The National Institutes of Health (NIH) recently updated the COVID-19 Treatment Guidelines: Therapeutic Management of Patients with COVID-19 guidelines highlighting recommended therapeutic treatment by COVID-19 disease severity level. As TrialSite has highlighted for months, there appears to be a distinct government bias in favor of certain kinds of COVID-19 fighting investments over others regarding investigational treatments. For example, the NIH has overwhelmingly focused research investment on vaccine candidates as well as novel monoclonal antibodies that have much yet to prove, as they acknowledge in the guidelines. This research translates into over $12.2 billion in Operation Warp Speed capital outlay, not including hundreds of millions more in NIH (ACTIV) sponsorship of clinical trials. When analyzing this spend, minute expenditure has gone into repurposing existing low cost and widely available therapies. So, well over $1 billion of taxpayer capital has been injected into clinical trials, manufacturing support and purchases of highly investigational monoclonal antibody products alone. As TrialSite and others have communicated, this class of experimental product raises significant health equity issues, not to mention fundamental challenges involving the administration and access for early-onset COVID-19 cases. A lack of emphasis on low cost, available treatment approaches for early-onset cases may have worsened the pandemic outcomes. TrialSite, at the founder’s expense, has incessantly chronicled and advocated for public support of Ivermectin research, for example, based on mounting evidence tied to case series, observational and randomized controlled studies in other parts of the world. The research and health establishment has exhibited no interest. TrialSite commends NIH/NIAID, Operation Warp Speed and prominent pharmaceutical companies (Pfizer/BioNTech, Moderna, Lilly and Regeneron, to name a few) for achieving historically notable results in both vaccine and monoclonal antibody therapy development. TrialSite only appeals that a small portion of public funds must be allocated into generic alternatives for low cost, early-onset COVID-19 treatment. Both investment tracks should occur simultaneously. The marketplace ultimately demands such a supply.
The COVID-19 Treatment Guidelines Panel reviews ongoing clinical trial data to offer up-to-date treatment recommendations for clinicians caring for patients infected with SARS-CoV-2. Note that NIH offers detailed summaries of the clinical data for the drugs currently under investigation for the treatment of COVID-19 in the following locations: Antiviral Therapy, Immune-Based Therapy and Adjunctive Therapy sections of the NIH Guidelines.
What follows is a table with a list based on disease severity, recommended therapy and TrialSite comment. Note that “Rating of Recommendations” equals, A = Strong, B = Moderate and C = Optional; while Ratings of Evidence equals I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb Nonrandomized trials or observational cohort studies and III = expert opinions. Note that the table below is a summary and is not meant to replace the full NIH table available at the source link or here.
|Disease Severity||Recommended Therapy||TrialSite Comment|
|Not Hospitalized: Mild to Moderate COVID-19||Although the NIH suggests the possible use of monoclonal antibodies, including bamlanivimab or Casirivimab plus imdevimab only for those outpatient in high risk of disease progression Dexamethasone should not be used (AIII)||These (monoclonal antibodies) are cumbersome and costly to administer and the evidence is nowhere near certain. The NIH has contributed substantial public funding to these high-cost, highly experimental treatments. Why haven’t they listened to a growing community of physicians to consider other, more low-cost approaches as well? What about Ivermectin? Evidence grows—see the ICON study in peer review journal chest. What about Favipiravir? Other nations have approved. What about hydroxychloroquine– Why is the WHO behind the ANTICOV study, which emphasizes early use of HCQ?|
|Hospitalized but Doesn’t Require Supplemental Oxygen||NIH suggests insufficient data for or against remdesivir. They suggest for patients in high-risk situations consider remdesivir. Dexamethasone should not be used (AIIa)||Note the World Health Organization (WHO) recommends against the use of Remdesivir due to findings of a large Solidarity trial. NIAID actually changed the endpoint for key study to contribute to FDA emergency use authorization. TrialSite point of view: a significant body of observed real-world evidence observation suggests NIH is correct that remdesivir can benefit those at risk in clinic or hospital even though Solidarity points to no efficacy.|
|Hospitalized and Require Supplemental Oxygen (But Does Not Require Oxygen Delivery via High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation or ECMO)||Use of one of the following options: Remdesivir–for patients who require minimal supplemental oxygen (BIIa) Dexamethasone plus remdesivir –e.g., patients who require increasing amounts of supplemental oxygen (BIII) Dexamethasone–when combination therapy with remdesivir cannot be used or not available (BI)||What about RLF-100? RECOVERY trial introduced the efficacy of Dexamethasone.|
|Hospitalized and Requires Oxygen Delivery through a High-Flow Device or Noninvasive Ventilation||Dexamethasone (AI); or Dexamethasone plus Remdesivir (BIII) Note, in rare cases where corticosteroids cannot be used baricitinib plus remdesivir can be used per NIH||RLF-100? Note Dexamethasone breakthrough was due to RECOVERY trial in the UK and not U.S. government expenditure|
|Hospitalized and Requires Invasive Mechanical Ventilation or ECMO||Dexamethasone (AI)||RECOVERY trial in the UK|
Before probing the question as to why the federal government research apparatus (e.g., NIH et al.) hasn’t probed enough into generic research for early-onset of COVID-19, the profound consolidation and rationalization of research activity must be understood.
