With the COVID-19 pandemic raging, the National Institutes of Health (NIH) announced the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership to develop a coordinated research strategy for prioritizing and accelerating development of what was to be deemed the most promising treatments and vaccines. Backed by the coordination efforts of the Foundation for the National Institutes of Health (FNIH), ACTIV represented the entire U.S. federal government research and health apparatus, including the NIH with its sibling agencies in the Department of Health and Human Services (including BARDA, CDC and FDA). Stakeholders also include other government agencies such as the Department of Defense (DOD) and Department of Veterans Affairs (VA), as well as small role by the European Medicines Agency (EMA) and representatives from academia, philanthropic organizations, and a number of biopharma companies. TrialSite’s review shows that participation is skewed toward just a few federal agencies and a handful of the largest biopharmaceutical companies. Given the magnitude and severity of the public health crisis, the impulse to consolidate and centralize much activity at the highest level certainly has a rational basis. But such an endeavor has the distinct possibility to become the gatekeeper to any and all federal dollars for COVID-19 research. Missing from ACTIV is representation from state and local health care systems, community providers, entrepreneurial biotech ventures, and a demographic cross-section of the US.
Why was ACTIV formed?
On May 18, Francis S. Collins from the NIH and Paul Stoffels from Johnson & Johnson announced ACTIV as, “an unprecedented partnership for unprecedented times.” These prominent figures were certainly correct when they stated that the rapidly unfolding crisis prompted the very rational decision to form a public -private partnership to help accelerate new therapy and vaccine development and approvals. The premise was actually quite simple: with dozens, then hundreds and then thousands of COVID-19 clinical trial starting around the world, and with limited resources, there was a recognized need to coordinate and streamline processes to make the best use of biomedical research and testing of preclinical compounds. With so many research trials commencing, targeting over 100 potential preventive therapies and treatments, it became imperative to coordinate efforts especially as many clinical trials were at risk of failing due to a lack of patient participation. Moreover, the NIH writes that the “lack of coordination” could very well make actual interpretation and comparison of the trial results a challenge. The premise was that the healthcare providers on the ground, or “the front lines,” caring for the severely to critically ill every day needed meaningful, evidence-based information on how to deal with the novel coronavirus.
ACTIV’s Fast Track Focus Areas
As those most influential and powerful in research came together over the last months, the NIH has established four fast-track focus areas declared “most ripe” for opportunity. Each one of these focus areas, or work streams, is led by a working group of senior scientists representing government, industry, non-profit, philanthropic and academic settings. What follows are these four fast-track sections.
Fast Track Area 1: Collaborative Streamlined Forum Identifying Preclinical Treatments
A critically-important focus area, this would be the group that identifies which treatments would enter into research. Since ACTIV includes the entire U.S. federal research apparatus and also Europe, much of the world’s research and selection of COVID-19 preclinical treatments would be governed and controlled by this working group. To ensure that this becomes a reality, ACTIV is to:
- Establish a centralized process and repository for harmonizing and sharing methods and evaluating animal models.
- Extending access to high-throughput screening facilities, especially in biosafety level 3 (BSL-3) labs.
- Increasing access to validated models.
- Enhancing comparison approaches to identify informative assays.
Fast Track Area 2: Accelerate Clinical Testing of the most Promising Vaccines and Treatments
Moving forward, only those compounds or therapies selected in Fast Track Area 1 would make it to this stage. Here ACTIV works diligently to do the following:
- Establishing a steering committee with relevant expertise to set criteria for and rank potential candidates submitted by industry partners for testing.
- Developing a complete inventory of potential candidates with different mechanisms of action and acceptable safety policies.
- Designing, launching, and openly sharing master protocols with agreed-upon endpoints, sampling, and analysis for evaluating candidates.
- Using a single control arm to enhance trial efficiency.
The language used here is informative of the influence, and potential control, of ACTIV over the world’s research agenda. That therapies or vaccines would be vetted and ranked by this steering committee will ensure select investigational products make it, while completely precluding others. Moreover, controlling the potential candidates to ensuring a master protocol introduces powerful efficiency while also assuring only those compounds that ACTIV committees select have a chance to receive any federal funding.
