that all costs associated with each phase are incurred at the start of the phase; therefore, Phase 1 costs are not discounted, Phase 2 costs are discounted over the length of Phase 1, Phase 3 costs are discounted over the combined lengths of Phases 1 and 2, and so forth.

While we apply discounting to trial costs in the operational model, the analysis presented below is based on raw i. In some cases, the site may negotiate overhead only on certain portions of the contract such as clinical procedures.

Thus, 25 percent of total per-study costs is likely to be an overestimate of actual overhead costs per study. Table 1 presents the total costs for each of the therapeutic areas included in our model by clinical trial phase assuming one trial per phase and not inclusive of failures. On the other hand, trials in central nervous system, dermatology, and genitourinary system tend to cost the least overall.

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.

This somewhat counterintuitive relationship is due to a variety of factors, including higher data collection costs, administrative staff costs, and site recruitment costs in Phase 2 than in Phase 3 for these therapeutic areas.

To compare average costs by phase across all therapeutic areas, we computed a weighted mean cost, , and its weighted standard deviation, s ij , , for each cost component, i , and clinical trial phase, j , where the weights are the total number of contracts i. As one would expect, the average per-study costs across all therapeutic areas increase as clinical development proceeds from Phase 1 to Phases 2 and 3 see Figure 4. While average Phase 4 study costs are equivalent to those of Phase 3, there is high degree of variability in Phase 4 costs across the different therapeutic areas.

Table 2 presents clinical trial costs by cost component across all therapeutic areas by trial phase. Similar to our evaluation of costs by trial phase discussed in Section 3, when averaging costs across therapeutic areas, we weighted the data by the number of contracts available by therapeutic area.

While not insignificant in dollar terms, Patient Recruitment Costs only account for 1. Note that the reported numbers represent weighted average costs and standard deviations. 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.

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