The Four Phases of Clinical Development for New Drugs or Biologics
Clinical studies of new drugs and biologics are usually divided into 4 phases, cleverly designated as 1, 2, 3 and 4, or, if you prefer I, II, III, and IV. Sometimes people talk about more specific phases, e.g. Phase 1a, 1b; or combined phases, e.g. Phase 1-2.
[And, just to complicate things further, there can be preliminary studies conducted in humans using very tiny doses of drug and very small blood samples that are designated Phase 0. These Phase 0 studies may be used to select one drug for further study from a small group of closely related compounds.]
There are usually several clinical studies done in each phase. If things go well and the drug "cooperates", the development program progresses steadily from one phase to the next over a period of several years.
Clinical studies of new drugs and biologics are usually divided into 4 phases, cleverly designated as 1, 2, 3 and 4, or, if you prefer I, II, III, and IV. Sometimes people talk about more specific phases, e.g. Phase 1a, 1b; or combined phases, e.g. Phase 1-2.
[And, just to complicate things further, there can be preliminary studies conducted in humans using very tiny doses of drug and very small blood samples that are designated Phase 0. These Phase 0 studies may be used to select one drug for further study from a small group of closely related compounds.]
There are usually several clinical studies done in each phase. If things go well and the drug "cooperates", the development program progresses steadily from one phase to the next over a period of several years.
The conduct of Phase 1- 4 studies is not set in stone; the Phases may vary depending on previous experience with the drug, the indication being studied and other factors. Nevertheless, it is useful to think about 4 Phases and to examine the questions that need to be answered in each Phase. (Note: when we talk about the "indication", we mean the reason that the drug will be used, e.g. "for treatment of community acquired pneumonia", or for "treatment of mild to moderate pain".)
Phase 1 studies are usually done in "healthy" volunteers called "subjects" but may be done in patients with the disease that you hope to treat. If the drug is intended to treat a life-threatening indication and preclinical studies indicate a chance of significant adverse events, it may not be ethical to enroll volunteers. Instead, patients with the disease of interest may be chosen for the Phase 1 studies since they would have a chance to obtain some benefit to balance the risks. Phase 1 studies of drugs to treat cancer (oncology studies) are usually done in patients, not volunteers.
Phase 1 studies provide the first chance to study the pharmacokinetics (pk) of the drug in humans. That means studies of absorption, distribution, metabolism, and excretion (ADME). Pharmacokinetic analyses depend upon how the drug will be administered. If the drug will be administered orally (e.g. as tablet or capsule), it is important to find out if it dissolves and releases the drug as planned and to determine exactly where it dissolves (stomach or intestine) and then how it is metabolized and eliminated. If it will be a topical drug (applied to the skin), you need to determine how much is absorbed internally (systemic absorption). If the drug will be administered parenterally, that is injected directly into the body, (e.g. an drug for IV injection), absorption from the GI tract is not relevant, but distribution, metabolism, and excretion must still be assessed.
Phase 1 studies usually start with single, ascending dose (SAD) studies. That is, studies start with a low dose of the drug given once to a small number of subjects. If these subjects do well, the next group can receive a higher dose of the drug. The number of subjects at each dosing level may be in the range of 6-15 subjects per group. After the first group of subjects has been dosed there is an observation period to watch for laboratory changes or adverse events before the next group of subjects is dosed. Each group of volunteers receives a higher dose until the decision is made to stop dose escalation. Dose escalation usually stops if several patients show some intolerance to the drug (e.g. nausea, vomiting). If the drug is tolerated well enough in the SAD studies, multiple ascending dose (MAD) studies may start. In MAD studies each subject receives several doses. MAD studies start with low doses administered daily for several days, e.g. 1 or 2 weeks. The dosing schedule may be modified depending on the results of the Pk analyses in the single dose studies.
A discussion of how to choose the starting dose for Phase 1studies and how to increase the dose is beyond the scope of this website, but we have included a link to the FDA Guidance on Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers in the Guidance tab under Resources.
Safety monitoring is critically important in Phase 1. The investigator and the Medical Monitor must watch carefully to see if any subject develops any clinically significant change in laboratory tests or manifests adverse events.
Dosing in either the SAD or MAD studies may progress until a maximum tolerated dose (MTD) is reached, meaning that subjects experience adverse event that are determined to be too bad to progress further. These adverse events are usually things like laboratory changes, e.g. increased in hepatic enzymes, or decreased white blood cell count, or signs or symptoms like nausea or headache. The intent is not to produce serious adverse events but to find some signs that higher doses should not be studied.
Sometimes, dosing is stopped after a previously-specified dose has been studied. For example, the company may decide that a higher dose would not be needed based on animal models of the disease or that commercialization of the drug would not be feasible if a higher dose were required because it would cost to much to make high doses.
