Learn how clinical trials progress through safety testing to market approval.
Before a drug ever reaches a human, it goes through years of laboratory and animal testing called preclinical research. Scientists study the compound in cell cultures and animal models to understand how it behaves in living systems, whether it appears safe, and whether it shows potential to treat the target disease. This process alone typically takes 3 to 6 years and is funded by pharmaceutical companies, biotech firms, or academic research institutions.
Once preclinical data shows enough promise, the drug sponsor files an Investigational New Drug (IND) application with the FDA. The IND includes all preclinical data, a proposed plan for human testing, and detailed manufacturing information. The FDA has 30 days to review and either approve the application or place a clinical hold. If approved, human trials can begin.
From there, clinical trials move through a series of phases. Each phase asks a different question, enrolls more people, and builds on the data gathered in the previous phase. The entire journey from lab to approved drug takes an average of 10 to 15 years and costs hundreds of millions to billions of dollars.
Could this compound work?
Laboratory and animal testing to evaluate safety, biological activity, and formulation. Researchers identify a target (like a protein or gene pathway), develop a compound that interacts with it, and test it in cell cultures and animal models. Preclinical studies also determine how the drug is absorbed, metabolized, and excreted.
Only about 1 in 1,000 compounds tested in the lab will ever reach human trials.
Is it safe for humans?
First-in-human testing with a small group. Researchers start with very low doses and gradually increase them (dose escalation) to find the highest dose that doesn't cause unacceptable side effects. They closely monitor how the drug is absorbed, distributed, metabolized, and eliminated by the body (pharmacokinetics).
Participants are typically monitored very closely, often in a clinical research facility. Phase 1 trials are not designed to test whether the drug works, only whether it's safe enough to continue testing.
Does it actually work?
The first real test of effectiveness. Participants who have the target disease receive the drug, and researchers measure whether it produces the intended therapeutic effect. Phase 2 also continues evaluating safety and helps determine the optimal dose for Phase 3. Many Phase 2 trials are randomized and some include a placebo or active comparator group.
This is where many drugs fail. A compound might be safe but simply not effective enough to justify the cost and risk of a large Phase 3 trial. For rare diseases, Phase 2 trials may be smaller due to limited patient populations.
Is it better than what already exists?
Large-scale, definitive trials that compare the new treatment against the current standard of care or a placebo. These are the trials the FDA relies on most heavily when deciding whether to approve a drug. Phase 3 trials are almost always randomized and usually double-blinded. They measure clearly defined primary endpoints (like survival time, tumor shrinkage, or symptom improvement) and track a comprehensive list of side effects.
Phase 3 trials are extremely expensive, often costing tens or hundreds of millions of dollars. If a Phase 3 trial succeeds, the sponsor submits a New Drug Application (NDA) or Biologics License Application (BLA) to the FDA for review.
Should this drug be approved?
After successful Phase 3 trials, the drug sponsor submits all clinical data to the FDA. An NDA or BLA includes results from all trial phases, proposed labeling, manufacturing details, and safety data. The FDA review team evaluates the evidence and may convene an advisory committee of independent experts. Standard review takes about 10 months; priority review (for drugs that offer major advances) takes about 6 months.
The FDA can approve the drug, request additional data, or deny approval. For rare diseases, the FDA has special expedited pathways: Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review.
What happens long-term?
Post-market surveillance studies conducted after a drug is approved and available to patients. These studies monitor long-term safety in much larger and more diverse populations than the clinical trials. Phase 4 studies can also explore new uses for the drug, test it in different patient populations, or study drug interactions.
Phase 4 data has led to drugs being pulled from the market years after approval when rare but serious side effects emerged. Vioxx is a well-known example: it was withdrawn in 2004 after post-market data showed increased cardiovascular risk.
