Source: National Institutes of Health
Most of us understand that drugs intended to treat people have to be tested in people. These tests, called clinical trials, determine if a drug is safe and effective, at what doses it works best, and what side effects it causes--information that guides health professionals and, for nonprescription drugs, consumers - in the proper use of medicines.
The process appears straightforward--simply recruit groups of patients to participate in a clinical trial, administer the drug to those who agree to take part, and see if it helps them. Sounds easy enough, and sometimes it is. In what may be medicine's most celebrated clinical trial, Louis Pasteur treated patients exposed to rabies with an experimental anti-rabies vaccine. All the treated patients survived. Since scientists knew that untreated rabies was 100 percent fatal, it wasn't hard to conclude that Pasteur's treatment was effective.
But that was a highly unusual case. Drugs rarely reverse fatal illness. More often than not they reduce the risk of death, but don't entirely eliminate it. They usually accomplish this by relieving the symptoms of the illness, such as pain, anxiety, heart failure, or angina. Or a drug may alter a clinical measurement--reduce blood pressure or lower the cholesterol level, for example--in a way that physicians hope will be valuable. Drug effects like these can be a good deal harder to detect and evaluate than a result as dramatic as Pasteur's rabies cure.
Because diseases don't follow a predictable path, many acute illnesses or conditions--viral ailments like colds or the flu, minor injuries, insomnia--can usually be counted on to go away spontaneously without treatment. Some chronic conditions like arthritis, multiple sclerosis, depression, or asthma often follow a varying course--better for a time, then worse, then better again, usually for no apparent reason. And heart attacks and strokes, for example, have widely variable death rates depending on treatment, age, and other factors, so that the "expected" mortality for an individual patient can be hard to predict.
A further difficulty in gaging the effectiveness of an investigational drug is that in some cases measurements of disease are subjective; relying in part on what is essentially a matter of interpretation by the physician or patient. Such measurements can be imprecise, influenced by a patient’s or physician's expectations or hopes. In those circumstances, it's difficult to tell whether treatment is having a favorable effect, no effect, or even an adverse effect. The way to answer this critical question about an investigational drug is to subject it to a controlled clinical trial.
Treatment trials test treatments like a new medicine (drug), new approaches to surgery or therapy, new combinations of treatments, or new methods. (COX inhibitors for anti-depression)
Prevention trials test new approaches, such as medicines, vitamins, minerals, or other supplements that doctors believe may lower the risk of developing a certain condition or disease. These trials look for the best way to prevent diseases in people who have never had the disease being studied. These trials may also look to prevent the disease from re- occurring or prevent a related disease in patients who have already had the disease. (Vaccines)
Screening trials test the best way to find a condition or disease, especially in its early stages. (Pregnancy Tests)
Quality of Life trials (also called Supportive Care trials) explore ways to improve comfort and quality of life for patients. (erectile dysfunction drugs, incontinence drugs).
It's important to test drugs in the kind of people they're meant to help. It's also important to design clinical studies that ask and answer the right questions about investigational drugs. That's no easy task.
Clinical trials follow strict scientific guidelines. These guidelines deal with many areas, including the study's design, who can be in the study, and the kind of information people must be given when they are deciding whether to participate. Every trial has a chief investigator, who is usually a doctor. The investigator prepares a study action plan, called a protocol. This plan explains what the trial will do, how, and why. For example, it states:
- how many people will be in the study;
- who is eligible to participate in the study;
- what study drugs participants will take;
- what medical tests they will have and how often;
- what information will be gathered.
Every research center that takes part in the trial uses the same protocol. This ensures that information from all centers can be combined and compared.
The process starts with a drug sponsor, usually a pharmaceutical company, seeking to develop a new drug it hopes will find a useful and profitable place in the market. Before clinical testing begins, researchers analyze the drug's main physical and chemical properties in the laboratory and study its pharmacologic and toxic effects in laboratory animals. If the laboratory and animal study results show promise, the sponsor can apply to FDA to begin testing in people.
Once FDA has seen the sponsor's plans and a local institutional review board--a panel of scientists, ethicists, and non-scientists that oversees clinical research at medical centers throughout the country--approves the protocol for clinical trials, experienced clinical investigators give the drug to a small number of healthy volunteers or patients.
Phase I studies assess the most common acute adverse effects and examine the size of doses that patients can take safely without a high incidence of side effects. Initial clinical studies also begin to clarify what happens to a drug in the human body--whether it's changed (metabolized), how much of it (or a metabolite) gets into the blood and various organs, how long it stays in the body, and how the body gets rid of the drug and its effects.