ACTIV Drives Research Agenda
The COVID-19 pandemic ushered unprecedented federal consolidation of research and development-funded activity to counter the incredibly dangerous pandemic. By April 17, 2020, the NIH helped form the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership to formulate and coordinate research strategy for prioritizing and accelerating the development of the most promising treatments and vaccines.
This effort was coordinated by the Foundation for the NIH and involved the combining of important federal agency participants such as the Biomedical Advanced Research and Development Authority (BARDA), Centers for Disease Control and Prevention (CDC), and the U.S. FDA. Other agencies involved included the Department of Defense (DOD) and the Department of Veterans Affairs. Operation Warp Speed, formed in May 2020, is also involved with ACTIV, as are other academic, philanthropic, industry-based and other organizations.
Although TrialSite certainly understood the drivers for the research consolidation–an unprecedented modern-day pandemic–an analysis of membership and decision-making authority led to concern for bias against the vast, decentralized and critical provider community.
ACTIV has organized coordination and allocation of federal money into four “Fast Tracks,” including the following:
|ACTIV Fast Track||Emphasis||Working Group Focus|
|Fast Track Area #1||Develop a collaborative, streamlined forum to identify preclinical treatments||• Centralized process & repository for harmonizing & sharing methods & eval animal models|
• Extending access to high-throughput screening facilities (BSL-3 lab focus)
• More access to validated animal models
• Richer collaboration to identify informative assays
|Fast Track Area #2||Accelerate clinical testing of the most promising vaccines and treatments||• Establishing a steering committee with relevant expertise to set criteria & rank potential candidates submitted by industry partners for testing|
• Develop a complete inventory of potential candidates with different mechanisms of action and acceptable safety profiles
• Designing, launching and openly sharing master protocols with agreed-upon endpoints, sampling and analysis for evaluation candidates
• Using a single control arm to enhance trial efficiency
|Fast Track Area #3||Improve clinical trial capacity and effectiveness||• Specializing in different populations and disease stages|
• Leveraging infrastructure and expertise from across NIH & on-NIH Networks and research organizations
•Establishing coordinated mechanism across networks to expedite trials
• Tracking incidence across sites and projecting future capacity
|Fast Track Area #4||Accelerate the evaluation of vaccine candidates to enable rapid authorization or approval||• Harmonizing efficacy trials to enable an analysis of correlates of protection across vaccines |
• Creating a collaborative framework
For purposes of this discussion, Fast Track Area #2 is most relevant. Although TrialSite must emphasize the unprecedented speed, agility and results of ACTIV across multiple Fast Tracks. From monoclonal antibodies to vaccines, the ACTIV consolidation has led to historical results and will be a notable move when university students study drug developments decades from today.
This article isn’t making a case that ACTIV hasn’t produced results. In fact, the reality is just the opposite: ACTIV has produced historical results for anyone with experience in the world of drug development. What TrialSite addresses here is a profound gap that ACTIV must now address. That is the investigation into low-cost, widely available options to prevent or inhibit the progression of COVID-19 and its severe potential manifestations.
