How a drug goes from the test tube, to animal testing and to the market

For more than a decade, I've served on an Independent Ethical Review Board (IRB), which is a panel that reviews and approves drug studies for research in human subjects. Here's a short information session on the process your prescriptions went through before they made it to the pharmacy.

Test Tube Stage: The lab stage of testing can take many years. Major pharmaceutical firms spend a ton of money on this type of research. I don't work for drug firms, but I've gained a lot of appreciation for what they do and the cost of getting a drug 'to market,' as they say.

The lab stage alone costs many millions of dollars. The pharmaceutical firm has to demonstrate to the FDA that the drug is ready to be tested in humans before they go to the next stage of research.

A drug firm can go through thousands of test-tube formulations before discovering one that has the potential for further research (in animals, and later in humans). Each stage has added costs (animals require lab tests, the same as humans do). The final cost of research can be more than $1 billion for a given drug or formulation, and the process can take many years.

After a drug or formulation shows some results in test tubes (how it reacts with various substances, etc.), it must be tested in animals before humans can be used in research.

I know this is a concern to those who love animals (and I am one of those people), but I also understand how crucial this stage is to advance science, to protect the humans who will test the drug in the next phase or research and to protect the safety of people who will take the drug to treat their health problems once it hits the market.

Animal testing yields a lot of information about how the formulation is processed through a blood system, how it is excreted, how long it stays in the system and, very importantly, whether it can harm a fetus or damage sperm. Animal tests also help reveal possible side effects in humans (even though humans may not react the same way). Lab scientists record whether the test animals had trouble sleeping, had changes in their appetites, developed any symptoms or changes in blood and urine tests or had other reactions that can help determine if the drug is suitable for human testing.

We all rely on drugs to keep us healthy or to treat various conditions, and animal testing is a key stage in developing drugs that are effective, but at the same time as safe as humanly possible.

People often cringe when they think about testing a drug in people before it's been approved by the FDA, and some wonder if it is ethical to do so. My answers are, "Would you want to take a drug that hadn't been tested in humans?" and "Would you want the FDA to approve a drug that hasn't been tested in people?" This usually helps people see the rationale for exposing humans to a drug not yet on the market and points out the purpose of human testing.

The Informed Consent:

Federal law requires that all subjects involved in research studies be properly 'consented' before they can participate. This is true whether it's a psychology study at your university campus or a drug study in a controlled environment. The Informed Consent is supposed to tell research volunteers what they'll be given (or be asked to do), the purpose of the research, possible side effects, their rights as a research subject, that they have the right to withdraw, that they are not to be coerced into volunteering and what help is available in the event of a problem. Those are just some of the basic elements of an informed consent; there's a lot more information in such documents, which are often 10-20 pages or more.

There are four phases of human drug research; here's a brief (very brief) description of each stage:

Phase I Research

Is often called 'First Time in Man,' however, many Phase I studies are in drugs that have been tested in a human population before. Phase I studies are performed under very controlled conditions. A small group of 'healthy normal' people will be tested at first, starting with very small doses and dosing is increased very carefully, under heavily monitored conditions.

The reason healthy volunteers are used for Phase I studies is to avoid needlessly exposing someone with a health condition to a research drug. It also helps give better research results, since all volunteers are screened to ensure they pass basic lab tests and are free of outside substances (such as tobacco products, or anything containing caffeine).

Phase I studies usually have set dosing periods, set meals and menus (subjects usually have to eat the same food, and they generally have to finish everything they're given), and are done in hospital-like environments. This helps protect the safety of volunteers and provides the equipment and conditions needed for blood draws, physical examinations and other tests. The meals study subjects consume are actually part of the research; drugs will often behave differently in the body (or cause different side effects) under fasting conditions or after a high-fat meal. This is the sort of information consumers see on pill bottles later on, such as a warning to take the medication with a meal, or to avoid certain foods (perhaps milk) while taking the drug.

