To get my children to finish their broccoli, I tell them that I experiment on people.

That is not far from the truth, as I design and run clinical trials for a pharmaceutical company.

To develop new medicines, we need to understand how they work and how they may cause trouble. There are many steps in this process, the last of which is testing these medicines in people as part of a clinical trial.

This is not an entirely benign proposition for potential subjects. More often than not, new medicines tested in clinical trials are not effective in treating the disease. Worse yet, they may not be sufficiently safe compared to currently approved medicines—if any.

To protect the participants in clinical trials, there are many safeguards.Beyond the study sponsors (companies, charitable foundations or government agencies) and investigators themselves, these include regulatory agencies such as the FDA, and Institutional Review Boards (IRBs). Before anything can happen to any potential subject, all of these groups review the detailed plans for conducting the trial (the protocol) and the disclosure of the potential benefits and risks (the informed consent form, or ICF).

Unique among groups charged with safeguarding subjects are “Data Safety Monitoring Boards” (DSMBs), sometimes called “Data Monitoring Committees” (DMCs). These committees do more than review the study plan; they actually have access to the results of the clinical trial as it is happening. In fact, DSMBs often have access to unblinded data that are not available to study investigators, sponsors, or even the subjects themselves.

And using these data, DSMBs are charged with actively intervening in the conduct of the study. The kinds of interventions that DSMBs may perform in a study can include such things as changing how subjects are monitored, or even halting the study entirely. This is indeed a heavy burden of responsibility, and members of the DMSB ought to take their role quite seriously.

Typically, the structure and composition of DSMBs are part of the arcane rules around the conduct of clinical trials, and hardly of interest to most people. However, with the high profile trials of SARSCoV2 vaccines underway, the term “DSMB” has “gone viral”, in this thread, for example.

There are many ways in which DSMBs may be structured, but they ought to have certain characteristics:

1/ The experience to expertly assess safety, efficacy or overall conduct of a clinical trial,

2/ The ability to make decisions with some degree of independence from the sponsors, investigators, others involved with the trial, or other influences,

3/ The skill to balance the scientific integrity, subject safety and interests of the general public.

Each of these characteristics deserve some further description.

Expert assessment on the part of a DSMB is driven by subject matter expertise and statistical acumen. What is the appropriate expertise? In the case of SARSCoV2, we hope to see Infectious Disease specialists, drug safety experts, and statisticians familiar with the design and interpretations of clinical trials. Are others needed? Cardiologists, of course. But how about virologists, bioethicists or epidemiologists? Maybe. Without knowing who is on the DSMB, we can’t say. Many DSMBs are also chartered to obtain outside council if deemed necessary. And if my experience with committees is representative, more members don’t always lead to better decisions.

Good quality of decisions by DSMBs are certainly influenced by the freedom to make them. To that end, the FDA guidance stresses the importance of DSMB members not to have conflicts of interest. Is it a conflict of interest that the DSMB members are paid by a company? It certainly could be. However, as the FDA guidance states,

“Independence is defined on a continuum. DMCs are rarely, if ever, entirely independent of the
sponsor, as the sponsor generally selects the members, gives the committee its charge, and pays committee members for their expenses and services. Aside from being compensated for their duties as DMC members, however, we recommend that these members generally have no ongoing financial relationship with a trial’s commercial sponsor and not be involved in the conduct of the trial in any role other than that of a DMC member.”

Being able to balance the scientific and ethical questions within a trial with those coming from without requires maturity and experience. Early in my career, I was advised by my mentors to find DSMB members with long-standing DSMB experience. A catch-22 to be sure, but advice born of its own sort of experience. To the novice DSMB member, safety signals can often be confused with noise. Early suggestions of efficacy may merely be due to the play of chance or from subtle influences of how large clinical trials are run. As examples: Where are the first sites? Are the early enrollees truly representative of the planned study population?

With the outsized importance of safe and effective vaccines for SARSCoV2, every element of the ongoing studies is under the microscope. And unlike clinical trials of, for example, anticoagulants in patients with cardiovascular disease, the vaccine studies have two big differences:

1/ The vaccine study subjects are healthy, so even minimal risks are potentially significant, and
2/ Vaccine efficacy may be more than preventing COVID in study subjects, but preventing the spread of SARSCoV2 within the general population.

These considerations add complexity to any discussion of safety, efficacy, or conduct of a clinical trial. It may be that a larger DSMB would be in order, or that a single “super committee” would monitor many of the leading vaccine trials, such as under the Operation Warp Speed. These are fair questions, but it behoves us to ask them only after doing our homework…

Or at least pleading ignorance.

At the end of the day, the public needs to have confidence in the process by which SARSCoV2 vaccines have been developed and tested. Are DSMBs important to that process? Absolutely. And we should definitely keep observing everyone involved—companies, regulators, and Twitter commentators alike.

Angry Cardiologist is a cardiologist working in drug development, and may be reached on Twitter at @AngryCardio.

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