A brief review of the major ACTIV Fast Track Area #2 activities is informative. Embracing a robust, comprehensive and rigorous process, the working group members (heavily industry and academic medical center-based) developed a process to vet and qualify agents for rapid testing.
The ACTIV Master Protocols
Ultimately, the ACTIV qualification and prioritization process led to select drug targets, whether they be antivirals, immunomodulators, supportive therapies or neutralizing antibodies, to be placed in “Master Protocols” designed to facilitate “coordinated and efficient evaluation of multiple investigational agents as they come available, but within the same clinical trial structure, across multiple study sites.”
Established as “Adaptive protocols,” they were established to rapidly “weed out” those agents that failed to evidence efficacy while focusing on the ones that do show promise. These adaptive protocols are important as they can streamline the process while reducing administrative and associated cost factors, important during a pandemic. Just as important is the flexibility that such designed trials afford: the ability to quickly identify therapies that may be working while rapidly introducing new drug targets into the study should evidence merit such a move.
What follows are the five Master Protocols with associated adaptive trials, drugs and industry association.
|Master Protocol||Focus||Key Drugs & Pharma/Trial Phase|
|ACTIV-1||Immune Modulators||• Remicade: monoclonal antibody donated by Janssen/(Phase 3)|
• Orencia: selective T-cell co-stimulation immunomodulator donated by BMS/(Phase 3)
• Cenicriviroc: blocks CCR2 & CCR5 chemokine receptors donated by AbbVie/(Phase 3)
|ACTIV-2||Outpatient Monoclonal Antibodies & Other Therapies||• LY-CoV555 which was accelerated through thanks to work in-conjunction with AbCellera and brilliant Lilly scientists (Lilly) Now FDA approves for emergency use authorization (mentioned in NIH guideline table and presently Phase 2 & 3)|
|ACTIV-3||Inpatient Monoclonal Antibodies & Other Therapies||• LYCoV555: this study is closed because the Data Safety Monitoring Board determined a low likelihood that the intervention would be of critical value in this hospitalized patient population.|
|ACTIV-4||Antithrombotic||• Apixaban: Direct oral anticoagulant donates by BMS/(Phase 3)|
• Aspirin: Anti-platelet agent donated by BMS/Pfizer/(Phase 3)
• UF & LMW heparin: agents used for in-hospital anticoagulation/(Phase 3 for in-hospitalized patients)
|Activ-5||“Big Effect Trial”||• Risankizumab: monoclonal antibody developed by Boehringer Ingelheim & AbbVie (Phase 2) |
• Lenzilumab: investigational monoclonal antibody developed by biotech firm Humanigen/(Phase 2)
TrialSite showcases a clear indication of preference of industry sponsor, advanced biologics for example, over the generic possibilities explored in other parts of the world (except for aspirin in the ACTIV-4 Antithrombotic master protocol.
Operation Warp Speed emerged alongside NIH as a key enabler to accelerate drug and vaccine development. What follows is a brief sample of the amount of taxpayer dollars allocated to these activities.
OWS/HHS Spending Available Timeline:
|March 30, 2020||$456 million||Janssen (J&J)||Vaccine: now fourth OWS candidate for vaccine in Phase 3|
|April 16, 2020||$483 million||Moderna||Vaccine: now in EUA process|
|May 21, 2020||$1.2 billion||AstraZeneca||Vaccine: now in Phase 3 (delayed due to safety pause)|
|July 7, 2020||$450 million||Regeneron||mAb: comprehensive gov. support|
|July 7, 2020||$1.6 billion||Novavax||Vaccine: comprehensive gov support|
|July 22, 2020||$1.95 billion||Pfizer||Vaccine: comprehensive support—now in EUA process|
|July 26, 2020||$472 million||Moderna||Vaccine: now in EUA process|
|July 31, 2020||$2 billion||Sanofi/GSK||Vaccine: Funds for advanced dev, including clinical trials & manufacturing for investigational adjuvanted vaccine.|
|August 5, 2020||$1 billion||Janssen (J&J)||Vaccine: funds for large manufacturing, distribution & purchase of 100m doses|
|August 11, 2020||$1.5 billion||Moderna||Vaccine: funds for large manufacturing, distribution & purchase of 100m doses|
|October 9, 2020||$486 million||AstraZeneca||mAb therapy candidate called AZD7442|
|October 28, 2020||$375 million with option for additional $812.5 million for total of $1.187 billion||Eli Lilly||mAb therapy candidate called LY-CoV555 government pays $1,250 per dose for $375m with option to buy 650,000 doses for additional $812.5 million|
The U.S government has to-date allocated at least $12.784 billion to just a handful of vaccine and monoclonal antibody (mAb) therapy candidates. The vaccine allocation is appearing to be a wise investment in public expenditure as high-quality investigational products appear in the making. Of course, with powerful biological-based vaccine candidates, the long-term effect cannot be known until at least a few years of data.