As with animal testing, Phase I shows how the drug is processed through the body, how it's eliminated, how long it stays in the system, and whether there are side effects. Every 'complaint' a volunteer has is recorded in the files as a potential side effect.

Phase 2 research is similar to Phase I, but in a larger population. After the research done in Phase I, the pharmaceutical firm decides the level of dose to give to a wider population (since the first tests were likely small doses that may have been increased bit by bit).

As with Phase I, Phase 2 research looks for side effects, monitors how and when the drug is passed through the body into the urine or feces and monitors how long the drug stays in the system before it is 'washed out.'

This stage is usually done under similar controlled conditions, but it can be outpatient as well, depending on the formulation being tested and the population its tested in.

Phase I and Phase 2 research is often done through Contract Research Organizations (CROs). These firms have advanced research facilities that offer controlled environments, emergency medical personnel and equipment, on-site lab techs and physicians, nutritionists and other professionals who are needed to conduct the study. It is often more cost-effective for drug firms (even large ones, such as Pfizer, Glaxo Smith Kline or Eli Lilly) to contract out the human phases of research rather than carrying the ongoing expense of the type of personnel when they may not have a drug in the research stage at a given point.

Often, volunteers must stay overnight in facilities; at many CROs, subjects stay in dorm-like rooms with recreation or community areas where they can watch television, surf the Internet on laptops, play games and visit with other volunteers. Strenuous exercise is usually forbidden, because it can change an individual's heart rate and other factors and can affect lab results.

People who volunteer for this type of research are generally compensated for their time (based on the number of days in the study, the number of overnight stays and return visits). This is not considered regular employment, and research firms (CROs have the right to restrict people from future studies if they have difficulty adhering to the protocol or 'house rules,' or if their safety could be jeopardized by participating. Even though it is not considered an actual job, research sites must report compensation to the IRS if it exceeds a certain amount.

If you tour one of these facilities, you will be impressed at the sophisticated technology used in the design of the building, such as providing areas where the lights can be adjusted to a color that will not interfere with the study drug for studies with light-sensitive formulations (ever wonder why pill bottles are usually tinted orange? Now you know!). You'll also be impressed and comforted at the emphasis on safety and protection of the research volunteers.

Phase 3 studies take the drug into the patient population. Once the pharmaceutical firm has studied the side effects in healthy subjects and identified the optimum dose for treatment use, research is done in patients who might benefit from the drug. As with Phase I & 2, these individuals are 'consented' before participating in the research.

Phase 3 often starts out in a limited number of patients, and as more information is gathered, the group is expanded. By the end of this stage, many thousands of people may have taken the drug in order to determine how well it treats a condition (or does not treat it, as the case may be). This stage can go on for many years in order to gather data on results and efficacy. Volunteers are monitored to see how they respond. Some volunteers might be compensated at this stage, and some will participate in order to have early access to the drug in the hopes it will help them.

Phase 4 studies are usually after-market research. A drug that is already on the market can be researched for various reasons or to adjust it in some manner (maybe it will be given in a capsule rather than a tablet). Even a drug that has been approved by the FDA will go through additional research if any changes are made to it in order to demonstrate that the formulation has the same efficacy it had before the changes.

The above is a very (very!) brief outline of what happens before drugs are approved and reach the pharmacy.

The IRB is involved during all four stages, but not after FDA approval for marketing the drug. Devices also go through similar research, but the process is slightly different (volunteers still need to give their 'informed consent,' of course).

An important fact to know: The patent for drug studies is very short; only about 16-17 years. The timeline for the patent begins when the formulation is first studied in humans. Since the phases of research can take many years, pharmaceutical firms often have only a few years left 'on patent' to recoup the many millions (sometimes billions) of dollars spent developing the drug. Not to defend high drug prices, but this may help you understand why the costs to the consumer are so high.

This information is meant to help shed light on the process, not to support or defend drug research, animal research or other elements of pharmaceutical development! I hope it's been helpful to you!