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. Key findings associated with each of these obstacles are provided below.
E.3.1 High Financial Cost
- Studies estimate that it now costs somewhere between $161 million and $2 billion to bring a new drug to market.
- The aging of a larger segment of the population has resulted in a shift to chronic and degenerative disease research and an ensuing increase in development costs. Nonetheless, many companies pursue drugs for chronic diseases to have a large and steady revenue stream. Drugs for shorter-term conditions are less attractive to drug sponsors and their investors because it is less likely that the high costs of development will be recouped through revenues and earn a profit.
E.3.2 Lengthy Timelines
- According to one study, the average length of time from the start of clinical testing to marketing is 90.3 months (7.5 years).
- Longer timelines increase costs and decrease revenues.
- Longer studies are needed to see if any safety issues arise when drugs are taken long-term to manage chronic diseases.
- The “one-off” nature of trial organization protracts trial initiation timeframes.
- The clinical trial business model has not kept pace with potential for efficiency gains through technological advances or centralized coordination.
E.3.3 Difficulties in Recruiting and Retaining Participants
- Patient recruitment requires a substantial investment of time and money.
- Failure to recruit can cause costly delays or trial cancellation, wasting resources.
- There is competition for limited patient pools for certain conditions, such as rare cancers and multiple sclerosis.
- Clinical trial sites are often selected based on the location of investigators rather than patients.
- Knowledge, attitudes, and incentives of potential participants and their physicians hinder participation.
E.3.4 Increasing Competition for Qualified Investigators and Sites
- According to some, there is a shortage of biostatisticians and informaticists across academic medicine, industry, and government; others say researchers exist but are difficult to find, often due to competition. There is more widespread agreement that there is a shortage of investigators who can enroll high-quality patients. There is also competition for qualified sites, especially in popular therapeutic areas.
- The rate of attrition among U.S. investigators is increasing.
- The clinical investigator career track is unattractive to researchers.
- It is difficult for new sites to attract business, as sponsors tend to use clinical research organizations (CROs) they know.
- For specialized areas such as anti-fungals, sponsors may have a very small number of qualified investigators to choose from.
E.3.5 Regulatory and Administrative Barriers
- U.S. regulations pertaining to clinical research could benefit from revisions. They were written at a time when the clinical trials enterprise was smaller and before multicenter trials became common.
- Ethical / Institutional Review Board (IRB) Approval (21 CFR 56)
- There is often a lack of clarity regarding the roles and responsibilities of various oversight bodies and what is expected of investigators.
- If the IRB process results in a request for changes to a trial, investigators may lack the resources to fulfill the request.
- Regulations vary by geographic location.
- Informed Consent (21 CFR 50) – The process of obtaining informed consent from trial participants is lengthy.
- Patient Privacy: U.S. Health Insurance Portability and Accountability Act (HIPAA) (45 CFR Part 160 and Subparts A and E of Part 164) – HIPAA requires patient authorization to use their health information for research. There are severe penalties for violating HIPAA, so IRBs enforce compliance. One result of HIPAA and other privacy laws is that site investigators are reluctant to attempt to contact patients to follow up on major outcomes if the patient drops out. This in turn reduces statistical power.
- Regulations Governing Clinical Trial Conduct – Regulations governing the conduct of clinical trials were devised when trials were smaller and involved fewer sites.
- Regulations Governing Serious Adverse Events (SAEs) Reporting for Investigational New Drugs and Biologics (INDs) (21 CFR 312) – In the past, FDA and investigators in multicenter trials have been flooded with expedited reports of serious adverse events which lack sufficient context from the aggregate data to be interpretable. A new safety reporting regulation (effective March 2011) may remedy this problem, but it is too early to tell.
- Regulations for Multiple Jurisdictions – Local, regional, national, and international regulations/guidances are numerous and not always well harmonized.
- Inadequate Clarity/Consistency/Practicality in FDA Guidance
- Delays can be caused by differing interpretations of regulations by the various parties involved in multicenter trials.
- Guidance is lacking for newer therapeutic areas or classes.
- In disease areas where guidelines are nonexistent, old, or otherwise lacking, sponsors find it difficult to understand FDA expectations before beginning their studies.
- FDA is understaffed and underfunded and the available resources end up being overtaxed.
E.3.6 Drug Sponsor-Imposed Barriers
- Excessive risk-aversion leads to unnecessary steps being taken.
- In multicenter trials, uncertainty and inconsistent enrollment success across sites creates a need to over-enroll and plan trials “defensively.”
- Internal review processes for organizations conducting/sponsoring clinical trials can delay a trial’s start.
- In trying to create a pure scientific experiment (to maximize likelihood of drug approval), sponsors may restrict enrollment using extensive eligibility criteria that may exclude, for example, people on other medications or with comorbidities. These constraints on enrollment make it even more difficult to find a sufficient number of participants and protract the recruiting process.
- Industry sponsors generally do not involve site investigators in the protocol design process, so the required procedures may not be easily integrated into clinical practice at the sites.
- Clinical trial protocols are increasingly complex (with more assessments, exploratory endpoints, biomarkers, biopsies, etc.), increasing the administrative burden of trials.
- More complex Case Report Forms (CRFs) including many data points can significantly increase trial monitoring costs.
- Sponsors unnecessarily collect data that may not even be relevant to the specific study.
- The lack of standardized CRFs and trial procedures across study sites can result in improperly conducted procedures or inadequate data collection at some sites.
- According to a Tufts Center for the Study of Drug Development (CSDD) study, nearly 60 percent of all trial protocols require amendments, a third of which are avoidable.
- Industry-sponsored trials are generally monitored through site visits that take place at intervals defined by standard operating procedures or study-specific monitoring plans. It is common practice to conduct site visits frequently, and source data verification (SDV) is a time-consuming part of these visits.
- 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).
E.3.8 Barriers at Academic Institutions
- Sponsors might be compelled to select academic centers as sites due to the presence of key opinion leaders or specific patient populations.
- Ethical and Regulatory Requirements
- Academic institutions can take their responsibility to provide ethical and regulatory oversight to extremes and create excessive barriers to conducting clinical trials.
- One study found that the average number of steps necessary to open a clinical trial at academic centers was over 110, in contrast to fewer than 60 steps at non-academic centers.
- Low Priority of Clinical Research in Academic Institutions
- Many academic medical centers undervalue or fail to incentivize clinical research.
- Fundamental principles of clinical research are not included in academic medical curricula at the graduate or undergraduate level.
- Those studying to be physicians are not adequately trained to interpret clinical trial results, impairing their ability to use such results to inform their clinical care and practice evidence-based medicine. For example, in a survey of 367 residents only 37.4 percent knew how to interpret an adjusted odds ratio from a multivariate regression analysis.
E.3.9 Barriers Related to the Globalization of Clinical Research
- The clinical research footprint is shifting overseas.
- There are a number of factors, including cost savings and shorter timelines, driving this shift and making it cheaper and easier to conduct trials outside the U.S.
- Ethical and scientific concerns may arise when conducting studies in other countries.
- Conducting trials at multiple sites across different countries magnifies the barriers associated with multicenter trials.