Last updated on February 7th, 2023 at 02:35 pm
There seems to be a myth, often promoted by your favorite anti-vaxxers, that once a drug enters clinical trials, the FDA approves almost anything. They want you to believe that the pharmaceutical companies are in the pockets of the FDA. If they are, Big Pharma ought to change its policies, because the vast majority of drugs that enter clinical trials don’t get approved.
This article will discuss the drug development process plus the success rate of drugs that enter phase 1 clinical trials. You can use it to debunk those claims that somehow a new vaccine or drug got a straight shot to FDA approval without any oversight.
The drug development process
I have previously detailed the whole drug development, so if you want the detail, you can find them there. I’m just going to summarize it here.
- Drug discovery — this is the process to sift through chemicals to find what may or may not work for the indication, such as small cell lung cancer or COVID-19 or whatever. If the new drug seems to have theoretical effectiveness, it moves on to the next stage.
- Preclinical studies — at this point, newly discovered drugs are tested on animals and other models for safety and effectiveness. This research may take years to complete. If the drug appears to work, it’s on to the next step.
- IND — before a new drug can enter the clinical trial phases, it must actually get approval from the FDA to do so. The pharmaceutical company (called the “sponsor” in the regulatory language of clinical trials) has to submit an application called Investigational New Drug (IND). This application contains all of the preclinical data, and the FDA must decide if it’s good enough to move to the next step. A significant number of drugs don’t make it past this point because either the FDA or the sponsor decides to stop further research.
- Phase 1 clinical trial — researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. This is necessary before efficacy studies may begin. Subjects are generally given doses that are a fraction of what was used in pre-clinical in vivo studies. The primary goal of the Phase I trial is to gather dose-ranging data, although safety and effectiveness are also observed. The testing is done on a small group, usually 20-100 individuals, of healthy volunteers. This phase usually takes one to two years to complete. After it is completed, the data is submitted to the FDA to proceed to the next phase. The FDA does not need to approve the move to Phase 2, but it can block it if the data shows some concerns. Usually, the sponsor and FDA together determine that it’s not worth proceeding to Phase 2.
- Phase 2 clinical trial — the part of clinical trials where the drug or treatment is given to a larger group of participants to see if it is effective and to further evaluate the drug’s safety profile. Generally, at the start of Phase II trials, the researchers may not know if the drug has any efficacy in humans. There might be some preliminary information from in vivo studies with animal models, but at this point in the clinical trial, researchers generally don’t know if observations of effectiveness are applicable to humans. It includes 100-300 patients using the predicted therapeutic dose, or range of doses since one of the bases of pharmaceutical drug development is that a drug follows a dose-response relationship – a higher dose should show a higher response. Phase II studies are designed to determine the overall effectiveness of the drug, but it also continues the Phase I safety assessments. This phase usually takes around two to three years to complete. And after the data is compiled, it is once again submitted to the FDA.
- Phase 3 clinical trial — this is also called the pivotal clinical trial since it is the one that will be critical to determine the safety and effectiveness that will be necessary for a successful New Drug Application (NDA). This phase usually includes 1000-3000 patients in multiple centers, sometimes, in a variety of countries. Each center’s research is generally managed by a lead researcher who recruits patients. Normally, if ethical and practical, the type of study that is employed is a randomized, double-blind, clinical trial. The study population is divided roughly into two halves (though it can be more), one that receives a placebo or standard treatment, and another that receives the new drug. This phase can take several years to complete, usually around three to five years.
- FDA submission — after all of the clinical trials are completed, the data is analyzed, and a huge document is delivered to the FDA. The NDA is usually delivered in boxes because it is so much information. It usually takes 6-18 months for the FDA to review this data. Often, the FDA has questions and concerns that need to be addressed by the sponsor.
As you can tell, the process to get a drug approved takes a lot of time. And a lot of expense — the whole process of developing just one drug can cost approximately US$2.6 billion. That’s one of the reasons that drug companies might stop their clinical trials in phase 1 or 2 because they know that the data doesn’t support the safety or effectiveness of the drug.
What’s the success rate of clinical trials?
It’s time to get to the meat of this article. In a 2010 study published in Clinical Pharmacology & Therapeutics, researchers estimated the clinical phase transition and clinical approval probabilities for drugs in the development pipelines of the 50 largest pharmaceutical firms (by sales).
The first pair of bars shows the probability that a drug candidate moves from phase 1 to phase 2. The second pair shows the same probability of making it from phase 2 to phase 3. The third pair is the probability that a regulatory submission is made after phase III testing. The fourth is the probability that this submission is approved. The final bars give the overall approval rate.
As you can see, the regulatory risk, which many politicians love to complain about, is really pretty trivial. One could argue that the FDA creates too many requirements and standards, but the agency places a high priority on being transparent about these requirements and on applying them consistently. Any well-run pharmaceutical company knows by the end of phase III whether they have an approvable drug or not. Rejections of NDAs have become almost freak occurrences because the sponsoring pharmaceutical company has reviewed the data itself, and it knows if it has a chance at FDA approval.
I think the key statistic is that during the time periods analyzed by this article, there has been around a 16% approval rate for drugs that enter phase 1. It’s nowhere near a 100% slam dunk that seems to be implied by people who don’t understand the FDA process.
Another analysis of clinical trials examined success rates of different drug classes. Here are some other key takeaways:
- The overall likelihood of approval (LOA) from phase 1 for all developmental candidates was 9.6%, and 11.9% for all indications outside of Oncology.
- Rare disease programs and programs that utilized selection biomarkers had higher success rates at each phase of development vs. the overall dataset.
- Chronic diseases with high populations had lower LOA from phase 1 vs. the overall dataset.
- Of the 14 major disease areas, hematology had the highest LOA from phase 1 (26.1%) and oncology had the lowest (5.1%).
- Sub-indication analysis within oncology revealed hematological cancers had 2x higher LOA from phase 1 than solid tumors.
- Oncology drugs had a 2x higher rate of first cycle approval than psychiatric drugs, which had the lowest percent of first-cycle review approvals. Oncology drugs were also approved the fastest of all 14 disease areas.
- Phase 2 clinical programs continue to experience the lowest success rate of the four development phases, with only 30.7% of developmental candidates advancing to phase 3.
Again, this study shows that the approval rate for drugs entering clinical trials is quite low, around 9.6%.
Of course, Big Pharma uses these kind of data to attempt to show how expensive it is to bring new drugs to the market, supporting their exhorbitant prices. However, they do have a point — it’s extraordinarily difficult to bring new drugs to market. And the vast majority of the time, from 84% to 90%, depending on the study, drugs simply fail during the clinical trial process.
Once again, if Big Pharma was controlling the FDA, they’re doing a miserable job.
- DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther. 2010 Mar;87(3):272-7. doi: 10.1038/clpt.2009.295. Epub 2010 Feb 3. PMID: 20130567.