Research at Romark: A cautionary tale for clinical research sites about Sponsors whom are unable to pay

By Ilene Schneider with Dan Sfera, and Chris Sauber

While people know about the COVID-19 vaccines that have gotten FDA approval, there have been other attempts to create drugs for people who already have the disease. One candidate comes from Romark, a research-based pharmaceutical company that concentrates on the discovery, development and delivery of innovative new medicines, primarily in the field of infectious diseases.

Last summer (2020) Romark announced the launch of a Phase 3 clinical trial of its investigational new drug candidate NT-300 (nitazoxanide extended-release tablets) as a treatment for mild or moderate COVID-19. NT-300 is being investigated as a broad-spectrum antiviral medicine to treat and prevent viral respiratory illnesses caused by seasonal, emerging and drug-resistant viruses, including COVID-19.

According to the world renowned scientist and key principal at Romark,  Jean-François Rossignol, M.D., Ph.D., Chief Medical and Scientific Officer, “As the COVID-19 pandemic continues to take a toll on our collective health, economy and well-being, we are pleased to broaden our NT-300 COVID-19 clinical program through the initiation of a third trial evaluating NT-300 as a treatment in addition to our two ongoing prophylactic trials. Along with vaccines and treatments for severe illness, oral treatments that can be given outside of a hospital setting to prevent infection or used as soon as symptoms appear to reduce the duration of illness and prevent hospitalizations are desperately needed. Given the broad-spectrum antiviral properties of NT-300, this research is an important step in our understanding of its potential impact on COVID-19 in its early stages.”

According to Romark, in cell cultures, the active ingredient in NT-300, nitazoxanide, inhibits replication of a broad range of respiratory viruses, including the SARS-CoV-2 virus that causes COVID-19. Nitazoxanide has also been shown to inhibit replication of SARS, MERS and other coronaviruses as well as influenza viruses, rhinoviruses, parainfluenza viruses, RSV and other respiratory viruses in cell culture studies. The broad-spectrum antiviral activity of nitazoxanide is attributed to its interference with human cellular pathways that the virus exploits to replicate, rather than to a virus-targeted receptor.

Nitazoxanide, the active ingredient of NT-300, was originally developed for treating intestinal protozoan infections caused by Cryptosporidium parvum and Giardia lamblia. Laboratory studies demonstrating broad-spectrum antiviral activity led to the development of nitazoxanide as a broad-spectrum, host-directed antiviral drug.

Laboratory studies to evaluate the potential for resistance of influenza A virus to tizoxanide have been unable to select for resistant viruses, suggesting a low potential for viral resistance. Other studies have shown that tizoxanide suppresses secretion of pro-inflammatory cytokines that are upregulated by viral respiratory infections. The antiviral and anti-cytokine activities of nitazoxanide are attributed to modulation of mitochondrial function and consequential effects on cell signaling pathways.

NT-300 (nitazoxanide extended-release tablets) is an investigational broad-spectrum antiviral drug undergoing Phase 3 clinical development for treating and preventing acute respiratory illnesses caused by a broad range of seasonal, emerging or drug-resistant respiratory viruses, including influenza viruses, rhinoviruses, other enteroviruses, coronaviruses, parainfluenza viruses, respiratory syncytial viruses (RSV), human metapneumovirus or bocavirus. The NT-300 tablets, administered orally, are designed to deliver antiviral concentrations of drug to the respiratory tract throughout twice-daily dosing.

The multicenter, randomized, double-blind trial was designed to study as many as 800 people twelve years and older with fever and respiratory symptoms consistent with COVID-19. These participants were to be given either NT-300 or placebo twice daily for five days. Efficacy analyses were to examine those participants who have laboratory-confirmed SARS-CoV-2 infection. The primary endpoint is a reduction in the time to sustained response (a measure of recovery time) compared with placebo, and the secondary endpoint is a reduction in the rate of progression to severe COVID-19 illness compared with placebo.

As previously mentioned, in 2020 Romark started two Phase 3 clinical trials for the prevention of COVID-19 and other viral respiratory illnesses in high-risk populations, including elderly residents of long-term care facilities and healthcare workers. Romark hopes to share results from these studies but as of the time of this writing these results have not been released. 

Around the 3Q of 2020 the authors were fielding inquiries from several newer Investigative sites asking if it "was normal" for Sponsors to not pay for work that they have completed and data that had been monitored and entered.  Several months later, the volume of similar inquiries the authors had been getting regarding Romark became larger.  Stories of "getting the run around" began to abound amongst Sites who would contact Romark to inquire on study payments, and "carrot on the stick" responses from Romark began to become a common theme.  One anonymous source told us "whenever we would call Romark to ask about a payment, we were told that it would be coming in 2 weeks and to please continue to enter the data" and Romark also told the same source, "We have more studies in the pipeline and are securing funding from investors so let's stay the course".  Apparently, we  were not alone.  Romark had partnered with a reputable study broker prior to the study initiations and this study broker selected sites for Romark to utilize for the studies.  About half of the sites not affiliated with this study broker also received the study opportunity directly from Romark.  "What was interesting about this study was how good the budget seemed as well as the large volume of patients that needed to be enrolled", an anonymous source told the authors.  Furthermore, this was a study desperately seeking patients for an obvious urgent COVID-19 treatment indication and because of this, lesser experienced sites, some for whom this was their first study, were given the opportunity to participate.  This was potentially great news for these Sites, until you consider the fact that they were required to: staff their sites with appropriate personnel, purchase PPE for site staff, pay the study volunteers upfront for their study visits (70-100 USD per visit), run advertising campaigns to drum up more interested study participants, and compensate their high-priced medical doctors and nurses for their time, all on their own dime!  As the budgets were better than average, and enrollment competitive, sites were in a mad rush to enroll as quickly as possible, incurring massive expenses along the way.  Needless to say, this reputable study broker got caught in the middle of a study sponsor that was not willing (or able) to pay and the sites (and study broker itself) that were getting fed up with the same excuses. 

