A Journey: Biotech, FDA, and Safety Committee Responses to COVID

While the COVID-19 pandemic has impacted numerous clinical trials, some biopharmaceutical enterprises have adapted their medical products and have applied them towards COVID. What is particularly interesting about this interview with Sudarshan Hebbar, CMO of CalciMedica, is that it reveals how the FDA, ethics committees and safety consortia have responded to helping to advance the application of novel therapeutics towards COVID.

Moe Alsumidaie: How has COVID impacted your clinical programs that are currently underway, and what has happened as a result of COVID?

Sudarshan Hebbar

Sudarshan Hebbar: Initially, our program was geared at treating patients with predicted severe acute pancreatitis based on the presence of systemic inflammatory response syndrome (SIRS) and hypoxemia. We were planning to start a Phase IIb trial after working with the FDA and finalizing the protocol when the pandemic hit the United States. Several patients with acute pancreatitis also present with respiratory failure and acute respiratory distress syndrome (ARDS), areas where we had observed signals of efficacy—lowering IL-6 levels, protection of respiratory function in these patients—and our investigators thought it would be a great idea to test our drug in COVID-19. The first thing that we did was make a rapid pivot in our development program, requiring us to work with different divisions of the FDA. The acute pancreatitis program was being overseen by the division of pulmonary and rheumatology products. We had to file the IND with the division of antivirals and what I always tell people is that the FDA has been great to work with—within ten days of us filing the IND, we enrolled a patient in the clinical trial.

During this time, we worked closely with the FDA to get the protocol up and running very quickly. As we started the clinical protocol and the study, what happened was interesting. Since Auxora has a novel mechanism, a lot of the IRBs that we worked with wanted us to do an open-label trial in case there were any drug-related serious adverse events (SAEs). This way, the doctors would know immediately if an SAE was related to our drug. We were also told by IRBs to be careful because we gave an immunomodulator to patients who potentially had severe immune dysfunction. We ended up setting up an independent safety review committee to look at the data very closely. After only the first day, we had patients enrolled in the trial, and 12 had been treated with our drug, and six had been assigned to standard care when they conducted their initial safety review.

The Safety Review Committee gave us the go-ahead to keep going, and the FDA also asked to see some of the data because they, too, were concerned about the potential issues of using immunomodulators in a viral infection. We shared the data with them, and by the time we heard back from them, we had increased enrollment from 18 to 30 patients. They wanted us to stop enrollment in the open-label trial and transition to a blinded trial. We took that to mean that they were impressed with the data and wanted to see more.

We then worked with the FDA on rewriting the protocol to make sure that we met their needs. We also got their permission to publish the data and went through a peer-review process that resulted in a publication in Critical Care, and notably, this study is one of the few that is randomized and has been peer-reviewed. The other thing that has been helpful for us in this transition is that the RECOVERY trial came through, and we knew that our drug would be beneficial in combination with other drugs or an immunomodulator.

We have a particular mechanism of action, and when dexamethasone and Remdesivir came to be used and shown to be effective in patients, we started to recommend it to all our sites. We believe that antivirals plus the steroids are great to use in combination with our drug. The FDA has allowed us to be flexible in changing the focus of our development program, they’ve worked well with us on that, and I think that this is the real key to protocol development and clinical trials here, the ability to be rapid and flexible in how things are done.

MA: Do you predict a difference in enrollment rates in part two of the trial?

SH: Yes, so previously, the pandemic was starting. Nobody knew what was going on, so we enrolled very rapidly. We enrolled 30 patients at three sites in less than a month. We believe that things may change now in that the patients may be a little different. They may be much younger patients who may not have the same degree of respiratory failure. So, I think clinical trial enrollment will be more challenging in this stage of the COVID-19 pandemic.

MA: Many clinical trials are now going into decentralized modes where all study operations are being done remotely. How are you approaching that in your COVID protocol?

SH: We’ve incorporated decentralization since the beginning of the study and have followed up with patients by telephone. Clinical research associates (CRAs) follow up with the sites remotely through their electronic medical records (EMRs). We haven’t physically been to any of our sites. Everything has been done remotely through telecommunications, and this includes communications with patients. By law, patients can now provide consent with electronic signatures. At one of our sites, patients sign a consent form on an iPad, and the IRBs have approved that as a means by which patients can provide consent. The study coordinator doesn’t go in the room, and they can handle the entire consent process electronically.

We’re working with a contract research organization (CRO), and we have a small number of sites activated, and we plan to activate 40 sites throughout the course of this part of the study. What we’ve worked with the sites on is the ability to access their EMR remotely, and if they don’t provide remote access to their EMR, we ask them to provide remote access to the data so that CRAs can then verify the data and do the quality checks of the data. Electronic communication with the sites is the norm for us now, and electronic oversight of the data, that’s of the source documents, is also the norm now. We haven’t had a CRA or any of us enter a site. All study operations are now being done remotely.

MA: What study endpoints are you focusing on right now, and how have you incorporated the study design to help achieve those endpoints?

SH: We’re taking the sicker patients, the ones who have respiratory failure. The endpoints are hospital-focused. Time to recovery is the endpoint that the FDA asked us to look at using their ordinal scale, the same scale that Remdesivir already used, and that’s going to be the primary endpoint.

The secondary endpoint, which we think is a significant endpoint, is the composite endpoint of death or mechanical ventilation. So, can we keep people off the vent, and can we prevent them from dying? And that’s what we saw in part one of the trial, that the drug is doing remarkably well. If we see the same results in part two of the trial, we think that this will be a significant advance in the treatment of patients with respiratory failure, and so the endpoints will be mainly hospital driven.

MA:What’s next, and what about global expansion? Do you plan on running studies in Asia?

SH:We hope to get an emergency use authorization, and we plan to incorporate this study into a general ARDS program. So, we would go back to the pulmonary division, do a second study, as mentioned with all causes of ARDS.

In terms of global, yes, we’ve thought about that. Being a small biotech company, we started in the United States. We knew everybody here, and we didn’t have the resources to go globally, but if part two of this trial goes well, I think it will be easier at that point to raise the required resources to take this global then.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.