Fast Track Area 3: Improve Clinical Trial Capacity and Effectiveness
Those compounds pre-vetted and selected, and guided by master protocols and shared single control arms for example, would leverage a shared infrastructure along with centralizing coordination function, including even shared incidence tracking to share future capacity. This would imply an unprecedented level of shared systems and processes. Key activities of this workstream:
- Leveraging infrastructure and expertise from across NIH and non-NIH networks and clinical research organizations.
- Establishing a coordinated mechanism across networks to expedite trials.
- Tracking incidence across sites and project future capacity.
Fast Track Area 4: Accelerate the Evaluation of Vaccine Candidates to Enable Rapid Authorization or Approval
Finally, ACTIV seeks to accelerate vaccine approval in the hopes of enabling rapid authorization and use. This body that controls all vaccine development, in at least the developed world, plans on accomplishing this by the following:
- Harmonizing efficacy trials to enable analysis of correlates of protection across vaccines.
- Creating a collaborative framework to share insights into natural immunity and vaccine candidate-induced immune response.
What about Governance?
ACTIV leadership has three layers, including the following:
Led by the NIH, government participation includes the Biomedical Advanced Research and Development Authority (BARDA), Centers for Disease Control and Prevention (CDC), Department of Defense, Department of Veterans Affairs, European Medicines Agency, and of course the U.S. Food and Drug Administration (FDA). A sizeable list of involved biopharmaceutical companies includes AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eisai, Eli Lilly, Evotec, Gilead, GlaxoSmithKline, Johnson & Johnson, KSQ Therapeutics, Merck, Moderna, Novartis, Novavax, Pfizer, Roche-Genentech, Sanofi, Takeda, and Vir Biotech. Finally, non-profits include the Bill & Melinda Gates Foundation, Fred Hutchinson Cancer Research Center, Foundation for the National Institutes of Health, and RTI International. Noticeably absent from ACTIV’s governance are: 1) community providers and non-academic medical systems, 2) patient-advocacy groups, 3) clinical research organizations, the groups that pharmaceutical companies outsource much of their clinical trials to, and 4) representation of the diverse populations of the US and Europe.
What about Leadership Participation and Decision Making?
TrialSite reviewed ACTIV leadership participation by executive committee and working groups in order to better understand what interests are being represented. The Executive Committee consists of the following individuals:
|EC Member||Title/Organization||Interest Represented|
|Francis Collins, MD, PhD, Co-Chair||Director NIH||NIH/Fed Gov|
|Paul Stoffels, MD, Co-Chair||VP of the EC, CSO, J&J||Big Pharma|
|Gary Disbrow, PhD,||Acting Dir, BARDA||HHS/Fed Gov|
|Mikael Dolsten, MD, PhD||CSO,Pres, Pfizer||Big Pharma|
|Anthony Fauci, MD||Dir. NIAID (NIH)||NIH/Fed Gov|
|Gary Gibbons, MD||Dir. NHLBI (NIH)||NIH/Fed Gov|
|Peter Marks, MD, PhD||Director, CBER, FDA||FDA/Fed Gov|
|William Pao, MD, PhD||Head pRED, Roche||Big Pharma|
|Andrew Plump, MD, PhD||Pres. R&D, Takeda||Big Pharma|
|Janet Woodcock, MD||Operation Warp Speed||Fed Gov|
Clearly, the Executive Committee is comprised of representatives from either: 1) the largest pharmaceutical companies, or 2) agencies within the federal government via the NIH or FDA. There is no seat at the table for even academic medical centers, let alone major health systems, provider networks, community providers, or even public payers. Out of ten leaders, there is one African-American, one with Asian heritage, and one female. This is hardly representative of society at large. But what about the Working Groups?
The Preclinical Working Group represents a critical workstream, among other things identifying what candidates even get federal funding moving forward.
This group is predominantly represented by federal officials (either FDA or NIH) at Big Pharma (combined 78%), small biotech (7%), Academia (14%) and non-profits (11%.) There are little to no “real world medicine” representatives from either health systems, hospitals, public health districts, or community networks. Of course, some of the academic medical centers maintain hospitals, but representation is very much from the academy.
What about the Therapeutics Clinical Working Group? Much like the Preclinical, this group excludes any health systems or hospitals and rather is represented predominantly by federal agencies and Big Pharma (78%). The academy is represented at 16% while small biotech (3%) and non-profits (3%) lag. The Clinical Trial Capacity Working Group is represented again overwhelmingly by federal government and Big pharma representatives (81%) while academia has 14% representation and non-profits have 5%. Finally, the Vaccine Working Group is a bit more diversified: the federal government and Big Pharma represent 48% of the members, small biotech 12% , the academy 32% and non-profits 4%.
