Guest Column | July 14, 2020

Regulatory Science & Clinical Research: Where Do We Stand (And Where Are We Going)?

By Alethea Wieland, founder and president, Clinical Research Strategies, LLC

Looking OVer Mountain

It’s no secret that the FDA has recognized for years that the clinical trial system, with some of the worst return on investment (ROI) of any industry, is broken. Our U.S. federal grants system continuously pours billions of dollars into bench science at prestigious universities, where the funds rarely translate into new solutions; instead, they add more publications to the research teams’ curriculum vitaes — the historical incentive in research. We have been weighing the value of this system, including reproducibility and rigor problems, and have engaged in critical discourse about what needs to change. And yet, year after year we ask what innovations we need to get behind to truly accelerate drug development and increase the public’s access to cost-effective treatments. We have all these new nifty ways to conduct research and the regulators are initiating new conversations about how we need to conduct research, but the guidelines and regulations we follow lag behind the digital transformation.

This article will share some thoughts on the current state of regulatory science, by reflecting back on  two prominent meetings. The first is the inaugural UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI) Summit for Innovations in Regulatory Science (Jan. 12, 2020) and the second is the Clinical Trials Transformation Initiative (CTTI) Virtual Meetings for Stakeholder Engagement on ICH E6 Guideline for Good Clinical Practice (June 4-5, 2020).

The CERSI Summit was five years in the making, assembling key stakeholders from industry, the FDA, and CERSI members and investigators. In 2016, the FDA had established a rare funding opportunity through an RFA for regulatory science and innovation, and awards were given to four CERSI institutions, two of which are joint partnerships: Yale University-Mayo Clinic, University of Maryland, The Johns Hopkins University, and UCSF-Stanford University. The CERSI-FDA collaborators are focused on improving drug discovery, addressing cost inefficiencies, reducing barriers to bringing new therapies to patients, and decreasing health disparities. While drug development dominates the headlines, the organizers of the summit acknowledge that these collaborations are widely applicable for medical devices, generics, and combination products.  Today, industry partners are building upon better methods and more machine learning and artificial intelligence, but significantly more work needs to be done. (See Appendix 1 for links to videos of the summit sessions.)

CTTI’s Virtual Meetings for Stakeholder Engagement on ICH E6 Guideline for Good Clinical Practice go hand-in-hand with the regulatory science policy of the CERSIs, as designated working groups contemplate the next revision to the International Council for Harmonization Good Clinical Practice (ICH GCP) E6R3. (See Appendix 2 for a link to videos from the meetings.) On the heels of the implementation of the second revision (R2), confusion still exists about how to conform more novel research approaches to the Guideline. The third revision (R3) will require a major overhaul and simplification to keep pace with nontraditional and precision medicine trials. Otherwise, we continue to dig ourselves into the “research is slow and costly” hole.

Building A Trust Infrastructure

At the CERSI Summit, Dr. Amy Abernathy of the FDA asserted we need a “trust infrastructure,” including new technology and enhancements to electronic health records (EHRs) that enable real-world evidence (RWE), broad distribution of clinical trials, data curation, monitoring of drug manufacturing, and management of the entire clinical research enterprise.

We have seen for decades that EHRs’ secure electronic platforms could enable research where medical data is collected as the original source in the first place. However, the various components of the clinical research enterprise — industry, service providers, central laboratories, contract research organizations, and digital technology companies — have addressed data reentry, collection, validation, and conformance of clinical trial data to good clinical practice (GCP) guidelines in separate and disparate electronic systems, to the detriment of progress and efficiency. Any public demonstration of EHR companies’ interest in being a part of this trust infrastructure has been oddly missing in my view.

Reimagination Of A Clinical Trials Playbook

Dr. Janet Woodcock of the FDA insisted at the CERSI Summit that we need to “stop doing artisanal one-at-a-time clinical trials” the old-fashioned way because they aren’t working. Experts in the field agree that we need to unlearn our set ways that have been the cause of our poor results and instead embrace minimization of randomization, methods that prevent information loss, adaptive designs and platform trials, and intermediate or surrogate endpoints. In addition, we must deploy artificial intelligence (AI), machine learning (ML), and other analysis methods to quantitatively interpret clinical data and health data together to inform the practice of medicine. The call to combine the practice of medicine and research is reaching the tipping point and demands a flexible, single-source data solution.

The Bad Worth Giving Up

Our fixation on quality, along with its interpretation, has tripped us up. Dr. Abernathy stated her belief that we need to “let go of our emotional reaction to the fact that clinical data is of poor quality.” We put ourselves at a disadvantage by insisting on p-values, significance testing, and hypothesis testing when alternative mathematical formulas, Bayesian designs, and other ways to analyze real-world data (RWD) with AI and ML need to be emphasized. The tools, adaptive approaches, and technology are available.

