Every year, WCG Clinical asks a number of thought leaders about what they think is coming in their areas of expertise for the coming year. In a two-part piece featured last week (CenterWatch Weekly, Jan. 6, 2020) and this week, 10 subject matter experts from WCG and our partners share the important shifts, trends, regulations and priorities that will inform clinical trial development in 2020 and beyond.

The insights and predictions are grouped into six topics. They are: Scientific Advancements, Study Design and Study Conduct, Technology & Data, Public Policy & Regulatory Oversight, and Patient Advocacy. To read the full report, click here: https://bit.ly/2FIUnRX. Below are five experts:

• MARK SUMMERS
  President, Patient Engagement Division, WCG

Placebo response reduction represents a tremendous opportunity in studies with subjective outcomes measures, such as those within the CNS specialties. Placebo response continues to cloud accurate signal detection and clinical endpoint measurements with huge costs in terms of inaccurate outcomes tracking and even failed trials.

New analytical tools have been introduced that allow clinical and data scientists to employ an automated rules engine, customized for the specific study design and patient population, to perform ongoing analyses of data in near real-time to spot outliers while data is being captured during a study — rather than having to wait for an interim analysis or study completion — in much the same way an onboard computer monitors automotive engine performance while driving. A clinician can then perform root-cause analysis to determine the reason for the anomaly and follow up with immediate implementation of corrective procedures, such as retraining the site or patient in specific areas, including process control or symptom capture and reporting.

These new early warning tools are equipping scientists with the ability to significantly decrease placebo response along with corresponding risk and cost in studies with subjective outcomes.

• KARMEN TRZUPEK, MS
  Director, Clinical Trial Services, InformedDNA

Until recently, genetic testing in clinical trials has been performed primarily to screen patients with rare genetic diseases, such as cystic fibrosis. Increasingly, genetic testing is being used in more common multifactorial diseases, such as Alzheimer’s disease and age-related macular degeneration, in which multiple genetic risk factors, in combination with environmental and lifestyle factors, can ultimately lead to disease.

In the past 15 years, more than 500 clinical trials have been conducted in Alzheimer’s disease, to nearly universally disappointing results. Trial sponsors are now being urged to test patients for different genetic risk variants in APOe to balance the treatment and placebo arms of their studies. APOe4 is a genetic-risk variant that can increase an individual’s risk of developing Alzheimer’s disease by up to 11-fold. Very recent data, published in November 2019, suggests that the APOe2 variant carries even more significant weight regarding disease risk -- but this particular variant is protective. (Individuals who have 2 APOe2 variants have up to a 99.6% lower risk of developing Alzheimer’s disease compared to someone with 2 APOe4 variants.)

Clinical trial participants in future studies will likely be tested for these genetic variants prior to assignment to a study arm to ensure that observed disease-progression differences can be attributed to the experimental therapy, and not underlying genetic risk.

It’s clear that in the near future genetic testing will be increasingly used to evaluate and stratify study populations even when the therapeutic isn’t a gene therapy.

• DANIEL KAVANAGH, PhD, RAC
  Senior Scientific Advisor, Gene Therapy, WCG

With regard to clinical product development in the coming year, I am looking forward to seeing new proof-of-concept approaches to cancer treatments that make use of advanced synthetic biology. Synthetic biology is the application of engineering principles to molecular biology, especially through the combination of validated, modular synthetic DNA and RNA components. These approaches will make future human gene transfer products more effective and responsive to clinical needs.

Currently the FDA has approved two chimeric antigen receptor T-cell (CAR-T cell) products, both for the treatment of B cell malignancies. Both products are based on genetic modification of the patient’s lymphocytes to recognize a single tumor antigen (CD19). Both products are always “on”— in attack mode, seeking to destroy CD19 targets. These products, the result of heroic development efforts, represent the first generation of gene-modified immune therapies.

Ideally, future CAR-T therapies will not be restricted to a single tumor antigen target; they will be “tunable,” with response intensity under the control of the treating physician; they will be versatile in terms of the selection of cell contact-dependent and -independent immune effector mechanisms they deploy; and they will incorporate genetic logic circuits —molecular computers — to execute programmable responses to changing clinical needs at the cellular level. In principle, the necessary design elements exist today, but practical deployment of these ideas will require careful planning and intense efforts to address clinical, commercial, regulatory and long-term safety needs.

• MARK OPLER, PhD, MPH
  Chief Research Officer, WCG MedAvante-ProPhase

2020 will be another exciting year for psychiatry and neuroscience clinical trials. The overarching story for 2020 will be one of “building momentum” — taking the achievements and gains of the past decade to the next level.

FDA approvals of new rapid-acting agents for mood disorders, such as esketamine and brexanolone, signal that the new era of CNS research is firmly rooted and poised to continue. Ongoing trials of PTSD, non-dopaminergic mechanisms for treatment of schizophrenia and continued progress in rare neurodevelopmental disorders all show that the industry continues to blaze new trails. This exciting flurry of activity in drug development comes at a time when entirely new paradigms are being constructed in digital therapeutics, i.e., “Digital Medicine (DiMe),” and novel applications of devices. We need to remember, however, that these advances have coincided with some notable stumbles in the face of high placebo response, causing massive late-stage failures and killing off promising avenues of investigation.

The extent of the progress we make in the next decade depends on the degree to which we address the rising cost and complexity of research, refine the role of technology to enable progress, and confront the ever-present issue of placebo response in neuroscience and beyond. The challenges and the opportunities of 2020 and the years to follow are considerable, requiring all stakeholders to find common ground and work together to achieve success.

• STEVE SMITH
  President, Patient Advocacy, WCG

In 2020, patient advocacy will continue to transform drug development, although positive results can be hard to see unless one takes a long-term look at the past for context. We see healthy skepticism that drug developers’ patient-centric efforts create real change. Protocols are still overloaded with burdensome procedures, endpoints don’t reflect what matters most to patients and dialogue with patient communities seems symbolic, even off-putting when informed consents and trial descriptions remain in complex language many patients don’t understand. Patients note how warmly trial sponsors reach out to them at first, then disappear, sharing neither trial outcomes nor the patient’s own data.

As discouraging as this sounds, patient/researcher collaboration continues the detailed work to transform this atmosphere. Today’s hard work stems from profound legislative changes to regulatory processes that collaborating patient advocates brought about in the past. It takes years to realize the benefits of such change, e.g., The Orphan Drug Act (1983), PDUFA V (2012) and 21st Century Cures Act (2016).

Five years from now, looking back at 2020, we will confirm improvements in the use of patient-friendly lay language, patient cohorts providing advice at trial design time, researchers sharing patient data with any legitimate researcher when collected in a federally funded trial, patient-friendly, online ways to search for trials and increasingly better-informed patients who have something positive to say about participation in clinical research.