Approximately $10.6 billion has been awarded for various vaccine subsidies and purchases, while a total of $2.2 billion has been allocated to novel monoclonal antibodies, two of which are now available under emergency use authorization. Although as TrialSite and others have discussed, access, availability and administration pose real challenges.
Hundreds of millions of dollars and perhaps more are also funneled into various ACTIV clinical trials, however, there is no available detailed accounting readily available.
A Clear Emphasis
The federal government under Operation Warp Speed and NIH-based leadership directing ACTIV have clearly emphasized a focus on industry-initiated efforts that, in the case of vaccines, appear to be headed for what is clearly a historical milestone. Although, as mentioned, the longer-term safety of highly novel-based vaccines must clearly be monitored.
ACTIV has undoubtedly been aware of the dearth of treatment options concerning early-onset, mild to moderate COVID-19 cases. A growing chorus of physician voices calls for attention to mounting evidence for alternative low-cost, widely available and easily administered potential options for both pre-exposure prophylaxis (PrEP) and Post-exposure prophylaxis (PEP).
What follows is a summary of potential candidates that the industry-influenced ACTIV group has gone to great lengths to ignore.
Ivermectin & the Forthcoming Presentation to Senate
TrialSite has chronicled dozens of Ivermectin studies, from case series and observational studies to a few randomized controlled trials. The influential Broward County Health study known as ICON was published in peer-reviewed Chest.
The authors of the ICON study, Dr. Juliana Cepelowicz and Dr. Jean-Jacques Rajter were showcased on the TrialSite podcast show. Dr. Jean-Jacques Rajter will present to the U.S. Senate Committee on Homeland Security & Governmental Affairs in a hearing titled “Early Outpatient Treatment: An Essential Part of a COVID-19 Solution, Part II.” This hearing occurs this Tuesday, Dec. 8, at 10 AM ET.
ICON & TrialSite Influences COVID-19 Critical Care Alliance (FLCCC)
Emerging physician groups such as the Frontline COVID-19 Critical Care Alliance (FLCCC), a group of highly published physicians/researchers, formed as a working group under emergency conditions in response to pandemic outcomes involving patients with inexplicitly high needs for prolonged mechanical ventilation and excessive mortality associated with a prevailing “supportive care only” guideline promulgated by national and international health care agencies and organizations. These physicians sought out answers for not only a growing pandemic but also a dearth of care options for early-stage onset COVID-19. Based on mounting evidence from a myriad of sources, including and importantly, from the efforts of TrialSite News since April, the FLCCC Alliance identified that ivermectin possessed potent real-world, anti-viral and anti-inflammatory properties against SARS-CoV-2, the virus behind COVID-19.
TrialSite covered in real time the group’s recent press conference in Houston, Texas.
Is Industry Economic Return Key Behind NIH-Funded Research?
With sufficient evidence from the accumulation of previously mentioned studies, the NIH/NIAID should now be moving proactively to investigate efficacy via ivermectin-based clinical trials. Why haven’t they to-date? With over $1 billion dollars spent on just three highly investigational monoclonal antibody products for the same purpose, would it be too much to allocate a few million dollars for a potential candidate that could treat millions of people economically?
Some may propose with imminent vaccines in the emergency use authorization regulatory pipeline; there is no need. That, of course, would be an outrageously false claim. After all, the NIH/NIAID just allocated over one billion dollars to one company alone for a highly investigational monoclonal antibody product to satisfy the same goals that FLCCC Alliance targets: those individuals with early-stage COVID-19 that could be at high-risk for disease progression, for example. No, rather, there is a clear bias toward big industry versus any generic-based approaches. Both objectives could be served: pharma companies can be incentivized to invest while generic possibilities are investigated. It’s not an “either-or” false dilemma.
