How drugs go from healing mice in the lab, to sitting on your pharmacy shelves

Illustration for article titled How drugs go from healing mice in the lab, to sitting on your pharmacy shelves

The news is full of headlines about some drug that has cured mice of everything from baldness to paralysis. Although these advances are real, their useful medical application for humans seems out of reach. What does it take for drugs to make the jump from animals to human testing? And when does a drug being tested on people finally make it into your pharmacy. We explain it all to you.

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The Initial Application: How Much Paper is Enough?

The first step for scientists to test their drugs on humans is getting FDA and Department of Health and Human Services approval. Naturally, this means mountains of paperwork. It's necessary to go in armed with a toxicology report and reports of least a few monkeys who made it through the initial testing alive. Researchers also have to describe the facilities and processes involved in the manufacturing of the potential drug. No starting out a report with, "I know a guy who can get us a great deal. He sells stuff out of the back of his van." The initial application also has to walk reviewers through plans for the potential human study, from gathering volunteers to follow-up care and addressing adverse reactions.


Although it seems a straightforward process, screw-ups do occur. Applications are reviewed by private review boards, paid by the companies filing the applications, and companies are allowed to keep trying until they find a review board that approves their drug. Rather famously, the Department of Health and Human Services once contracted a review board which approved an application for human testing of a non-existent drug. The DHHS has also accidentally enlisted the aid of fake review boards, despite names like "Phake Medical Devices" and "April Phuls."

Phase One: The Healthy Suffer First

If the stamp of approval is given for human testing, the drug goes into Phase I clinical trials. Ideally, at no point during Phase I will the drug go near a sick person. Healthy volunteers are recruited for the first phase of a trial, even though they won't get any benefit from the drug. Phase I is about how the healthy body processes the drug. Researchers study how the drug enters the body and how it leaves. They figure out the rate at which it's metabolized. Most importantly, they note any bad reactions or worrying effects of the drug.

Since Phase I is basically a disaster check, it often only lasts for a few months. Still, thirty percent of drugs are eliminated. There is little information about failures in Phase I, but occasionally healthy people do die. No one wants to publish these results in a medical journal. In 2007, the FDA set up a registry and a law was passed that required all drug studies to be registered, and their results recorded. Usually, though, the results are a vague comment of "safety issue" or "study voluntarily terminated". These brief notes hide a lot of pain. Although most Phase I trials are conducted on the healthy, the FDA makes provisions that allow patients suffering from very serious or terminal diseases to take part in such trials, as long as it is made clear that fatal reactions, overdoses, or underdoses of the medication are possible.

Phase II: But Does it Work?

It's in Phase II of the trials that the real winnowing process begins. It's now that the drugs need to prove their basic effectiveness. Only about forty percent of drugs make it out of this phase. Not only does it require a larger pool of subjects, all of whom fit a certain profile, but there's the delicate matter of testing the results. This is no problem when the patients have the condition they are being treated for. It's a little tougher when researchers are working on preventative medicine.


For example, scientists have been working on HIV vaccines for a long time. It looks like, despite the efforts of scientists and governments world-wide, they will be working on it for a long time to come. The HIV Vaccine Trials Network coordinates many trials internationally, from the very general to the very specific. There's even a trial that's only focused on twins from San Francisco, Seattle, and Boston.

Although there is a lot of support for these HIV vaccine trials, the going is necessarily slow. Obviously, the participants in the studies can't actually be dosed with HIV positive blood to test its efficacy. In fact, study participants receive counseling in infection prevention in an effort to make sure that they don't take unnecessary risks. The study participants simply have to come in for regular HIV tests and to discuss any risky behavior they might have taken. You can see why nobody should be waiting on the edge of her seat for an HIV vaccine.


Phase III: Out of the Little Pond

Once Phase II has established that the drug has some efficacy, Phase III brings it into the big time. The pool of subjects widens, and the weighing of adverse and positive reactions becomes more serious. Some HIV vaccine tests have made it to Phase III, and even look promising. The results of one 16,000 person test in Thailand showed a twenty-six to thirty-one percent reduction in the rate of infection.