Phase 1 studies focus on safety and pharmacokinetics but sometimes it is possible to get a hint of efficacy. If a drug is intended to act on a particular enzyme or metabolic pathway, it may be possible to determine if any of the doses studied affects the drug target as expected. If the Phase I subjects are patients with the disease of interest, additional “efficacy” evaluations may be possible.
Phase 1 studies are usually done in "healthy" volunteers called "subjects" but may be done in patients with the disease that you hope to treat. If the drug is intended to treat a life-threatening indication and preclinical studies indicate a chance of significant adverse events, it may not be ethical to enroll volunteers. Instead, patients with the disease of interest may be chosen for the Phase 1 studies since they would have a chance to obtain some benefit to balance the risks. Phase 1 studies of drugs to treat cancer (oncology studies) are usually done in patients, not volunteers.
Phase 1 studies provide the first chance to study the pharmacokinetics (pk) of the drug in humans. That means studies of absorption, distribution, metabolism, and excretion (ADME). Pharmacokinetic analyses depend upon how the drug will be administered. If the drug will be administered orally (e.g. as tablet or capsule), it is important to find out if it dissolves and releases the drug as planned and to determine exactly where it dissolves (stomach or intestine) and then how it is metabolized and eliminated. If it will be a topical drug (applied to the skin), you need to determine how much is absorbed internally (systemic absorption). If the drug will be administered parenterally, that is injected directly into the body, (e.g. an drug for IV injection), absorption from the GI tract is not relevant, but distribution, metabolism, and excretion must still be assessed.
Phase 1 studies usually start with single, ascending dose (SAD) studies. That is, studies start with a low dose of the drug given once to a small number of subjects. If these subjects do well, the next group can receive a higher dose of the drug. The number of subjects at each dosing level may be in the range of 6-15 subjects per group. After the first group of subjects has been dosed there is an observation period to watch for laboratory changes or adverse events before the next group of subjects is dosed. Each group of volunteers receives a higher dose until the decision is made to stop dose escalation. Dose escalation usually stops if several patients show some intolerance to the drug (e.g. nausea, vomiting). If the drug is tolerated well enough in the SAD studies, multiple ascending dose (MAD) studies may start. In MAD studies each subject receives several doses. MAD studies start with low doses administered daily for several days, e.g. 1 or 2 weeks. The dosing schedule may be modified depending on the results of the Pk analyses in the single dose studies.
A discussion of how to choose the starting dose for Phase 1studies and how to increase the dose is beyond the scope of this website, but we have included a link to the FDA Guidance on Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers in the Guidance tab under Resources.
Safety monitoring is critically important in Phase 1. The investigator and the Medical Monitor must watch carefully to see if any subject develops any clinically significant change in laboratory tests or manifests adverse events.
Dosing in either the SAD or MAD studies may progress until a maximum tolerated dose (MTD) is reached, meaning that subjects experience adverse event that are determined to be too bad to progress further. These adverse events are usually things like laboratory changes, e.g. increased in hepatic enzymes, or decreased white blood cell count, or signs or symptoms like nausea or headache. The intent is not to produce serious adverse events but to find some signs that higher doses should not be studied.
Sometimes, dosing is stopped after a previously-specified dose has been studied. For example, the company may decide that a higher dose would not be needed based on animal models of the disease or that commercialization of the drug would not be feasible if a higher dose were required because it would cost to much to make high doses.
Phase 1 studies focus on safety and pharmacokinetics but sometimes it is possible to get a hint of efficacy. If a drug is intended to act on a particular enzyme or metabolic pathway, it may be possible to determine if any of the doses studied affects the drug target as expected. If the Phase I subjects are patients with the disease of interest, additional “efficacy” evaluations may be possible.
How long does Phase 1 last? Phase 1 lasts until several important questions can be answered. These are some of the questions that must be answered to make the "Go decision" to proceed to Phase 2:
Is the drug safe enough to proceed? Did we find any unexpected safety problems that need additional evaluation before we decide to study more subjects?
Do we know how to monitor safety?
Did the formulation work as expected?
Do we understand the pharmacokinetics well enough to go to Phase 2?
Did we learn enough to choose a dose or doses for Phase 2 studies? Do we have enough drug?
Do we have the staff and budget to move to Phase 2?
Does this formulation look good enough to study further? Would it be better to use our resources to study a different drug or wait for a new formulation?
Do we need or want to find a partner to move on?
Is the drug safe enough to proceed? Did we find any unexpected safety problems that need additional evaluation before we decide to study more subjects?
Do we know how to monitor safety?
Did the formulation work as expected?
Do we understand the pharmacokinetics well enough to go to Phase 2?