Diversity Lacking in ACTIV
What about gender and racial/ethnic diversity among this incredibly influential and powerful group? Afterall, there are more calls than ever from government and industry to include the underrepresented, whether it be the elderly, female, or ethnic minorities in all facets of research. In a recent interview with the Dean of Stanford University Medicine, Dr. Anthony Fauci of the ACTIV Executive Committee mentioned, “It’s like a broken record; it’s the same thing. Minority populations are disproportionately negatively impacted by diseases like this [COVID]. And in your state, its mostly African Americans and Latinx, with some Native Americans.” Fauci has been a big advocate of diversifying research. But how diversified is this collective and influential decision-making body? Out of 116 participants in ACTIV, 31% are woman which the TrialSite applauds. For all of ACTIV’s key 116 members, 9% are ethnic minorities. This is well below the national total of approximately 40% minority (17.6% Hispanic, 13% African American, 5.5% Asian and 4.8% other). Asians (mostly Indian) make up the largest representation at 6% or 7%, while African-Americans represent 2%, and Hispanics include just one member out of 116 participants. African-Americans and Hispanics represent less than 3% of ACTIV Executive Committee and Working Groups, yet they represent over 20% of the U.S. population and are demographics at high risk during this pandemic.
Recommendation to ACTIV
ACTIV represents a critically-important collaborative organization directing the nation’s research in the worst global pandemic in the modern era. Representing a diverse array of stakeholders and interests, the leadership and working group representation prioritize certain interests over others. TrialSite suspects it may be difficult due to a number of socio-demographic factors to recruit ethnic or gender-balanced representation, however undoubtedly the group could have done a little better in forming such an influential group to represent a broader array of segments of society as well as actual health providers.
The current members undoubtedly were selected based on their experience, expertise, and pedigree in research (and the TrialSite can attest they have assembled a high powered, experienced group), but from the standpoint of healthcare today there appears to be a substantial division between research and real-world care.
Hence, the complete preclusion of physicians and researchers from the nation’s health systems, hospitals, public health systems and community health networks. The membership is dominated by federal agencies and Big Pharma, with some representation by academic medical centers. There isn’t sufficient representation from dynamic, agile biotech’s, nor purpose-driven non-profits.
Many of the COVID-19 vaccine candidates have been developed by partnerships combining non-profits, innovative biotech’s, and some academic participation. Therefore, it would be beneficial to consider participation from more nimble, entrepreneurial firms. Based on overall representation, this critically important research apparatus will be run, managed, and governed by a group overwhelmingly represented by federal agencies (NIH, BARDA, FDA, etc.) and Big Pharma. These are great perspectives, but others are needed as well. The group should consider diversifying to add more physicians from health systems, community provider networks and even public health districts.
What about “Real-World Evidence” (RWE) with COVID-19?
There is a concern that ACTIV represents an antiquated, slow, and laborious system that must be transformed via technology and innovative thinking. With the advent of a technology revolution, enabling electronic health records, smart phones, and the internet of things, the emergence of wearables, biosensors, and FDA regulated apps leads to massive amounts of health-related data.
This data, the FDA has recognized, holds huge potential to inform, better design, and conduct clinical trials and studies in the health care setting including in response to COVID-19. The FDA suggested on its own website that heretofore not solvable health questions can now be answered thanks to too vast troves of health data combined with sophisticated analytical capabilities.
The 21st Century Cures Act, passed in 2016, emphasized the additional focus on the use of real-world data to support regulatory decision making, including the approval of new indications for approved drugs (e.g. off label use). Congress defined RWE as data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials. FDA went on and expanded the definitions to include data from a variety of sources such as:
- Electronic health records (EHRs).
- Claims and billing activities.
- Product and disease registries.
- Patient-generated data including in home-use settings.
- Data gathered from other sources that can inform on health status, such as mobile devices.
Many send the TrialSite comments that they see a chasm between the research community, with lengthy, complex, and costly randomized controlled trials, and the needs on the ground in the nation’s health systems. The FDA, Big Pharma, and others need to start embracing real-world data (and the providers on the ground) to influence research and drug development. The lack of representation of health systems, or even technology companies, in ACTIV is yet another signal that perhaps the paradigm behind the group could be somewhat dated.