Clinical Trials

Clinical Trials

The global clinical trials market is said to be expected to reach USD 65.2 billion by 2025.

The globalization of clinical trials (led by the emergence of CROs as a driving force in the clinical trials market), development of new treatments and evolving technologies such as personalized medicine and programs as well as digital monitoring services along with the increasing demand for data and analytics by way of CRO support all are said to play key roles in shaping the future of clinical trials.
However, the complexity of trials, patient recruitment, adoption of technology, regulatory requirements, high cost levels and many others issues 
create challenges conducting and working in the clinical trials market. High rates of failure resulting from lengthy and complex study designs and the constraints driven by the complexities of guidelines have resulted in all-time high clinical trials.  Additionally, patient access to appropriate clinical trials and engagement is declining, and staff and operations management is more challenging than ever.
The overall cost of failed clinical trails is extremely high, with estimates varying between $800 million and $1.4 billion USD.
0%
Percentage of Clinical Trials that Fail Due To Non-Adherence
0%
The standard estimates for overall probability of clinical succes http://blogs.sciencemag.org/pipeline/archives/2018/02/02/a-new-look-at-clinical-success-rates
Given the significant time and cost of drug development, coupled with the poor performance of clinical trial participants in following the medication regimens of clinical trial protocols, pharmaceutical clinical trials present a significant need and opportunity. 

Approximately 16,000 clinical trials are currently being conducted worldwide, and pharmaceutical companies spend on average of USD $1.2 billion to obtain FDA marketing approval for each new medication. In addition, it takes an average of 10 to 15 years to obtain marketing approval from the FDA for a new medication.

According to an article published in The New England Journal of Medicine in 2005 (Lars Osterberg, M.D. and Terrence Blaschke, M.D., “Drug Therapy: Adherence to Medication”), average adherence rates among patients in clinical trials receiving treatment for chronic conditions are just 43% to 78%. Non-adherence to study medications and unknown levels of adherence introduce tremendous risk and uncertainty into clinical research and drug development.

Non-adherence is one of the most important sources of variability in drug response and may result in failed studies and shelved drugs.

source: https://medrio.com/blog/overcoming-patient-recruitment-and-retention-hurdles/

Approximately 50% of Phase III trials fail

Among the most common reasons for failure in Phase III trials are efficacy (a failure to meet the primary efficacy endpoint), safety (unexpected adverse or serious adverse events), and commercial / financial (failure to demonstrate value compared to existing therapy).
Common failure triggers for Phase III trials are flawed study designs, inadequate basic science, sub-optimal dose selection, flawed data collection and analysis, and problems with study operations, including recruitment, dropouts, and noncompliance.
In a clinical trials environment patient or subject compliance is one of the most important areas of focus. Recent studies show that industry professionals view success rates in Subject Compliance at 25%.[2] 20% to 30% of all clinical trials are said to fail due to non-adherence.
CROs and Adherence-monitoring technologies have increasingly focused on attempting to address both poor overall clinical trials performance as well as poor adherence by creating systems and platforms that can monitor patient adherence and activity through a collection of patient-driven methods.

Prevalence of Study Non-Adherence

It would be ideal if all patients adhered to investigational medical product (IMP) and the study protocol, nonetheless, many patients do not.
Figure 1 below illustrates that approximately 40% of patients become nonadherent to IMP after 150 days in a clinical trial, and Figure 2 demonstrates that IMP non-adherence not only causes temporary bouts of toxicity (double dosing) and lack of efficacy (skipping doses), but also introduces data variability into the equation.

Non-Adherence: A Direct Influence on Clinical Trial Duration and Cost

  • Ongoing Challenges

    The long duration and subsequent costs of conducting clinical trials has always been at the forefront of development organizations within bio-pharmaceutical enterprises, as clinical trials remain costly and continue to increase in duration.
  • Non-Adherence

    Although novel initiatives aimed at improving study efficiency and data quality (i.e., RBM, adaptive trial design, and novel pilots) offer promise to reduce trial duration and cost impact, the bio-pharmaceutical industry is overlooking one critical element that affects study timelines: patient non-adherence.

Costs and Impacts

We have demonstrated previously that patient non-adherence in clinical trials leads to enrolling more patients to achieve the same statistical outcomes, increases study timeline slippage, and subsequently, elevates operational costs. In this section, we will estimate the cost of non-adherence, and the opportunity cost of reducing non-adherence.

Table 1 demonstrates the average estimated cost of enrolling patients for all therapeutic indications in a variety of study phases.

Table 1 demonstrates the average estimated cost of enrolling patients for all therapeutic indications in a variety of study phases.
Trial PhaseCost of Enrollment Per PatientAverage Cost per Trial (2014)Average Patients / Trial (2014)
Phase I$15,700$1,177,50075
Phase II$19,300$3,917,900203
Phase III$26,000$21,528,000828
Phase IV$26,000$10,972,000422
Table 2 models the operational costs associated with clinical trial IMP non-adherence.
1,273 trials and corresponding patients that were categorized as N/A by phase were re-allocated based on existing trial allocation patterns. Medication nonadherence impact based on 30% and 50% non-adherence rates requiring 50% and 200% increases in sample size respectively. This does not include costs of investigational product; only project management and enrollment costs are included.
Table 2: Estimated cost of IMP Non-Adherence and Opportunity Cost of Non-Adherence Reduction
Trial PhaseEstimated Avg Added Patients Needed to Maintain Statistical Power at 40% Non-Adherence…at 39%Estimated Wasted Capital on Cost of Enrolling Additional Patients at 40% Non-Adherence…at 39%Average Cost Savings Per 1% Improvement in IMP Adherence
Phase I4241$655,475$636,439$19,036
Phase II113110$2,171,250$2,120,346$50,904
Phase III460447$11,960,000$11,624,275$335,725
Phase IV234228$6,093,750$5,926,700$167,050

Addressing Non-Adherence

The analysis above shows only one case of study non-adherence (IMP non-adherence), which has a direct impact on data variability and statistical outcomes. When combined with other forms of clinical trial non-adherence (i.e., subject dropout, not completing ePRO questionnaires, missing study visits, and not adhering to study procedures, etc.), further study prolongation is imminent.
The issue of nonadherence can easily be addressed with novel technologies. For example, Artificial Intelligence (AI) has advanced to the point where it is capable of acting as a digital companion with patients to guide them through a clinical trial. IMP reminders, answering questions, and study procedure guidance can all be automated through AI, and preliminary data is showing promise.8 Additionally, novel patient centric study design models are now introducing innovative ways of collecting clinical data via Electronic Device Reported Outcomes (eDROs), or data collected directly from patients through wearables and mHealth.
In the future, it is likely that advanced technologies and patient centric study design will not only make studies more convenient and accessible for patients, but also improve patient compliance with study procedures and IMP, generate higher data quality and ultimately shorten study duration and minimize cost impact.

 The overlapping nature of nonadherence, professional subjects, and placebo response suggests that these issues should be considered and addressed together. Following this approach, we describe a novel clinical trial design to minimize the adverse effects of professional subjects on trial outcomes and discuss methods to monitor adherence.