What a Data Monitoring Committee Does
With each clinical trial, an independent committee is formed to monitor the conduct and progression of the trial and to determine if there are any safety or efficacy issues that might necessitate stopping the trial. Members are distinguished physicians, statisticians, academics and other health care personnel knowledgeable about conducting and monitoring clinical trials. The members are not employed by companies and are not compensated by companies. This important group is called the Data Monitoring Committee (DMC).
During the conduct of a clinical trial, the Company and all other people with the exception of the DMC members are blinded to the data. If the blinding were to be broken, it would be perceived by regulatory agencies as compromising the integrity of the trial. If this were to happen, the study could not be used to file for regulatory approval. Regulatory agencies are fanatical about making sure that all people except for the DMB members are completely blinded to results.
Most trial protocols prospectively define points in the trial at which an interim analysis is done to determine safety and efficacy results. The trial can be stopped at any time if a safety reason arises, but the efficacy analysis is only done at pre-determined interim looks. The DMC at an interim look reviews the clinical data and usually makes one of four recommendations: (1) the trial should be halted because the primary endpoint of the trial has been reached; this would lead to filing for registration, (2) the data suggests that the primary outcome of the trial cannot be reached and that it would be futile to continue; the trial should be stopped, (3) because of safety issues the trial should be halted immediately, and (4) there are no issues with safety and efficacy; the trial should continue. I would note that point 4 being reached does not mean that the trial will be successful.
It is usually the case with interim looks of clinical trials that the DMC says that there are no safety or efficacy issues and that the trial should continue. Under no possible circumstances would there be any release of clinical results from the trial and under no circumstance would there be any hint given on how the data is trending. As was just noted, the release of such information would immediately compromise and ruin the trial.
The DMC is the only entity that has an insight into what is going on in a clinical trial. Their grave responsibility for making sure the trial is being safely conducted and their independence means that they are the only credible source of information on what is going on in a clinical trial.
Recent Investor Confusion
There has been a lot of speculation on what is going on with the DCVax-L trial on blogs by people holding a bearish view on the stock. Based on comments from the chairman of the DMC, key elements of their bear arguments appear to be factually incorrect. They essentially maintain that an interim look at the phase 3 trial was performed and that the interim analysis showed that DCVax-L was performing badly and they concluded that the trial was doomed to fail. They further suggested that NWBO management had seen the efficacy results and knowing that they were disappointing had changed the design of the clinical trial. I would refer you to article one and article two which express this viewpoint.
The Chairman of the DMC Speaks on the Phase 3 Trial of DCVax-L.
Some of the key conclusions reached in the above cited blogs are incorrect in the opinion of the DMC. Apparently, the comments by these authors came to the attention of the Chairman of the DMC. In a recent press release by Northwest Biotherapeutics (NASDAQ:NWBO), he explained why these authors were wrong in maintaining that an efficacy analysis had been done and that NWBO knew the results were bad. It is highly unusual for a chairman of the DMC to make a public statement, but in this case he felt compelled. Here is what he said.
"As the Company has stated clearly and specifically in its public announcements, the DMC has not conducted any efficacy analyses and the DMC has not provided any access for the Company to any clinical trial data. The DMC adheres to established clinical trial monitoring procedures and does not release any data while the trial is ongoing. This is an important issue, and it is surprising and troubling to see inaccurate claims being made by commentators who seem to lack a fundamental understanding of clinical trial monitoring. I have been on the DMCs for more than 60 clinical trials, and I have never experienced this type of attack."
There are a significant number of bears on NWBO. One of their key arguments is that the interim analysis on efficacy was performed and they question why efficacy results have not been released. They maintain that NWBO somehow buried the data. These issues are directly addressed and rebutted by the comments of the chairman of the DMC. Just to summarize, there has been no efficacy analysis performed in the trial. Also, NWBO has no knowledge of the trending of results in the trial.
Why the Confusion
Part of the confusion was caused inadvertently by the Company. The original protocol of the trial called for it to be halted and data analyzed after 110 events; i.e., 110 patients in the trial with glioblastoma multiforme either died or saw their disease progress. The first interim look for safety and efficacy was scheduled when 60% of these 110 events or 66 had occurred. In March of this year, the Company announced that it was about to reach the number of events needed to conduct the first interim look for safety and efficacy. Hence, investors were awaiting the results of this interim look.
At about this time, the Company made another decision to slightly change (they called it enhancements) the protocol of the trial. These enhancements were to allow for a statistical adjustment on dealing with the risk factor of white blood cell levels at the time that the final statistical analysis is done. I won't go into a lot of detail, but this type of analysis was previously specified in the statistical analysis plan for other risk factors in the trial including age, degree of surgical resection and performance status. Hence, the risk factor of white blood cell count was added to the list.
The size of the trial was increased from 312 patients to 348. Also, the number of events needed to halt the trial was placed at 248 up from 110. I am not a statistician and I cannot explain the statistical reason for these changes. All I can say is that the UK, US and German regulators reviewed and approved the changes. I think we can assume that the basis for these changes are statistically and clinically sound based on the approval by the regulators.
The complication and confusion about the interim look arose from the Company seeking approval for these enhancements. Remember that I previously said that regulators are fanatical about making sure that the trial is totally blinded. It was possible that the regulators could perceive that performing the interim look at 66 events had the potential to convey information about efficacy results in the trial and therefore would have potentially unblinded the trial. This might have prevented their acceptance of the enhancements to the trial design.
Because of this and as verified by the Chairman of the DMC, performing an interim efficacy look at 66 events had the potential to compromise the blinding of the new enhanced trial design. Therefore, they did not perform an interim analysis for efficacy. The first interim analysis on efficacy will now be performed at 60% of 248 events or 149 events. The DMC has not issued any information on whether the trial is close to 149 events.
The Company was in a difficult position. They could not anticipate that the enhancements to the trial would be approved and had to wait for the regulators decision. They felt that they could not directly address the issue of whether the interim efficacy analysis had been conducted until the enhancements to the trial had been approved. This left them open to the bear arguments that I previously discussed.
I can partially understand the criticism of the bears that the interim safety and efficacy data had been indicated as being imminent and never materialized. However, the extensions of their arguments that maintained that NWBO had seen the data, that the data was bad and that they were hiding the data from the public were clearly wrong from the beginning.
None of this information has much of an effect on my investment thinking on the fundamentals of NWBO. I view the potential development of DCVax-L as high risk which is the case for most paradigm changing technologies. However, there is evidence of efficacy in phase 1/2 trials and compassionate use studies of DCVax-L. There form the basis to hope for success and if confirmed in the current phase 3 trial DCVax-L could be a significant advance in the treatment of glioblastoma. However, I must emphasize that there is also a risk of failure.
The importance of this article is not what it does to my investment view as it really hasn't altered my thinking in a meaningful way. Please refer to several prior articles on Seeking Alpha for a detailed discussion of my investment thinking. However, by negating a meaningful component of the bear case, it could improve the psychology surrounding the stock and potentially its performance.
Disclosure: The author is long NWBO. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it. The author has no business relationship with any company whose stock is mentioned in this article.