If phase I studies don't reveal major problems, such as unacceptable toxicity, the next step is to conduct a clinical study in which the drug is given to patients who have the condition it's intended to treat. Researchers then assess whether the drug has a favorable effect on the condition.
Phase I
– Number of Patients: 20-100
– Length: Several months
– Purpose: Mainly safety
– Percent of Drugs Successfully Tested: 70 percent
In a controlled trial, patients in one group receive the investigational drug. Those in a comparable group--the controls--get either no treatment at all, a placebo (an inactive substance that looks like the investigational drug), a drug known to be effective, or a different dose of the drug under study.
Usually the test and control groups are studied at the same time. In fact, usually the same group of patients is divided in two with each subgroup getting a different treatment. That is the best way to be sure the groups are similar.
In some special cases, a study uses a "historical control," in which patients given the investigational drug are compared with similar patients treated with the control drug at a different time and place. "Historical control" can also refer to a comparison of groups of patients treated at about the same time but at different institutions.
It's important that treatment and control groups be as similar as possible in characteristics that can affect treatment outcome. For instance, all patients in specific groups must have the disease the drug is meant to treat or same stage of the disease.
Treatment and control groups should also be of similar age, weight, and general health status, and be similar in other characteristics that could affect the outcome of the study, such as other treatment being received at the same time.
Phase II
– Number of Patients: Up to several hundred
– Length: Several months to 2 years
– Purpose: Some short-term safety but mainly effectiveness
– Percent of Drugs Successfully Tested: 33 percent
There is little difference between Phase II and Phase III Clinical Trials. Phase III represents a massive scale-up of what was analyzed and learned from Phase II and processes for commercializing the product are put into motion. For instance the installation and validation of new filling equipment, or other manufacturing processes, accelerated stability studies, cycling studies, drug presentation, marketing, and special packaging considerations.
Phase III
– Number of Patients: Several hundred to several thousand
– Length: 1-4 years
– Purpose: Safety, dosage, effectiveness
– Percent of Drugs Successfully Tested: 25-30 percent
On average, the drug sponsor has 6 ½ years invested to this point. They are in the home stretch but still about 10% of the drugs that made it through Stage II will fall out of the race during Stage III. Now, only a total of 25-30% of the drugs that entered Stage I will make it to the finish line. And making it to the finish line does not guarantee FDA approval.
Because of the magnitude of Stage III Clinical Trials, which can include thousands of subject patients, multiple countries and up to 4 years of data collection, it is the most expensive part of the drug approval process. Producing good, “clean” data during Stage III trials is critical. To that end, every research center that participates in the trial uses exactly the same protocol to insure that the information collected can be accurately compared. Good clinical trial managers attempt to eliminate or at least minimize every possible variable that may adulterate the results or muddy the data which may delay its approval. Often, drug and performance variability is related to temperature.
The effects of temperature on a drug can have a significant impact on its efficacy and potency. Temperature stability on the drug is still being ascertained during Stage III Trials. Therefore, temperature control during storage and transport is critical.
Add to that, the pressure to push a drug to market. It is nearing critical mass. Patents are filed when the drug is first discovered. Patents protect drugs from copycat versions for 20 years after the drug is invented. But it can take up to ten years after invention to accumulate enough data to get a drug past the U.S. Food and Drug Administration. Once the patent expires, 80% of the brand name sales can vanish within a year as generic competitors reach the market. Each day that passes before the drug is approved is a day of lost revenue. So mistakes and miscues cannot happen.
Late within Stage III data supporting a broader range in storage or transport temperature has been collected. Companies set their focus on product launch and begin to mine for a reduction in packaging costs.
You can expect the clinical trial process to operate in fits and starts. As batch lots of the drug are manufactured, Clinical Trial Managers are hard at work aligning their research participants. The lot is distributed to the research facilities, the drugs administered to the subject patients, and the data are collected. Depending on the protocol and the dosage months may go by as the results are collated, and analyzed before the process begins again. Then again, trials may end abruptly.
As a drug moves from clinical trial to the commercial side of manufacturing and distribution, final qualified packaging has to be developed and implemented by the Pharmaceutical company so that they can hit the market on the day of FDA approval.
Phase IV
This occurs post market introduction to determine and monitor life-cycle management, safety surveillance, adverse effects, and pharmico-kinetics: delivery and operational improvements.