For patient-centric improvements, we need to give up lengthy, unintelligible informed consent forms, randomization that leads to ineffective treatment, and nuisance on-site visits comprised of performance tests and procedures that impose on the study subjects’ time and participation levels.

If we give up doing the “smaller crappy trials” described by Dr. Woodcock, we should be able to leverage alternative sources of data and structures that allow accumulated data to be reviewed in predefined interim analyses and the previous data to be cleaned in the continuum.

Consensus is building for radical reformation of our national funding that has been limiting drug and device development science. If the U.S. is serious about accelerating the translation of science into new and better medicines, we need to modify the incentives in order to drive toward technological advances and solutions. We can’t get much worse than the abysmal statistic that 1 out of 10 molecules makes it to market with unsustainable costs and wasted resources.

Put another way by Ilan Gur in his article “How the US Lost Its Way on Innovation,” we need to fund innovation through grand challenges, including engaging industry startups, and alter the funding rules that have for decades given the larger academic centers the biggest access to those funds.

Similar conversations are also happening in the European Union and other critical areas throughout the Asia-Pacific, African, and Central and South American regions.

Finally, we must give up the middlemen service and technology providers who clutch onto old process customs by refusing to innovate and who ultimately are losing their place and relevance in the new age of research. 

Guidelines And Regulations Stifle Innovation

According to various international working groups developing Revision 3 to ICH GCP E6, who gave updates at the CTTI Virtual Meetings, we need to improve our definitions of quality and the application of the definitions to address data provenance, flexibility, and these new realities.

We know that innovation in clinical research involves decentralized trials, digitization, real-time sensors, wearables, patient reported outcomes (PRO), and telemedicine. Our quality systems and attitudes on processing clinical data for GCPs currently lack the flexibility we need to conduct more agile trials, including in underrepresented patient populations, as well as more efficient and dynamic clinical trials that explore new paradigms such as site-less, non-investigational, adaptive, and platform trials and trial registries. Growing precision medicine areas such as biomarkers, companion diagnostics, AI, and algorithm development are also missing from guideline definitions.

Further, the overly conservative interpretation and policing of GCPs through auditing functions requires overhaul.  ICH GCP E6R2 Section 5.0 Quality Management states: “The sponsor should implement a system to manage quality throughout all stages of the trial process….The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected. The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection….”

ICH GCP E6R2 is woefully inadequate today and has widely misled interpretation of quality conformance and risk review in the virtual, digital age of research by making processors believe in extreme policing, which also adds to the cost and delay of research. Revision 3 must make considerable updates to account for trial oversight if we want to add any speed to drug development.

How COVID-19 Amplified The Broken System

I doubt that many of us in the industry with prior knowledge of the numerous problems in our clinical trials system were surprised by how much COVID-19 amplified those problems or by the instant crippling of hundreds of millions of dollars’ worth of R&D programs when trials were cancelled or closed prematurely. Patient visits could not be maintained, on-site monitoring schedules were halted, and the studies that did remain open required protocol amendments to address data quality and integrity issues. There was significant job loss.

After a period of shock and adjustment, we then proved to ourselves that virtual visits, telemedicine, and patient-centric reporting tools and apps could actually work en masse for many trials. The virtual conference model offered solutions to problems we have been talking about for years.

Although not without criticism, abuse, and fraud, one of the most impressive responses to the pandemic was the FDA’s rapid deployment of guidances, fast-track initiatives, emergency use authorizations (EUAs), and billions of dollars of government funding backing calls to action. Industry and entrepreneurs stepped up and collaborated to develop new vaccines, make new diagnostic tests, build ventilators and personal protective equipment (PPE), and repurpose existing drugs for coronavirus clinical trials.

In just a short period of time, we saw the worst and best of the situation.


Rejection of the things that have held us back, along with inspiration and movement to a single-source data collection solution, can ultimately change the practice of medicine, improve drug and device development, and enable regulatory decision-making for the next generation of medical products. We can’t afford a repeat of the economic crisis the next time a global public health concern hits without warning. The question is when, not if, there will be a next time, and whether our international response communities will be ready. Ask yourself what you are willing to do and sacrifice to accelerate this universal bigger purpose.

Appendix 1:

Videos of the CERSI Summit for Innovations in Regulatory Science sessions are available on YouTube:

Appendix 2:

Videos of the Stakeholder Engagement on ICH E6 Guideline for Good Clinical Practice meetings are available on Vimeo:

About The Author:

AAlethea Wieland is founder and president of Clinical Research Strategies, LLC, an executive-level management consulting firm and boutique, functional service provider for the life sciences industry. Her firm’s solutions include analyzing the intersection of healthcare innovation and policy; providing flexible clinical trial resourcing; developing sustainable corporate affairs programs and policies; training and managing resilient, high-performing clinical operations teams; mitigating risks of clinical trials; and facilitating transparent, accountable sponsor-CRO partnerships. Learn more by connecting with her on LinkedIn and by visiting her website,