Did we learn enough to choose a dose or doses for Phase 2 studies? Do we have enough drug?
Do we have the staff and budget to move to Phase 2?
Does this formulation look good enough to study further? Would it be better to use our resources to study a different drug or wait for a new formulation?
Do we need or want to find a partner to move on?
Phase 2
Phase 2 is usually the first time that a new drug is tested in patients with the disease of interest. Some people refer to Phase 2 as “Exploratory Therapeutic Studies” or “Proof of Concept” studies. They are studies of safety and efficacy in a selected patient population.
Subjects in Phase 2 studies are usually carefully chosen to increase the chance of seeing a beneficial effect if one occurs. Usually the subjects have the disease of interest but don't have significant comorbidities. For example, if you want to see if the drug lowers blood pressure, you want Phase 2 patients who have significant hypertension, but would prefer that they not have diabetes, or significant heart disease, or some other concomitant illness that would interfere with observation and safety analysis of the study drug. Alternatively, the Phase 2 patients may be chosen because they have severe disease and it may be easier to observe a therapeutic effect or because their chance for benefit outweighs the risks of significant adverse events.
Phase 2 studies are usually randomized, double-blind, controlled studies. “Controlled” means that some patients get the drug being studied, others do not. A placebo group is used if possible. If it is not possible to use a placebo, an observational control group may be used. Randomized means the assignment of patients to each treatment group is done by chance. "Double-blind" means that neither the investigators, nor the patients, nor the study monitors know whether the subjects are getting the active drug or placebo. The randomization schedule is kept under lock and key until the study database is frozen and the results are ready to be analyzed.
Phase 2 studies usually evaluate several dosing levels of the investigational drug and the duration of treatment is usually long enough to see if there are any signs of efficacy as well as to monitor safety.
How long does Phase 2 go on? Until the important questions are answered. These are some of the questions that need to be answered at the end of Phase 2 in order to make the Go/No Go decision to proceed to Phase 3:
Is the drug safe enough to go to Phase 3?
Does the drug do what we expected it to do?
Is the risk/benefit profile good enough to move on? Will it be commercially viable based on what we know about current treatments or competitive products in development?
Is the formulation and packaging good enough to use in large Phase 3 studies or does it need to be modified before moving on. (Note: A modification of the formulation will usually require additional Phase 2 work and might require a return to Phase 1 to for additional Pk studies.)
Do we know how to measure efficacy for the disease under study? Are there standard assays or rating scales that we need to use? Will our planned efficacy assessments be acceptable to regulatory authorities and to the investigator community?
Did we learn enough about response rates in Phase 2 to predict how many subjects we will need to enroll in Phase 3 to have a chance of evaluating efficacy?
Do we know what dose(es) we want to study in Phase 3?
Can we produce enough drug?
Do we have the resources (staff, money, drug, patients and investigative sites) to allow us to go to Phase 3?
Do we need or want to find a partner to move on?
Phase 2 is usually the first time that a new drug is tested in patients with the disease of interest. Some people refer to Phase 2 as “Exploratory Therapeutic Studies” or “Proof of Concept” studies. They are studies of safety and efficacy in a selected patient population.
Subjects in Phase 2 studies are usually carefully chosen to increase the chance of seeing a beneficial effect if one occurs. Usually the subjects have the disease of interest but don't have significant comorbidities. For example, if you want to see if the drug lowers blood pressure, you want Phase 2 patients who have significant hypertension, but would prefer that they not have diabetes, or significant heart disease, or some other concomitant illness that would interfere with observation and safety analysis of the study drug. Alternatively, the Phase 2 patients may be chosen because they have severe disease and it may be easier to observe a therapeutic effect or because their chance for benefit outweighs the risks of significant adverse events.
Phase 2 studies are usually randomized, double-blind, controlled studies. “Controlled” means that some patients get the drug being studied, others do not. A placebo group is used if possible. If it is not possible to use a placebo, an observational control group may be used. Randomized means the assignment of patients to each treatment group is done by chance. "Double-blind" means that neither the investigators, nor the patients, nor the study monitors know whether the subjects are getting the active drug or placebo. The randomization schedule is kept under lock and key until the study database is frozen and the results are ready to be analyzed.
Phase 2 studies usually evaluate several dosing levels of the investigational drug and the duration of treatment is usually long enough to see if there are any signs of efficacy as well as to monitor safety.
How long does Phase 2 go on? Until the important questions are answered. These are some of the questions that need to be answered at the end of Phase 2 in order to make the Go/No Go decision to proceed to Phase 3:
Is the drug safe enough to go to Phase 3?
Does the drug do what we expected it to do?
Is the risk/benefit profile good enough to move on? Will it be commercially viable based on what we know about current treatments or competitive products in development?
