It’s more than just a phase
FDA’s three-phase process of drug approvals
When a company announces an infusion drug has completed Phase II trials for Food and Drug Administration (FDA) approval, or has completed a Phase I trial, what does that mean to you in terms of how far away the drug is from a release to market? The truth is that a drug just entering a Phase I trial could be available to providers before a drug that long ago began Phase III trials.
Thomas Hassall, an assistant director of regulatory affairs for one of the FDA’s five Offices of Drug Evaluation, says that a drug’s trip through the FDA pipeline is anything but a set formula, particularly once testing begins.
Preclinical research
Before a drug even makes its way to the FDA, the manufacturer must have conducted animal testing to identify various properties of the drug and its toxicity in animals. However, there is no set standard as to the acceptable toxicity of a drug that the FDA will allow to progress to human testing. The level of risk that is acceptable depends to a large degree on the disease for which the drug is targeted. In essence, progress throughout the drug development is a series of risk-vs.-benefit decisions.
"If a drug may be a carcinogen over a long period of time, that wouldn’t necessarily block it from study as an oncology drug if it has the potential to provide a significant survival benefit, and the likelihood of suffering carcinogenic effects in a human taking the drug for chemotherapy would be fairly remote," notes Hassall.
During preclinical research, the FDA requires a drug’s sponsor to, at the minimum:
1. Develop a pharmacological profile of the drug.
2. Determine the toxicity of the drug in at least two species of animals.
3. Conduct short-term toxicity studies ranging from two weeks to three months.
Once this information has been compiled, the sponsor completes an investigational new drug application (IND), which Hassall notes is required for reasons other than you might suspect.
"The Food, Drug, and Cosmetic Act really has to do with shipping drugs in interstate commerce," he says, "and the IND is really asking for an exemption from the act’s prohibition against shipping an unapproved drug in interstate commerce to the investigators who are going to conduct the additional research required for drug approval."
However, the act is considered to cover all the components of a drug, including packaging materials. So while it is technically possible to do everything in-state and avoid the FDA, it would be almost impossible for everything involved with a drug to come from within any one state.
Hassall points out that sponsors conduct preclinical studies on a drug without an IND because the compound isn’t technically a drug until a claim for a specific use is made. The IND is required for the first time you want to administer the drug to a person in Phase I trials.
When the initial application is filed, there is a 30-day period from the day the FDA receives the IND that the sponsor cannot begin its study. That allows the FDA to review the IND and evaluate the potential risk to human recipients. If after 30 days the sponsor has not heard from the FDA, testing may begin. However, if the FDA finds something it feels is an unacceptable risk to the study subjects, the sponsor is contacted by phone, and a letter is issued giving the reasons that testing cannot begin.
"We don’t invoke that lightly because it puts a stop on things going forward, and that is a clinical hold," says Hassall. "Where there are no unacceptable safety concerns, we may simply make suggestions to provide additional safeguards that are short of a clinical hold or simply to improve the quality of the data to be obtained from the study."
A sponsor does not necessarily have to follow the suggestions. In some cases, the FDA may request additional information before allowing the drug to progress to another trial. This is referred to as a partial hold. Issues addressed in a clinical hold or partial hold must be resolved before the drug can move on. The inability to clear up such concerns is where many drugs simply die on the vine.
Once the IND is filed and the FDA allows the sponsor’s plans to go forward, the approval process isn’t a simple, three-step, Phase I-Phase II-Phase III endeavor.
"The rate at which they progress is in the hands of the applicant," says Hassall. "There’s no proclamation that they have finished Phase I. Most times, they don’t do one study and wait until that is done until they do another. As the first study is progressing, the sponsor may initiate additional trials that will run concurrent with the first trial."
For each future study, regardless of which phase it is, the applicant must submit a new protocol to the IND. However, unlike the initial IND submission, testing may begin right away although the FDA can put the study on hold if upon review there are safety issues.
Phase I
Phase I trials usually involve just a handful of humans, and for good reason.
"It is essentially the first time the drug has been given to humans after you have gotten some idea of the pharmacology of the drug, and organ systems that might be affected by the drug — both adversely and in a favorable way," notes Hassall. "But because of species differences, when you first go into humans you’re not going to go into them in a large scale."
The main thrust of Phase I trials is to determine the safety of the drug in humans. For the most part, Phase I trials don’t focus on investigating the drug’s effect on the disease it is being targeted for. Many times, subjects who receive a Phase I drug are healthy volunteers, although this is not always the case.
"Would you give an oncology drug with potential for serious toxicity to a healthy volunteer? Probably not," notes Hassall. "But, depending on the potential benefit, administration to patients with the disease may be acceptable with appropriate safeguards."
Investigators usually look to establish the various pharmacokinetic properties of the drug in humans, such as the degree of absorption, the rate of absorption, how it is metabolized and how it is secreted. In essence, this allows investigators for the first time to see how the drug behaves in humans. Additional Phase I trials may involve different dosages of the drug to further establish an initial safety profile and serve as a basis for the doses chosen for Phase II studies.
According to New York City-based investment company Bear Stearns, the typical Phase I period lasts a year and costs $9 million. Yet, 38% of drugs that enter Phase I trials fail.
Phase II
"Many drugs fall by the wayside in Phase I and others are able to go forward," says Hassall . "But the phases are not really distinct, and there are gray areas as you go from one phase to another. A company might do limited hypothesis testing in Phase I to develop the appropriate testing in Phase II."
Once a drug begins a Phase II trial, researchers have established the initial safety profile and pharmacokinetic properties of the drug. Phase II then exposes a greater number of humans with the targeted disease to the drug, with a typical patient sampling in each Phase II study in the neighborhood of 50 or 60. Because of the gray area, Phase I trials may still be ongoing when a Phase II trial starts, but the intent is now much different than focusing on safety.
"Phase II is the first place you begin to assess the efficacy of the drug," says Hassall. "The trials involve a larger number of patients and involve comparators, such as a placebo or some known treatment."
According to Bear Stearns, the Phase II period lasts anywhere from one to three years, costs $22 million, and has a failure rate of 40%.
Phase III
If the drug shows promise and survives Phase II trials, a sponsor will move forward to Phase III.
"This is when a sponsor will initiate what we call pivotal clinical trials that will result in writing a label for the product that will include the dose or range, the interval, how long to treat the patient, adverse events that have been observed in a large enough population that a clear profile of adverse events develops, precautions to take while taking the drug, and known drug interactions that have been determined," says Hassall. "Phase III trials are big numbers of patients where you are going to definitively determine what the drug does, and this can get from the hundreds into the thousands of patients."
In some rare instances, a Phase III trial may be the first trial in the United States.
"There may be products that have use elsewhere in the world that may not have been submitted for approval in the U.S.," says Hassall. "A company with a drug like that with sufficient information about the safety of the product may initiate the IND with a Phase III study. They can supplant Phase I and Phase II with information."
Final approval
If all trials go well, the sponsor still must submit a new drug application (NDA), a daunting task in and of itself.
"Picture 300 to 500 volumes of the Washington, DC, phone book," says Hassall. "The NDA is usually that big because it includes full reports and data from all their studies."
The FDA currently tries to review an NDA within 10 to 12 months of receiving it, although priority drugs have a goal of six months.
"We either approve the NDA or not, and if we approve it they can go to market," says Hassall.
For applications that are not approved, the applicant is sent a letter describing all the deficiencies that need to be addressed before the drug may be approved. An applicant may then amend its application with the needed information. The FDA’s goal is to complete its review of such amendments within six months of receipt.
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