This brings us to the virtual "townhall meeting" that Romark CEO, Marc Ayers hosted on Thursday April 8, 2021 with solely the investigative sites that are part of the reputable study broker's clients.  Why ALL of the sites, regardless of how they got the study, were not invited is rather telling to the authors.  It is apparent that the reputable study broker has clout and was able to convince the CEO of Romark to host this event.  The theme of the call was for Romark to attempt to reassure the sites (or at least those that are part of the reputable study broker network) that financing is "getting finalized" and "payments should be sent out in a few weeks".  Does this mean that other sites are not worth reassurance?  Does it mean only study broker network sites will be paid?  This decision probably raises more questions than it was supposed to answer.

One of the authors' site owner sources attended the virtual event and provided the following summary word for word:

CEO of Romark, Marc Ayers, held a teleconference on April 8th, 2021 to discuss the lack of payment, for work rendered on a Romark COVID study, to study sites within the XXX study site network. There are many other study sites, working for Romark on this COVID study, but they were not invited to this teleconference. The main purpose of this teleconference was to reassure study sites they would be paid for their work on this COVID study. However, this has been an ongoing promise, by Romark, to ALL study sites working on this study for the last six months.  It has been a continuous mantra of Romark executives and representatives, study sites will be paid within the next three to four weeks. Marc Ayers continued with the mantra and espoused this same time line to those attending the teleconference. One individual from a study site asked, "why is this time any different than all the other previous promises?" Marc Ayers response, "all the previous promises of payment were in good faith but external financing fell through and financing has now been secured from other sources and all XXX study sites will be made whole within three to four weeks' time." A follow up question was asked, will study sites not in the XXX site network be paid? Marc Ayers initially hesitated to respond but after a bit of stuttering, assured those in attendance that all study sites would be paid what they were owed.

Whether any sites get paid when the dust settles is almost beside the point.  There are a few take away lessons from this situation that all Sites can implement if ever needed:

1.) Understand the study sponsor's financial situation as best as you can: Thankfully, most study sponsors are publicly traded companies.  This means that they have access to the public markets and do not typically rely on private investors to finance their clinical trial costs.  In the 2008 Great Recession, there have been a few situations where many public biotech companies lost market cap, got delisted from the stock exchanges and went bankrupt.  Although even during that time this was not a common occurrence, this did end up putting some Sites out of business.  Sites should be extra cautious when dealing with a non-publicly traded study sponsor as trials are unbelievably expensive, and financial planning should not be an afterthought as it apparently was in the case of Romark.  If unsure about the company's financial stability, a simple Dun & Bradstreet check would suffice.  Running Romark through this check would yield a resounding "high risk" status. Even a simple Google search would have revealed an article stating the company could not pay rent for one of it’s facilities and was in the process of getting evicted.

2.) When dealing with extraordinarily late payments from study sponsors, a tactic of last resort for Sites has often been to "hold data hostage".  Sponsors pay sites ultimately for one thing: study data.  Holding this until payment is received is one way of expediting the process.  Other slightly less dramatic options have popularly been to restrict CRA access to conduct interim monitoring visits until overdue payments have been made to Site.  It is important to understand that these tactics should never come as a substitute for attempts at effective communication between the Site management and sponsor or CRO study team.  Soft skills still should be the default, and aggressive strategies should rarely, if ever, be utilized. 

Those are some Site takeaways, that in the authors' opinions, should at least be looked into by all Site management teams.  A possibly more interesting question in regards to these types of situations should be considered by industry in general: should regulations exist to preemptively reduce or eliminate these types of financially unprepared or mismanaged study sponsors?  Should standards be set up to ensure financial solvency and ability to finance the study being submitted to the FDA?  Does industry owe this service to study participants who also end up being victims in these situations?  If Sites are not generating revenue because of a study sponsor not honoring the clinical trial agreement, they have two options: eat the bill themselves and allow patients who are doing well in the study to complete the trial, or discontinue all subjects regardless of health outcomes in order to remain financially viable themselves for the long run.  Do we as an industry want to deal with these kinds of issues, even if they are not very common, or should we do something about it?  Definitely questions to ponder as we enter what is seemingly going to be a decade of "long tail" study opportunities and record number of trials from new sponsors globally.