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Stepping Away from Convention in Clinical Trial Design

Clinical trial design, like much of the industry, is experiencing a wave of innovation and disruption. Classical randomized control trials institute the purest way to determine treatment effectiveness against placebos. While statistically sound, the resources these studies require put immense burdens on sponsors. As innovations push forward, the FDA supports the implementation of non-traditional clinical trial designs that alleviate pressure on patients, CROs, and sponsors while upholding the integrity of outcomes. Through innovative trial designs and unconventional data collection, companies can significantly decrease the cost, time, and effort it takes to gain market approval while preserving the scientific integrity of the trial.

What Are the Advantages of Non-Conventional Clinical Trial Design? 

Consumer Convenience

Traditional studies can put burdens on both clinicians and participants as everyone involved must jump through various logistical hoops. Currently, 85% of all clinical trials fail to meet their enrollment goals, and 80% are delayed due to this issue. Even if enough patients are recruited, the average dropout rate across all trials is 30%, leading many studies to delay and even fail if data-delivering participants are lost before completion.

Better Outcomes through Diversity

Many groups are underrepresented in trials, and the health level of traditional trial recruits may not reflect how effective a treatment is in the general population. In July of 2019, the FDA issued draft guidance to increase the diversity of trial populations that explored adding children and adolescents earlier in drug development, recruiting patients of diverse ethnicities, and decreasing burdens of enrollment. Specifically, by placing trial sites in areas with a higher concentration of minority and underrepresented groups, companies can embrace inclusivity and increase the efficacy of trial outcomes.

Non-Conventional Clinical Trial Design Types

Decentralized

As digital technologies support new possibilities in research, clinical trials no longer require a physical location where patients receive treatment and education. With direct-to-patient, “siteless,” or decentralized models, tools such as wearables, apps, sensors, online diaries, and video dosing confirmation can collect data remotely and enable patients to receive and confirm treatment without travelling to a facility. Decentralized trials using digital technology can provide continuous, real-time data collection, and while this translates into a vast volume of data for sponsors to manage, the collection of data in the patient’s home and natural environment can bring a study closer to real-world applications. Leading to long-term therapeutic value by understanding of the patient environment.

While remoteness introduces new complexity and risk into the study, reputable devices and data integrity can decrease the resources required for long-term and cohort studies, making participation more appealing. Currently, 70% of eligible trial participants live over 2 hours from the nearest study center, and in a study of over 4000 phase II & III trials, virtual trials took an average of 4 months to recruit 100 participants while other trial types averaged 7 months. The convenience presents greater value to the patient.

Master Protocols

In September 2018, the FDA proposed new guidance on the use of master protocols, trials that enable the evaluation of more than one investigational component under a single trial structure. These are best suited for complex or rare disease areas and enable sponsors to reduce redundancy by testing hypotheses in parallel through one of two trial designs.

In umbrella trials, one population receives several treatments as sponsors test drugs head-to-head. Conversely in basket trials, one treatment is tested on varying populations to examine its effect on diverse recipient groups. FDA regulators have specifically reached out to CROs and patient groups to encourage the design and use of master protocols but remind sponsors that robust and detailed statistical analysis plans are required to keep these incredibly complex studies efficacious.

Adaptive

In an adaptive clinical trial design, adjustments are made during trial processes as data is collected from participants, allowing investigators to account for information that was unknown at the study’s genesis. This design has a greater chance of detecting a treatment’s true effect and is more ethical as early shut-down of failing trials can decrease participants’ risk.

As efficient as this design is, a September 2018 FDA draft guidance recognized that adaptive trials increase the risk of Type 1 errors and have a higher risk of bias due to early unblinding. For an adaptive design to have reputable results, sponsors must have strict data governance protocols and firm statistical thresholds.

Complex Innovative Trial Design (CID)

CID extends from adaptive design but incorporates external and historical control data into the study’s analysis. These clinical trial designs generally require computer simulations to determine statistical properties and are supported under both the Prescription Drug User Fee Amendments of 2017 and the 21st Century Cures Act. An FDA pilot program for CID was launched in August of 2018 to apply CID in areas where traditional approaches may be infeasible, such those with small populations or unmet medical needs.

Non-Conventional Data Collection Methods

Innovative trial types often incorporate or even require non-conventional data collection. This spring, the FDA formulated a framework for the use of real world evidence (RWE) in trials, as provisions for the use of RWE were made under the 21st Century Cures Act of 2016. RWE includes data gathered from EHRs and other records paired with machine learning capabilities to simulate the results of a DBRCT.

Beyond RWE, leading FDA regulator Janet Woodcock is facilitating trial designs around patient reported outcomes (PROs) to emphasize patient centricity and encourage participant retention. These methods are promising as there have been three cases where RWE was used in a drug approval, and increasing personalization in medical care is leading to higher emphasis on PROs in all sectors.

Supportive Climate at the FDA

The recent uptick in FDA approvals is set to continue as progressive regulators carry on the innovative work of former commissioner Scott Gottlieb. There is a proposed reorganization of the FDA’s Office of New Drugs, and campaigns are underway to implement more basket studies, delayed start trials, and dose comparison trials specific to immuno-oncology fields. The FDA’s acting head Norman Sharpless continues to push his predecessor’s progressive agenda, and is in the running against two others to solidify his position as commissioner. It’s unclear how the Trump Administration with choose the new commissioner, but Woodcock and her fellow regulators are going full speed ahead with Gottlieb’s protocols, signaling that clinical trial designs will continue to change in the near future.

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Coauthor and contributions by Kyleigh Andries

Tags: Clinical Operations, Life Sciences Trends, Regulatory Strategy & Compliance
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