Unfortunately, this hasn’t been the case. The government-backed ACTIV has opted for highly investigational, difficult to administer and access monoclonal antibodies, as they will bring a far greater financial return to the industry than would a cheap, generic alternative. But again, there is good news. They can sponsor both! Key physicians involved with ivermectin research in the United States have communicated that with just a few million dollars well-designed studies could be organized and executed to finally prove efficacy beyond a reasonable doubt.
HCQ: Is there a Case at All?
Hydroxychloroquine (HCQ) has of course become a taboo topic after POTUS improperly touted the drug (by the way, he did the same for the monoclonal antibodies but there was no overt criticism then); however, the studies continue including some successful ones. In fact, the Henry Ford Health System, among others showcased positive results. It was quite interesting that just days after the Henry Ford substantial observational study, Dr. Anthony Fauci quickly moved to squash the study results in front of Congress. Why not have the decency to meet with the doctor-led study first and get their point of view? Read TrialSite’s “Care Providers vs. Feds and Research Establishment: Its Getting Nastier” for more details.
There is no doubt that the evidence for HCQ is balanced in favor of no efficacy; however, many physicians that communicate with TrialSite make the case that many of these studies were flawed. They posit that HCQ studies should center on use in the early stages of the disease and not at the point of hospitalization. The ANTICOV study in Africa may echo this point.
If No HCQ then Why ANTICOV?
What is the ANTICOV study? This major clinical trial aims to respond to the urgent need to identify treatments that can be used to treat mild and moderate cases of COVID-19 early, and thus prevent spikes in hospitalizations that could overwhelm fragile and already unburdened health systems in Africa. Does this sound familiar? Could this be applied in America? Brazil? Or even some parts of Europe?
As it turns out, a lot of smart organizations involved with drug development, affiliated with the Bill and Melinda Gates Foundation as well as the World Health Organization, have come together to organize the ANTICOV study in Africa centering on the early use of HCQ. This study aligns with the WHO framework. Why is the situation different in Sub-Saharan Africa? Why would so many prominent organizations with so many smart people establish HCQ as such a prominent study drug in such an important clinical trial if HCQ was just out of the question?
Favipiravir: Is there an Opportunity Here?
In Russia, India and even China, Favipiravir has been approved on either a permanent or an emergency basis for mild to moderate, early-onset COVID-19. Although there are a few clinical trials going on in the U.S., why hasn’t the U.S. research and health agencies looked closer at the clinical trials that have led to approvals abroad? This now generic drug is already approved in Japan for influenza. Moreover, the U.S. government funded extensive research into this antiviral drug from Japan, even allocating over $200 million in Phase 3 research as recently as 2015. Why aren’t there any disclosures in Clinicaltrials.gov as to the results?
What about PrEP Trials?
Interestingly, physicians communicate with TrialSite that HCQ should have always been used early on as an inhibitor to slow or stop disease progression or as a preventative measure. For example, a group of prominent physicians involved in the early years with the development of HIV/AIDS drugs points out that in addition to the focus on post-exposure prophylaxis (PEP), there should be an emphasis on pre-exposure prophylaxis (PREP) medication investigation using low-cost generics where possible such as HCQ or ivermectin. HCQ has become so politicized at this point, and indeed a number of studies lead to a negative conclusion, but as mentioned previously, a majority of these studies were designed for latter stage usage, which defeats the early-stage use intention. Again the organization of ANTICOV in African raises questions about the use of this drug.
TrialSite News shares information and opinion on an informational basis. The independent and unbiased media platform was founded by technologists that have developed enterprise clinical trial collaborative systems for the largest pharmaceutical sponsors. TrialSite tracks and monitors research around the world with the aim of improving transparency and accessibility. The ultimate goal of TrialSite emphasizes the advancement of value-based care. TrialSite does not offer any medical advice nor any formal interpretation of the COVID-19 Treatment Guidelines, Therapeutic Management of Patients with COVID-19 guidelines for purposes of treatment nor any medical decision: that should only be done so by a licensed physician.