It seems like it's easy going for drugs that make it to this phase, but there is still room for failure. About 70-90% of drugs make it through Phase III. But that's cold comfort to researchers who have poured work (and money) into drugs that fail at the last minute. One hay fever drug failed due to low allergy symptoms in patients who got the drug - as well as in patients who got the placebo. Obviously, your drug needs to be more effective than a placebo. The manufacturers protested that it was a low allergy season, and they couldn't demonstrate a reduction in allergies if there weren't severe allergies to start with. But they still didn't get approved to bring their drug to market.

Illustration for article titled How drugs go from healing mice in the lab, to sitting on your pharmacy shelves

A more disturbing Phase III failure was a recent test of a gene therapy that was meant to treat obstructions in the cardiovascular system. After a promising Phase II trial, the therapy caused more amputations and higher mortality rates than a placebo in Phase III testing.

Even a Phase III trial that's a success can be a failure. Say a drug has a low side effects and a much better rate of success than a placebo. It sill has to rate high against its competitors. Unless a drug is better than what's already out there, or can serve a group that existing drugs can't, there's no point in putting it on the market.


Phase IV: But are We Going to be Graded on This?

After successful completion of Phase III, a drug or device can be marketed to the public, but the trials don't stop. Adverse reactions and new side effects need to be monitored and recorded. The trouble is, the drugs are now on the market, and it often cost pharmaceutical companies a lot to get them there. So companies do sometimes get lax after what, economically at least, is the finish line.


But what if the drug is causing problems? The FDA is now the organization that has to jump through hoops if they want to pull a drug off the market. As a result, sometimes Phase IV trials are unresolved. One study shows that between 1990 and 1994, 88 new drugs were approved to go into Phase IV by the FDA. But by 1999, only 13 percent of these Phase IV studies were marked as ‘completed.'

Slow bureaucracy, or lethargic business? Tough to say.

Maybe it's better to just stick to generic aspirin.

Via, Essortment, the FDA, Journal of Clinical Oncology, and SF is Ready.


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Dr Emilio Lizardo

I don't know where this info comes from, but the process is very different in Oncology.

Phase I trials are done on cancer patients, not healthy volunteers (also known as medical students). These patients have exhausted or are not interested in standard treatment. While efforts are made to steer patients with specific diseases towards drugs that the science suggests may help them, any cancer patient may recieve any drug. The sole goal of Phase I is finding how much you can safely give to people - the MTD or Maximum Tolerated Dose. Unfortunately, less than 10% of patients who enroll in Phase I trials get any personal benefit beyond the good feeling of knowing they are helping other people in the future.

Phase II trials are when a drug is directed against a specific disease, say lung cancer. The dose found in Phase I is used and information on toxicity and efficacy are collected. If the drug shows efficacy with acceptable safety the drug can be approved on the basis of Phase II data. From a regulatory standopoint it is not necessary to show that it is better than anything, technically not even a placebo. It only has to be safe and effective, not safer or more effective.

Phase III are comparitive trials where a manufacturer is trying to show that one drug or combination is superior to another. Often the control arm will be a placebo, especially if there are few effective treatments in a given disease. Good Phase III data is not required but if you have it your drug will almost certainly be approved unless toxicty is unacceptable. It is an interesting fact and the subject of much research that response rates in Phase II studies are often much better than in Phase III. There are many reasons for it.

Phase IV is exactly what you said it is. The FDA likes your data enough to approve the drug but wants to see more to confirm that it really is all that and a bag of chips. You are right that even when the FDA "requires" phase IV testing it often does not get done. The only situation that guarantees it will be is "accelerated approval." That process is usually spun in a positive light by the drug companies; you can see why people would think a drug granted "accelerated approval" is great stuff. In actuality it means that the FDA sees promise in your data and the drug is meeting a need currently unmet by any other drug but they want to see more. therefore they approve it but set an actual date to re-review it for final approval. It allows people to get drugs that otherwise would have to undergo further testing. The vast majority of drugs granted accelerated approval are eventually granted full approval.

Maybe the process is just different for oncology drugs?