How long must a drug company prove a drug safe and effective to win FDA approval?
December 15, 2011 10:51 AM   Subscribe

When a drug company is trying to get the FDA to approve a new drug, my understanding is that they have to demonstrate that it's clinically effective and not acutely toxic for a finite period of time (weeks or months). But how long?

I Googled for this and, to my surprise, couldn't find it. Thank you!
posted by toomuchkatherine to Science & Nature (11 answers total) 1 user marked this as a favorite
A quick glance at FDA's Guidance for Industry -- Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (pdf) seems to indicate that there's not a time period that's set in stone. But I haven't read through the whole thing. Lots more information from FDA is available here.
posted by Balonious Assault at 11:00 AM on December 15, 2011

A pharma company has to submit evidence to the FDA of efficacy, but I actually don't think the period of time for demonstrating efficacy is codified, at least in part b/c different levels of efficacy/toxcity are acceptable for different indications. (I.e., drugs which treat cancer can also have a bazillion side effects, some of which can be pretty intense, but these drugs are still approved -- whereas if that drug were being marketed for a pain indication, it might not be FDA approved based on the toxicity profile.)
posted by oh really at 11:05 AM on December 15, 2011

You may want to look at the Code of Federal Regulations pertaining to an NDA (new drug application) -- you can find it here -- but I really don't think you'll find anything concrete.
posted by oh really at 11:06 AM on December 15, 2011

It depends on the drug, whether it's prescription or OTC and what it's used to treat. There's no standard timing, but a typical prescription drug needs to prove both safety and efficacy (e.g. it's safe and does what it's supposed to) through several phases of development:

Phase 1 - first in humans - typically tested in a clinic setting in healthy normals to see if it can be tolerated. Can last anywhere from 1-4 weeks in-clinic/controlled envioronment (e.g subjects live in the lab for the entire duration).

Phase 2 - if Phase 1 works, Phase 2 occurs to look at dose ranges to determine the minimum effective dose (e.g. the minimum amount of active ingredient that can be safely tolerated while treating whatever disease). This is the balancing act and oftentimes Phase 2 can be repeated over and over again. Depending on the type of drug this could last one month (e.g. vaccines) or years (pain, inflammatory studies, GI, cardiology, etc.)

Phase 3 - long studies to determine if the combination found in Phase 2 works in the actual diseased population. These can last anywhere from a year to 5 years or longer.

Once Phase 3 has been established, replicability oftentimes needs to be shown, so the trials are repeated. This is why drug trials can get extremly expensive and time consuming. It really comes down to the type of drug being developed, for what purpose and whether or not Phase 1/2 are successful.
posted by floweredfish at 11:06 AM on December 15, 2011

Generally, there are three phases for FDA drug trials. The first phase determines general toxicity and how the body processes the drug, the second determines whether the drug is as or more effective than existing drugs, and the third phase expands testing to a larger group of subjects. The process can take up to ten years, and the first phase of trials can take two to three years. Even after the drug is brought to market, it can be recalled if serious issues are found (see: Vioxx).
posted by Blazecock Pileon at 11:10 AM on December 15, 2011

I think drugs have to have been tested in animal trials before starting the phases of testing on humans outlined above.
posted by vitabellosi at 11:15 AM on December 15, 2011

To piggyback on what floweredfish said, in oncology clinical trials, Phase I testing is often first-in-human, but the research involves participants who have cancer, not healthy controls (b/c of the toxicity of the drugs). Phase I testing in onc research is to determine the maximum tolerated dose -- i.e., not whether the drug is effective, but how much of the drug can be given before the participant starts experiencing "unacceptable" toxicities. Phase II testing looks at safety & efficacy -- i.e., developing a feel for what the toxicity profile of the drug is & how disease responds to treatment. Response is often tracked during a Phase I study but it's not a primary endpoint. Phase III studies compare the new treatment to the established treatment to see if the new treatment offers any kind of benefit (better response rate, longer survival time, more manageable side effects). I know that drug testing for cancer research is slightly different from drug testing for other indications, though.

& what Blazecock Pileon said is absolutely right -- recently a drug that has been approved for colorectal cancer (bevacizumab/Avastin) was later approved for breast cancer, & then that approval was rescinded due to bevacizumab's nasty side effect of GI perforations, which is apparently considered an acceptable risk when treating certain kinds of cancer but not when treating breast cancer (b/c it doesn't confer a benefit).
posted by oh really at 11:23 AM on December 15, 2011

I don't deal with this stuff directly, but I do serve on an Institutional Review Board committee that reviews and approves/modifies/denies several of these clinical trials per month. From our point of view, there are no specific rules on how long/short the trial must be for us to approve it. It does have to have been approved for scientific validity by someone (if it's a corporate drug trial, typically it's the university scientific review commitee; for federally funded research, it wouldn't have gotten funded without scientific review so just getting funded is good enough.) The lengths of trials seem to vary, as does the length of follow-up done afterwards. I don't know what factors the committees are weighing, but it seems to be at least somewhat subjective.

That said, our IRB needs to have appropriate subject matter expertise, and if a reviewing oncologist on the commitee tells us that the suggested length is not scientifically valid or not safe for the participants, then we can and will override the committee and tell the researchers they have to change their research plan. Another committee might or might not have made the same recommendation.

Many sources of variability.
posted by Stacey at 11:28 AM on December 15, 2011 [1 favorite]

and not acutely toxic for a finite period of time (weeks or months). But how long?

I work at a pharmaceutical company. The answer is complicated, and depends on many factors. If it's a drug to help a patient with a very deadly form of cancer, chances are the treatment is going to be fairly toxic. The benefit has to outweigh the risk, and that has to be proven in very rigorous clinical trials.

It's important to realize that trials don't stop once products are approved, that's why you see some drugs get pulled from shelves way after product approval. It's safety profile is continually monitored. And sometimes the FDA approves "risky" drugs if they believe that it's worth it to get the drug out to the public more quickly.

As for efficacy, the drug has to prove that it is better than the current standard treatment. When a new drug comes on the market that beats the old drug, the old drug doesn't get kicked off the market, they just naturally lose market share.
posted by pwally at 12:02 PM on December 15, 2011

Rough rule of thumb:
1) Drug must be as safe as an existing treatment and more efficacious (better results or for longer);
2) Drug must be safer than an existing treatment and as efficacious;
Used to be that it just had to be safe, so you could produce a new drug with same safety and same efficacy, but that no longer flies.
posted by blue_wardrobe at 6:39 PM on December 15, 2011

Acutely toxic, kind of by definition is a days/weeks kind of thing - chronic toxicity does matter.

A lot of safety stuff is dependent on the nature of the drug - there are certain things you're going to look for in an immune modulator that you wouldn't worry about for a drug to treat type II diabetes. If you know what you're looking for, a lot of times you can find indicators - liver enzymes or something fairly early on.

Sometimes an effect is subtle and unanticipated, which is why they keep adverse event records more or less forever. I once received training that told me that I was supposed to contact the people who track our adverse events if someone I knew mentioned an adverse event with one of our products, even in idle passing. (And immediately if death was involved.)

This is where I'm going to have to confess that my commitment to safe medication was trumped by my unwillingness to look like a total idiot and I never called them to report that a guy I knew only as "Trombone of Fury" mentioned that one of our products gave him "teh worst farts evar!"
posted by Kid Charlemagne at 12:35 AM on December 16, 2011 [1 favorite]

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