For multi-center, open label clinical trials, can individual investigation sites disclose results from their sites while study is ongoing?

The golden standard for clinical trials is RCT (randomized, control trials) including three key components: randomization, including a control group (preferably concurrent control), and blinding (or concealment of the treatment assignment). The blinding can minimize the biases (conscious or unconscious) introduced into the study by investigators, patients, and the study team.

However, in some situations, blinding is not possible or is very difficult to implement. A randomized, open-label study may be more appropriate. In the randomized, open-label study, while patients are randomized assigned to receive the experimental new drug or control, the investigator, patients, (in some cases the sponsor study team) are aware of the treatment assignment. 

In an early posting "Some Blinding Techniques in Clinical Trial", some blinding techniques can be applicable even for the randomized, open-label study. On the conservative side, the sponsor can follow the same procedures in handling the randomization, open-label study as the double-blind study - i.e., establishing a firewall to keep the sponsor study team or anyone with the capability to do the aggregate analyses and decision making from accessing the data during the study. 

With a randomized open-label study, both site investigators and patients participating in the study know which treatment group the patient is receiving - knowing the treatment assignment itself may cause biases in efficacy and safety assessments, in concomitant medication selection, in subsequent therapy selection,...

In the last several days, we see an extreme case (presumably due to the special situation in fighting the Covid-19 pandemic). In multi-center, randomized, open-label studies for remdesivir, while the studies are ongoing, the individual sites start to disclose the results / experiences from patients in their perspective sites. 

Statnews.com (04/16/2020) Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment  

"The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir."

"The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.

 Komo News (04/21/2020) Experimental anti-viral drug Remdesivir used to treat COVID-19 patients

Dr. Vinay Malhotra said at his hospital, 40 patients have been treated with the anti-viral drug.

According to Dr. Malhotra, 32 patients were in severe condition. 8 were in moderate condition. Of the 40 patents treated, Malhotra said 17 of them have already been discharged.

“Everyone is talking about the discharge of these patients. Everyone is talking about how good the effect is in three days,” Malhotra said. "We were fortunate to be chosen for this trial. And that has helped our population tremendously."

Both the University of Chicago Hospital in Illinois and the Multicare Institute for Research and Innovation in Tacoma, Washington are investigation sites participating in two pivotal clinical trials sponsored by Gilead:

• A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19
• A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment

Both studies (one for severe Covid-19 and one for moderate Covid-19 patients) were designed as randomized, open-label studies with one group receiving Remdesivir (on top of standard of care) and one group receiving standard of care only. According to clinicaltrials.gov, there are 179 and 178 investigation sites for these two studies.

If all sites do the same as the University of Chicago hospital and Multicare Institute for Research and Innovation to disclose their experiences, we could see many reports: some may be good, some may not be very good. The sites with good results may be eager to get their information out; the sites with results not very good may keep silent.

In both of these reports, there was no mention of how many patients in the control group (receiving standard of care) - maybe these patients in the control group are doing pretty well too (unless there are selection biases in determining which patients are allocated to receiving remdesivir or not receiving remdesivir (standard of care)). 

It is not clear if there is an agreement between the sponsor (Gilead) and the investigation sites about disclosing the data while the study is ongoing. Disclosing the data for individual sites while the study is still ongoing should certainly be discouraged or prohibited even in the public health emergency situation. The better way will be that the sponsor designs the study as group sequential design and perform the interim analyses using the data from all sites - if the results are indeed great, the pre-specified boundaries may be crossed and the sponsor may be able to stop the study for efficacy. In this way, the study results may be disclosed earlier while the study integrity is maintained. 

There are already reports that the motive and wrongdoing should be investigated: 

• Congressman calls on SEC to look into leaked remdesivir data: report
• Congressman calls for SEC investigation into leak about possible coronavirus drug

There are also reports that criticize the study design (no adequate control group and no blinding) for Gilead's designed studies: 

The world wants answers on Gilead’s Covid-19 drug. Experts worry next studies may increase uncertainty

 

Gilead's Remdesivir Clinical Trials - What Do Drastic Design Changes Mean?

