For the last 2 years I have been working with an excellent team, aiming to begin enrollment in a new clinical trial in January 2022. A clinical trial is when someone (or, really, a large group of people) try to determine if a new intervention (a medicine, a new type of surgery, a new way to educating someone) is superior to treatments already in use. In the clinical trial we will start in 2022, the intervention will be used in addition to standard of care therapies; in medical-speak we say it is “adjunctive.” We are testing this new adjunctive drug in Malawian children with cerebral malaria.
Long term (perhaps 10-12 years from now) we will hopefully do a future clinical trial to see if the drug we are testing (6-diazo-5-oxo-L-norleucine, also known as DON), saves lives. First, though, we must prove that DON is safe to give to these critically ill children. Clinical trials that prove safety are termed “Phase I.” So, to sum it up, we plan to start a Phase I clinical trial of adjunctive DON in pediatric cerebral malaria early in 2022.
Doctors cannot simply proceed with a clinical trial that they believe is a good idea without oversight. There are several groups from whom we must obtain approval. Before we give DON to anyone in Malawi, we must obtain approval from a Malawian ethics board (which we have completed) and the Pharmacy and Medicines Regulatory Authority (PMRA), the Malawian regulatory body that assures that medications imported into the country (including those used in clinical trials) are being used ethically. PMRA will conduct a rigorous review of all known information about DON: how it is manufactured and previous uses in animals and humans. I will submit our application to PMRA this week; it is almost 500 pages long.
Doctors cannot simply proceed with a clinical trial that they believe is a good idea without oversight. There are several groups from whom we must obtain approval.
In addition to the Malawian ethics board and PMRA, there are 3 American regulatory agencies involved in the DON clinical trial. One of these is the National Institutes of Health (who have already approved and are funding the study). The second is George Washington University, where I am an Associate Professor. The third is the United States Food and Drug Administration (FDA). The first two are required, but approval by the FDA is optional.
The FDA was established in 1930 to safeguard the United States from unsafe food and drugs. Lately, the news is filled with mentions of the FDA’s Emergency Use Authorization or Full Approval. The DON project is not nearly there. If our group decides to involve the FDA in this clinical trial, it will be by filing an investigational new drug (IND) application with them. Sound easy, right?
Submitting an IND is very complicated.
An IND submission is thousands of pages long and details everything that is known about a drug, including all previous use in animals and humans. It includes every detail about how the drug is made, optimal storage conditions, and how long the drug remains potent while sitting on a shelf (or in a refrigerator or freezer). The FDA then analyzes whether what is known about the drug is sufficient to ethically administer it to humans. The process of IND submission is often handled by experts in the language, jargon, and complexities of the FDA. Often, these experts are employed by Contract Research Organizations (CROs). The NIH went through a long process to find a CRO to work with the team in Malawi on the DON clinical trial. Hundreds of emails were sent, many dozens of documents created and edited. After a yearlong selection process, the CRO was identified. We had several meetings to discuss the project. All was going on track until the CRO submitted their bill for the 5-year study. It was 30-50 times what it should cost, almost double the cost of the clinical trial itself. Ridiculous. After months of back-and-forths, final and last offers, hundreds of emails, and dozens of meetings, the CRO was told their services would no longer be needed. Fortunately, someone was watching out for the American taxpayer.
Since then (3 weeks ago) we were back to Square One with getting the IND submitted to the FDA. The consensus of our research group is that, even though the FDA has no jurisdiction in Malawi and their involvement with DON is optional, it would be optimal to have their oversight. But is that preference grounded in any fact?
In my opinion, the FDA’s involvement is redundant to the Malawian version of the FDA, known as PMRA. Is wanting to have the FDA involved an example of America First, or (more bluntly) “the FDA knows better than the Malawian PMRA what is safe to give to Malawian children?” The Malawian review process is rigorous. I am certain that PMRA has smart, thoughtful, intelligent people working for them, people who are just as smart as those working for the FDA. Are we being elitist in our desire to have the United States FDA involved in this clinical trial?
Conversely, we know that if this clinical trial—performed by a US doctor and funded by the United States government—were held in the USA or Europe, it would require the submission of an IND. Would skipping the FDA’s involvement be an example of not providing social justice to the children of Malawi?
