# What are side effects frequencies based on?

I am one of these patients who reads everything that comes with their pills. Including, of course, the sometimes really long side effects list. Where I am, and from what I read online this is common, these side effects are sorted into several frequency categories (common/rare/very rare/sporadic, something like that).

Yesterday, after years, I realized I had no idea where those frequencies come from. Do they come from scientific studies? From people participating in really large-scale trials?

Or from doctors reporting back on what their patients report? From patients reporting it? But then, how are the frequencies determined? "Common", for example means something around 10 percent where I am, so you don't just need to know how many people report that side effect, you need to know how many people took the medication (and did so as instructed, and didn't take anything that interfered with it, etc.).

So, where do these frequencies and these lists of side effects come from?

I'm in Germany, but I am open to an answer as to how this works in any country.

Side effects frequency narrative words are defined by the council of International Organizations of Medical Sciences. See slide 10 of this presentation on the subject. As shown, "Very common" means equal to or greater than 10% [of the patients tested for that drug]. "Common" or "frequent" means more than 1% but less than 10%. "Uncommon" or "infrequent" means between 1 per 1,000 and 1%. Rare means equal to or more than 1 per 10,000 but less than 1 per 1,000. Very rare means less than 1 per 10,000.

In turn, for any specific drugs the above metrics are derived, not by doctors, but by specialized clinical trials statisticians conducting clinical trials of such drugs. Clinical trials are conducted by separating patients into at least two groups. One control group just takes a placebo. The test group takes the drug. This type of study is sometimes called randomized double blind placebo control study. This process is further described in this paper. You conduct the clinical trial for a certain period of time. And, then you observe the frequencies of side effects using the semantic as described above. Granted, the statisticians deal with the actual precise numbers and are not satisfied by using narrative categories instead of calculations.

Next, the statisticians will compare the frequency of side effects between the Control group and the Test group. And, they pay much attention where the Test group's side effects are much larger than for the Control group. And, they measure whether that difference is real and not due to just randomness. The latter (probability that occurence is just random) is captured in a probability called a p-value. If that p-value is less than 0.05, the side effect is deemed to be statistically significant (and greater than for placebo).

In the US, the mentioned clinical trials are submitted for assessment and drug approval or denial to the Federal Drug Administration (FDA). In Germany, such clinical trials are submitted to Bundesinstitut für Arzneimittel und Medizinprodukte BfArM.

If you are interested on the subject, the BfArM website has most probably some very interesting information.

• Thank you for your answer, I'll look into the BfArM. I'm afraid this leaves me with a few follow up questions - I already knew about the frequency names, but as far as I know, very rarely do drugs get tested on the number of patients you'd need to determine a rare/very rare side effect, so where do these come from? If all side effects listed just come from clinical trials, what happens if one is rare and only shows up once the drug is used on a larger scale? Dec 26 '15 at 8:02
• I think clinical trials can vary in sample size, but the statisticians and epidemiologists engaged in structuring such trials know at the onset how many patients they need to test to derive the statistical significance they need to determine the safety and efficacy of a drug. As far as reaching into the rare and very rare levels, clinical trials probably are often not that large. But, FDAs and the BfArM, I believe do get pharmaceutical companies to keep on tracking such drugs once sold to the entire population. And, that's how rare and very rare effects are detected. Dec 26 '15 at 19:49
• To answer your question what happens if one is rare and only shows up once the drug is used on a large scale? I think either the drug gets removed from the market, or its label get revised to fully disclose those rare and very rare side effects. Dec 26 '15 at 19:53
• FYI the studies don't always compare the drug to placebo for side effects. I am in a study comparing side effects for two different doses of a drug (the similar effectiveness of the two doses was already established by an earlier study.) May 21 '17 at 14:49

To answer this question, I think it would be better to know how a drug gets into the market. There are a number of trials done on a drug before it is approved for general/commercial use. These are

1. In-vitro studies
2. Animal studies
3. Phase 1
4. Phase 2
5. Phase 3

In-vitro and animal studies are done to evaluate the mechanism and efficacy of a specific drug while Phase 1, 2 and 3 trails determine (or rather estimate) the efficacy and adverse-effects of the drug in clinical trails done on real patients/volunteers with increasing sample size.
Phase 3 trails are the largest and usually the last trails before a drug is approved for routine clinical prescription. The sample size in these trails varies considerably depending upon the prevalence and nature of the disease for which the drug is being developed. For example, around 15000 children were included in phase 3 trails for the new vaccine currently under consideration against malaria. For diseases like cancer the sample size is likely to be smaller.
Most of the time the sample size in these trails is inadequate to catch all the possible adverse effects of a drug. It will however, bring the common ones to light. To counteract the issue of relatively rare adverse effect, another kind of trail is in use, often called phase 4 or post-marketing surveillance in which the physicians report any hitherto unknown adverse effects of the drug to the regulation authorities after the drug has been approved for commercial use. If these adverse effects are deemed serious, the drug may be recalled from the market and banned from further use (as was the case with Rofecoxib, and several other drugs).
I hope it helps you understand the concept at least a bit.

• Welcome to health SE :-). This is a good, concise answer, but references are required on health SE. Please refer to meta for more information. Thanks! Dec 27 '15 at 10:03
• @drFayyaz. Don't take this personally. This forum somehow is far more officious than any other one you will participate in within Stack Exchange. I personally feel like they push the "reference" policy way too far; and end up discouraging people from exchanging valuable information. On the other hand, it is hard to argue that health answers that are readily interpreted as health advice (whether they should or not) are inherently a lot more dangerous in terms of their implications than other answers. So, the "reference" bit is not a bad safeguard after all. Dec 29 '15 at 23:18