In the midst of the Covid-19 pandemic, people are rushing to find effective treatments for Covid-19 infected patients. Among the drugs being investigated is remdesivir, an experimental antiviral made by the US drug company Gilead Sciences. It has been characterized as one of the most promising by health authorities, including WHO officials—though that optimism is inspired only by anecdotal information.

There are four randomized, controlled trials with remdesivir that may have the results available in very near term. Two studies conducted in China should have the results available very imminent (before the end of April). Two studies conducted by Gilead itself should have results sometime in May, 2020. 

We noticed that for two pivotal studies run by Gilead, the study design was significantly modified. According to the clinicaltrials.gov, the major changes are listed below: sample sizes are increased; the primary efficacy endpoint is revised, the treatment arms are tweaked.

See the article "Gilead supersizes remdesivir trials, changes primary endpoint".

Protocol Title	Previous Version (before April 6, 2020)	Revised Version (after April 6, 2020)
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19	400 Subjects Two Strata and Three arms: Remdesivir for 5 days versus Standard of care; Remdesivir for 10 days versus Standard of care	2400 Subjects Four Strata and Five arms: Remdesivir for 5 days (Not Mechanically Ventilated) versus Standard of care; Remdesivir for 10 days (Not Mechanically Ventilated) versus Standard of care Remdesivir, 5 or 10 Days (Extension) versus Standard care Remdesivir 10 days (Mechanically Ventilated) versus Standard of care
	Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14 This is a composite outcome measure. Criteria for fever normalization: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours and criteria for oxygen normalization: peripheral capillary oxygen saturation (Sp02) > 94% sustained for at least 24 hours.	The Odds of Ratio for Improvement on a 7-point Ordinal Scale on Day 14. The odds ratio represents the odds of improvement in the ordinal scale between the treatment groups. The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: 1. Death 2. Hospitalized, on invasive mechanical ventilation or Extracorporeal Membrane Oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring low flow supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (coronavirus (COVID-19) related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer required ongoing medical care (other than per protocol Remdesivir administration 7. Not hospitalized.
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment	600 Subjects Three arms: Remdesivir for 5 days Remdesivir for 10 days Standard of care	1600 Subjects Added a fourth arm: Experimental: Part B: Extension Treatment, Remdesivir 5 or 10 days Participants will receive continued standard of care therapy together with RDV 200 mg on Day 1 followed by RDV 100 mg on Days 2, 3, 4, 5, 6, 7, 8, 9, and 10.
	Proportion of Participants Discharged by Day 14	The Odds of Ratio for Improvement on a 7-point Ordinal Scale on Day 11. The odds ratio represents the odds of improvement in the ordinal scale between the treatment groups. The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: 1. Death 2. Hospitalized, on invasive mechanical ventilation or Extracorporeal Membrane Oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring low flow supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (coronavirus (COVID-19) related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer required ongoing medical care (other than per protocol Remdesivir administration 7. Not hospitalized.

It is not clear what these protocol changes are based on: the external data from other studies or the cumulative data to date from these two ongoing studies? The fact is that these two Gilead-run studies are randomized, open-label – unless they treated them as the blinded studies, the Sponsor would be able to see the cumulative data and monitor the treatment effects along the way. 

A dramatic increase in sample size seems to suggest that the treatment effect is much smaller and the previous study design may be underpowered.

It may also indicate that two randomized, double-blinded Remdesivir studies in China will most likely be underpowered as well (308 subjects for study in mild-moderate patients and 453 subjects for study in severe patients). Unless there is a magic or luck, these two studies from China may not be able to reach the statistical significance because of the smaller sample size. We hope that there will be at least some trends - at a time of no effective treatment for Covid-19 infection, a study with a trend will be encouraging news. 

For the primary efficacy endpoint, odds ratio should be more sensitive to detect the treatment difference for the ordinal data - ordinal logistic regression will need to be used to calculate the odds ratios.