About 90% of drugs that enter Phase 1 testing never make it to FDA approval. That is not a failure of the system. It is the system doing exactly what it is designed to do. Clinical trials exist to separate treatments that actually work from ones that don't, and to catch safety issues before a drug reaches millions of patients. The phases function as a series of increasingly rigorous filters.
Phase 3 trials are the most critical hurdle. They're large, expensive, and they're what the FDA ultimately relies on to decide whether a drug should be approved. If a trial you're considering is in Phase 3, that means the treatment has already cleared safety testing and shown signs of effectiveness in earlier phases. That's meaningful.
Success rates vary significantly by disease area. Oncology drugs have historically had lower Phase 3 success rates (around 30–40%), while drugs for infectious diseases and hematology tend to have higher rates. Rare disease drugs have benefited from regulatory incentives like the Orphan Drug Act, which provides tax credits, extended market exclusivity, and fee waivers to encourage development.
The FDA recognizes that rare diseases face unique development challenges, including small patient populations, limited natural history data, and fewer commercial incentives. To address this, several expedited programs exist that can significantly speed up the approval timeline.
Fast Track designation is for drugs that treat serious conditions and fill an unmet medical need. It allows more frequent meetings with the FDA and eligibility for rolling review (the FDA can review sections of the application as they're submitted, rather than waiting for the complete package).
Breakthrough Therapy designation is for drugs that show substantial improvement over existing treatments based on early clinical evidence. This provides all Fast Track features plus more intensive FDA guidance on efficient trial design.
Accelerated Approval allows the FDA to approve a drug based on a surrogate endpoint, meaning a lab measurement or physical sign that is reasonably likely to predict clinical benefit, even if the final clinical outcome has not been measured yet. The drug can reach patients faster, but the sponsor must conduct confirmatory trials afterward.
Priority Review shortens the FDA review timeline from the standard 10 months to 6 months. It's granted to drugs that would be significant improvements in safety or effectiveness compared to available therapies.
If you're looking at a Phase 1 trial, you're among the first humans to receive this drug. The focus is on safety, not effectiveness. You may be helping establish the right dose for future patients. These trials involve the most uncertainty but also represent the earliest access to completely new treatments.
Phase 2 trials are where you start to see whether the drug might actually help your condition. If a Phase 2 trial for your disease is recruiting, it means the drug has already demonstrated a reasonable safety profile. You'll be closely monitored, and researchers will be measuring specific outcomes related to your disease.
Phase 3 trials offer the most data about what to expect. By this point, researchers know the drug is reasonably safe and have evidence it works. Phase 3 compares it against the current best treatment (or placebo if no standard exists). These trials typically have the most structured protocols and the largest support teams.
Phase 4 trials are conducted after a drug is already approved and available. If you are in a Phase 4 trial, you are receiving a drug that has full FDA approval. These studies help researchers understand how the drug performs in broader, real-world populations.
Phase 0 trials (sometimes called exploratory IND or microdose studies) are a smaller, earlier step than traditional Phase 1. The FDA introduced this category in 2006 to allow drug developers to test very small, sub-therapeutic doses (typically less than 1/100th of the dose expected to have a pharmacological effect) in a small number of human volunteers.
The goal of a Phase 0 trial is not to test safety or efficacy in the traditional sense, but to confirm that a drug behaves in humans the way preclinical models predicted. Phase 0 studies use ultra-sensitive analytical techniques like accelerator mass spectrometry to detect tiny amounts of drug or its metabolites, helping researchers decide whether to invest in a full Phase 1 program.
Phase 0 trials are not common in rare disease development because the patient populations are already small, but they can shorten the development timeline for drugs that need rapid go/no-go decisions before larger investment.
Adaptive trial designs allow researchers to make pre-specified changes to a trial based on accumulating data, without compromising statistical validity. The FDA published formal guidance on adaptive designs in 2019, and these approaches are increasingly common in rare disease research.
Seamless Phase 1/2 trials combine dose-escalation safety testing with early efficacy assessment in the same protocol, allowing the trial to move from dose-finding to expansion cohorts without a pause. Phase 2/3 trials similarly merge proof-of-concept and confirmatory testing.