Is the formulation and packaging good enough to use in large Phase 3 studies or does it need to be modified before moving on. (Note: A modification of the formulation will usually require additional Phase 2 work and might require a return to Phase 1 to for additional Pk studies.)
Do we know how to measure efficacy for the disease under study? Are there standard assays or rating scales that we need to use? Will our planned efficacy assessments be acceptable to regulatory authorities and to the investigator community?
Did we learn enough about response rates in Phase 2 to predict how many subjects we will need to enroll in Phase 3 to have a chance of evaluating efficacy?
Do we know what dose(es) we want to study in Phase 3?
Can we produce enough drug?
Do we have the resources (staff, money, drug, patients and investigative sites) to allow us to go to Phase 3?
Do we need or want to find a partner to move on?
Phase 3
Phase 3 studies are usually large, randomized, double-blind studies that enroll patients similar to those who will be treated if the drug is approved and marketed. These are the so called “pivotal studies” that will be used submitted to regulatory agencies for approval to market the drug. Usually more than one Phase 3 study is done to gather sufficient safety data and to have a primary and a confirmatory study.
The dose or doses to be studied in Phase 3 are determined after analysis of Phase 2 results. Because the Phase 3 studied will be large and long, it is better if a single dose of drug and/or a single dosing regimen can be studied but that is not always possible.
Subjects in Phase 3 are treated long enough to measure effects using standard efficacy evaluations and rating scales. The study endpoints are defined in the protocols and they may include a primary endpoint and perhaps several secondary endpoints as well. The number of subjects to be treated (the sample size) must be large enough to determine whether a beneficial effect is likely to be “real” and not due to chance alone.
Depending on the indication being evaluated and the disease endpoints, Phase 3 studies may enroll hundreds of patients and they may be treated for a year or more to measure results.
These are some of the questions that need to be answered at the end of Phase 3 in order to make the Go/No Go decision to submit the data for regulatory review:
Is the drug safe enough for the expected indication?
Did the drug do what we expected it to do?
Did we meet our study endpoints?
Is the drug safe enough and effective enough to be approved?
Is the drug safe and effective enough to be competitive in the marketplace?
Do we have enough information to write the prescribing information?
Can we manufacture enough drug?
Do we want or need a partner to move on?
Phase 3 studies are usually large, randomized, double-blind studies that enroll patients similar to those who will be treated if the drug is approved and marketed. These are the so called “pivotal studies” that will be used submitted to regulatory agencies for approval to market the drug. Usually more than one Phase 3 study is done to gather sufficient safety data and to have a primary and a confirmatory study.
The dose or doses to be studied in Phase 3 are determined after analysis of Phase 2 results. Because the Phase 3 studied will be large and long, it is better if a single dose of drug and/or a single dosing regimen can be studied but that is not always possible.
Subjects in Phase 3 are treated long enough to measure effects using standard efficacy evaluations and rating scales. The study endpoints are defined in the protocols and they may include a primary endpoint and perhaps several secondary endpoints as well. The number of subjects to be treated (the sample size) must be large enough to determine whether a beneficial effect is likely to be “real” and not due to chance alone.
Depending on the indication being evaluated and the disease endpoints, Phase 3 studies may enroll hundreds of patients and they may be treated for a year or more to measure results.
These are some of the questions that need to be answered at the end of Phase 3 in order to make the Go/No Go decision to submit the data for regulatory review:
Is the drug safe enough for the expected indication?
Did the drug do what we expected it to do?
Did we meet our study endpoints?
Is the drug safe enough and effective enough to be approved?
Is the drug safe and effective enough to be competitive in the marketplace?
Do we have enough information to write the prescribing information?
Can we manufacture enough drug?
Do we want or need a partner to move on?
Phase 4
Phase 4 studies are done after a drug is approved. Phase 4 studies can take many forms and answer many questions.
There may be regulatory requirements for Phase 4 studies. If the drug has been approved using a short-term endpoint or a surrogate endpoint, a regulatory agency may require longer studies to evaluate survival or long-term efficacy or safety.
Similarly, a company that has shown that a drug is effective for a short-term endpoint might want to evaluate a survival benefit.
Phase 4 studies may evaluate safety in a larger population than the number of subjects studied in the pivotal studies.
Phase 4 studies are also used to answer commercial questions, e.g. how does this drug fit into standard medical practice; can this drug be used instead of other treatments; are there educational materials that can help patients and doctors use the drug more effectively?
Sometimes, Phase 4 studies are done by a clinical research group in the marketing division of a company instead of the Clinical Research Division that conduct the Phase 1-3 studies. In a large multinational company, individual countries may conduct different Phase 4 studies to meet local market needs.
