Bolster your reporting with a basic grasp of the path from molecule to medicine

How is it supposed to work?

That’s the question that one of my former editors used to ask when one of us went rushing in with some supposed wrongdoing scribbled in our notebooks.

If we were saying something had been done wrong, then how was it supposed to be done right? Was there a law being broken? If not a law, then some other generally accepted guideline or practice that could be well defined and explained to our audience?

Those were the questions that kept running through my head as I was researching my post about chemicals that are essentially ignored by the state and federal agencies charged with protecting the public’s air, water, and food. And so when you see something as a journalist that appears wrong but for which there are no applicable laws or regulations, you can start by asking the question: How is it supposed to work?

There are whole classes of chemicals that are heavily regulated and that many of us ingest every day: medicines. The process a company goes through to produce a chemical that becomes a medicinal product is night-and-day different from what happens to a company that produces a chemical that ends up being dumped into the water we drink or spewed into the air we breathe

In the midst of the COVID-19 pandemic, more of us than ever before are focusing on how quickly drugs can get approved. Will there be a vaccine before the holidays so we can all get on with our lives? Will our kids get to spend at least part of the school year in a classroom?

The typical story of a molecule on its way to becoming a drug spans more than a decade, not the mere months people are hoping it takes for a COVID-19 vaccine to arrive. Because it can be so difficult to find a clear explanation of the pathway from molecule to medicine, I spent some time researching it and will try to break it down as simply as possible below. (My thanks to the following sources for their work in explaining the various steps of the process: the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Pharmaceutical Journal, FDA Review, Clinical Research Pathways, and the FDA itself.)

Laboratory testing: two to three years. Before a chemical (a drug is a chemical substance) is ever tested on a human or animal, it is tested in a laboratory to understand its basic components and how it reacts under different conditions. “As many as 10,000 compounds may be considered and whittled down to just 10 to 20 that could theoretically interfere with the disease process,” Ingrid Torjesen wrote in the Pharmaceutical Journal. “The next stage is to confirm that these molecules have an effect and that they are safe.” Imagine if the thousands of chemicals that non-pharmaceutical companies dispose of in the water and air every year had to go through this kind of testing just to understand how they behave?

Animal testing: three to four years. Most drugs are tested on at least two different animal species. “A drug may not be toxic to rats but may be toxic to guinea pigs, and, by using two different species, the chances are greater that the toxicity of a drug will be discovered before it is ever given to a person,” wrote the National Institutes of Health in a publication on animal testing. What are they testing for? Whether the chemicals change the genetics of the animals, whether they cause cancer, whether they make the animals infertile, and whether they cause birth defects, among other things. What if the chemicals that non-pharmaceutical companies freely dispose were forced to undergo testing even just to find out whether they cause birth defects? You might recall that Dupont was taken to task by the EPA in part because it had dumped chemicals into community waterways while knowing they caused birth defects in humans.

Phase 1 Trials: One to two years. The focus here is safety. How much of a chemical can be given to a person without triggering a negative side effect? Pharmaceutical companies recruit a small group of people to knowingly take the drug and then those people are closely monitored to see what happens as a result. About two-thirds of the drugs make it out of Phase 1 trials. “As this Phase is typically conducted for safety testing and is not dependent on efficacy results for candidates to advance, it is common for this phase to have the highest success rate among the clinical phases across most categories,” wrote the Biotechnology Innovation Organization.

Phase 2 Trials: Two to three years. Now the chemical candidates start to get winnowed down significantly. The success rate is cut in half. Only about 31% of the drugs tested in this phase will move to the next phase. This is because the focus changes from safety to efficacy. We may consume a lot of things that are relatively safe, especially in low doses. But do they actually make us healthier? Finding out the answer to that question is harder than you might think. And the answer might ultimately get lost because of the way the trial is designed.

“One of the most troubling and potentially avoidable consequences of a Phase 2 failure is that a useful compound is terminated and not further developed because the clinical trial was not appropriately designed,” a group of researchers wrote in the Journal of Allergy and Clinical Immunology. That’s one of the reasons the trials grow in size in this phase, often approaching 100 people. It’s sometimes referred to as “powering” the trials. If you don’t have enough people in the trial, you might not be able to detect a health effect. If you have too many people, you might get a lot of data but not a lot of helpful information.

Phase 3 Trials: Three to four years. Now the size of the trial grows from under 100 people to more than 100 and often into the thousands. This is usually what non-scientists think of when they are talking about a clinical trial. The gold standard is the randomized clinical trial. “Randomization, in which people are assigned to groups by chance alone, helps prevent bias,” wrote the National Cancer Institute. “Bias occurs when a trial's results are affected by human choices or other factors not related to the treatment being tested. For example, if doctors could choose which patients to assign to which groups, some might assign healthier patients to the treatment group and sicker patients to the control group, without meaning to.”

Regulatory Review: One to two years. In the U.S., this process is handled by the FDA. Companies have to make their case to the agency. There’s no guarantee that a drug will be approved at this stage. Most of the drugs that began clinical trials will not become approved drugs. Only between 10% and 14% of drugs that enter clinical trials will become approved drugs in any given year. That means that as many as 90% of the drugs will end up being kept off the market. What does that tell you about the safety and efficacy of most chemicals being considered for human consumption?

Even after a drug is approved, companies are required to continue monitoring the safety of the drug in the market. It’s why sometimes drugs are pulled from pharmacies and store shelves because of dangerous and even fatal side effects that were not revealed during clinical trials.

So, in answer to “How is it supposed to work?” you might answer that all of these chemicals that are being put into our air and water should go through similar levels of scrutiny. That does not currently happen. It does not have to be all or nothing, either. At this point in history, any review of any of the thousands of chemical compounds that are entirely unregulated would be a step forward.