Basket trials test a single drug across multiple diseases that share a common molecular target (for example, drugs targeting BRAF mutations across melanoma, thyroid cancer, and rare childhood cancers). Umbrella trials test multiple drugs against a single disease, with patients matched to the drug arm based on their specific molecular profile.
Master protocols (used in research consortiums like I-SPY for breast cancer or REMAP-CAP for COVID-19) allow multiple drugs to be tested simultaneously with shared infrastructure, control arms, and analysis plans. These designs are especially valuable for rare diseases where pooling participants across drug candidates is more efficient than running separate, small trials in parallel.
The four phases of clinical trials are Phase 1 (first-in-human safety testing in 20 to 100 volunteers), Phase 2 (initial efficacy and dose-finding in 100 to 300 patients), Phase 3 (large-scale confirmatory trials in 300 to 3,000+ patients to establish efficacy and safety against current standard of care or placebo), and Phase 4 (post-market surveillance after FDA approval to monitor long-term safety and effectiveness in real-world populations).
Phase 1 clinical trials focus on safety, dose-finding, and pharmacokinetics in a small group (20 to 100 participants), typically without testing whether the drug works. Phase 2 trials focus on whether the drug actually treats the target condition while continuing safety evaluation, typically in 100 to 300 patients with the disease. Phase 1 lasts several months to 2 years; Phase 2 lasts 1 to 3 years.
Phase 1 trials typically take several months to 2 years, Phase 2 trials take 1 to 3 years, Phase 3 trials take 2 to 4 years, and FDA review takes 6 to 10 months after Phase 3. The full trajectory from preclinical research through FDA approval averages 10 to 15 years. Phase 4 post-market surveillance is ongoing and can last years or decades after approval.
Approximately 9 to 14% of drugs that enter Phase 1 clinical trials eventually receive FDA approval. About 70% of Phase 1 drugs advance to Phase 2, about 33% of Phase 2 drugs advance to Phase 3, and about 25 to 30% of Phase 3 drugs receive approval. Success rates vary by therapeutic area, with hematology and rare disease drugs showing higher historical success than oncology or central nervous system drugs.
A Phase 0 clinical trial (also called an exploratory IND study or microdose study) is a small, early-stage study introduced by the FDA in 2006. Phase 0 trials test sub-therapeutic doses (typically less than 1/100th of the expected pharmacological dose) in a small number of human volunteers to confirm that a drug behaves in humans the way preclinical models predicted. Phase 0 trials are not designed to test safety or efficacy and are used primarily to make go/no-go decisions before launching a full Phase 1 program.
Phase 3 clinical trials generally carry less safety uncertainty than Phase 1 trials because the drug has already been given to hundreds of people through Phase 1 and Phase 2, and most common side effects are documented in the informed consent. Phase 1 trials carry the highest uncertainty because the drug has been given to few or no humans before. That said, individual risk depends on the specific drug, disease severity, and patient health, more than on the trial phase alone.
FDA Breakthrough Therapy designation is granted to drugs that show substantial improvement over existing treatments based on early clinical evidence, typically for serious or life-threatening conditions. Breakthrough Therapy designation provides intensive FDA guidance on efficient trial design, eligibility for rolling review, and expedited evaluation. As of 2024, the FDA had granted more than 600 Breakthrough Therapy designations across diverse disease areas.
Accelerated Approval allows the FDA to approve a drug based on a surrogate endpoint (a measurement reasonably likely to predict clinical benefit) before the final clinical outcome has been confirmed. Traditional FDA approval requires the trial to demonstrate clinical benefit directly. Accelerated Approval is contingent on the sponsor running confirmatory trials after launch, and if those trials fail, the FDA can withdraw approval. As of recent years, the FDA has used Accelerated Approval most extensively for oncology and rare disease drugs.