Authors: Aylin Sertkaya, Anna Birkenbach, Ayesha Berlind, John Eyraud

Link to paper

Synopsis

This report contains discussion of barriers to clinical trials from the consulting firm Eastern Research Group Inc., based on the authors’ interactions with industry experts.

The barriers are grouped as follows:

• High financial cost
• Lengthy timelines
• Difficulties in recruiting and retaining participants
• Increasing competition for qualified investigators and sites
• Regulatory and administrative barriers
• Drug sponsor-imposed barriers
• Barriers at academic institutions
• Barriers related to the globalization of clinical research

Summary

High financial cost

High costs are downstream of all other barriers and come from the following sources:

• Data collection, management and analysis
• IRB approvals/amendments
• Source data verification
• Site recruitment/retention/monitoring
• Administrative staff
• Patient recruitment/retention
• Registered nurse/clinical research associates
• Physicians
• Clinical procedures
• Central lab costs
• Site overhead/other sources (remaining 50% of costs). What are these other sources?

The largest costs come from clinical procedures, site retention/monitoring, and administrative staff. The reason why these costs are increasing include the following:

• Shift toward drugs that are variations of existing drugs, which requires larger number of patients to demonstrate significant improvement over standard of care
• Shift toward chronic and degenerative disease research, which require long and expensive trials

Lengthy timelines

Having a trial that takes a long time will increase costs for obvious reasons. Timelines are long due to the following reasons:

• Shift to chronic diseases
• Regulatory barriers
• Lack of consistent trial infrastructure (each trial requires investigators, staff, sites, and other resources that are assembled and used for only a single trial)
• Lack of consistent usage of electronic records
• Use of on-site visits instead of centralized monitoring
• Unwillingness (particularly from academic institutions) to use centralized IRBs

Difficulties in recruiting and retaining participants

This is noted as one of the largest barriers. These difficulties include:

• Competition among drug companies for the same patient pools
• Some diseases (like certain cancers) are only found in patients in remote areas
• Diseases with long-term endpoints (like multiple sclerosis) have trouble retaining patients
• Stringent inclusion/exclusion criteria that eliminate many patients with other comorbidities
• Fear/inconvenience/discomfort with randomization

Increasing competition for qualified investigators and sites

This is also noted as one of the largest barriers. It is challenging to find qualified researchers able to enroll high-quality patients. Some clinical research organizations have sole access to staff/resources/investigators which they only provide to companies they are partnered with. It is also unprofitable for many sites to run trials.

Regulatory and administrative barriers

• Barriers around IRB approval. IRBs have taken on more tasks which requires approvals from more different people. This issue is exacerbated with multi-site trials. 
• Barriers around informed consent. Patients need to fill out a lot of different forms that are long and hard to understand. 
• Barriers around HIPAA. HIPAA violations carry severe penalties, so investigators can be hesitant to follow up on patients that drop out of studies.
• Differences in regulatory requirements between different states/countries
• Too much risk aversion from the FDA. For example, after a diabetes drug was found to increase heart attacks in 2008, the FDA started to require diabetes drugs to undergo evaluation for cardiovascular risk (a much longer and more expensive process)
• Lack of clear guidelines. The FDA apparently has vague regulatory guidelines for new disease areas like nervous system disorders.
• Too much responsibility/power in the hands of a few FDA reviewers. Oftentimes a single reviewer will handle each drug.

Drug sponsor-imposed barriers

• Administrative
  • Drug companies haven’t used available standard templates for negotiating contracts with clinical trial sites
  • Long internal review processes (~8 months) for protocols
• Study design
  • Stringent enrollment restrictions (e.g. excluding patients with comorbidities or on other medications to have a higher chance of success in trial)
  • Complex clinical trial protocols. Protocols have become very long and complicated (hundreds of pages).
  • Complex/non-standardized case report forms (CRFs). CRFs are used to collect data from each patient in the trial and span dozens of pages. Sponsors often collect much more data than needed in FDA submission (unused data estimated to be 15-30%). Reasons for this include: following customs, caution under uncertain requirements from the FDA.
  • Frequent protocol amendments. ~60% of all protocols require amendments, with the average # being 2.3, each amendment requiring 6.9 changes.
  • Sponsors usually don’t consult with site investigators when designing protocols. As a result, sometimes the protocols include procedures that don’t smoothly integrate into clinical practice.
• Data and site monitoring
  • Common practice for sponsors to frequently conduct in-person site visits to verify source data. This comes from risk aversion. Source data verification consumes 1/3 of the budget of a phase 3 trial (!!).
  • Many sites still do everything on paper instead of electronically. This comes from following customs (seems to be a trend in pharma).

Disconnect between clinical research and medical care

• This issue contributes to shortage of investigators/patients, high costs, lengthy timelines, etc.
• Most community physicians do not participate in clinical trials because there is no incentive for them to do so (not good for reputation, time consuming, etc.)
• Measurements collected in routine clinical care overlap with those collected for clinical trials but are not used due to different formats.

Barriers at academic institutions

• Academic institutions tend to have even more restrictive administrative stuff, requiring approval from may different people. Also unwilling to defer to central IRBs since they have their own internal IRBs.

Barriers related to globalization of clinical research

• Many sponsors are moving to sites overseas because it’s cheaper (lower costs for human labor in developing countries, faster recruitment due to larger patient populations, less regulatory bureaucracy). Also have access to more commercial markets.