How the FDA Could Change the Way It Approves Drugs
fivethirtyeight.com
fivethirtyeight.com
The FDA already does this. Take a look at the Duchenne's muscular dystrophy drugs currently up for review. One of them fail to show a statistically significant difference from the control group and the other one only had a single trial of 10 patients.
The likelihood is that one or both of the drugs will be approved since no treatments currently exist.
Then take a look at diabetic drugs. Any hint of cardiovascular side effects and the FDA slaps a black box warning on the package and asks for a 10,000 patient follow-up trial. This makes sense because drugs already exist to control diabetes.
This article seems to lay out a more mathematically driven method for statistical testing, but it's a bit ingenuous to say this is something new for the FDA.
Pharmaceutical companies are very reluctant to even give drugs to desperate patients because the FDA requires them to report all adverse side-effects even though they have no control over the conditions in which the drug is used. You can actually kill a totally fantastic drug by letting people use it outside of a controlled clinical trial.
Not really, you just have to buy it from a compounding pharmacy.
The reason we need very large, expensive, and strict clinical trials is because it's hard to see if a drug actually works or not otherwise - too many confounders. So if we pass drugs through with a higher error rate, we'll likely never know if some of them actually work or not. Maybe not a problem for a disease with no treatment at all, but imagine you have 10 treatments and you suspect that 7 of them don't actually work, but you don't know which 7. Is that better than just having 3 available treatments where only 1 of them doesn't actually work?
People bring up the "more harm than good" issue, but they're only thinking of one kind of harm: drugs that actually hurt people. But having ineffective drugs on the market also has a cost, and it's probably the bigger one. The market for effective drugs is almost certainly not efficient given the difficulty of ascertaining efficacy and the information asymmetries involved. Thus, there is a real risk of people dying because the inefficient market selects for drugs with good marketing over ones that work.
The other major reason for failure at Stage I/II is that the preclinical models we are using are not a good match for human disease. This means that a drug that works in a mouse model can’t ever work in humans because the mouse model does not reflect the human disease (Alzheimer's is the classic for this). We are using preclinical models we know are useless and are then surprised when the drugs found using them don’t work in humans.
If you want to medicine to build on the foundations of history, you need to be able to reference the history.
Well, they ran the bigger trial and it showed no benefit at all. The FDA rescinded conditional approval.
Avastin probably does work for some breast cancer patients if they have a cancer with the right mutations, but if the percentage is a small enough then the large study would not be able to detect this effect in the broad population.
Besides, the proposal is not to approve all drugs easier. Drugs for same conditions would be harder to approve under the proposed model.
Previous discussion: https://news.ycombinator.com/item?id=10145606
Also a long post on MR: http://marginalrevolution.com/marginalrevolution/2015/08/is-...
If he's more willing to gamble, then why not just let him do it? The FDA's job should be to enforce truth-in-labelling (which means drugs with no beneficial use should be labelled as such, and those with horrible side effects should be labelled as such), and patients working in concert with their physicians should determine which drugs to take.
For this to work, we may need to limit the ability of drugs to be advertised. I'm okay with limiting the civil right to free speech of pharmaceutical companies in order to respect the fundamental human right to ingest whatever one wishes of patients.
They already do. It's called expanded access programs. If a patient is going to die, they can ask the FDA for permission to take an unapproved drug. The FDA says yes 99% of the time.
You might wonder how this could be. Basically the cost of getting a drug approved is such that large sections of the human population (poor people especially) have diseases for which we have no treatment or no cheap treatment. We need to get the cost of drug development down to the level that pharmaceutical companies can make a profit developing and selling medicines to poor people or people with what are considered rare diseases.
The only losers here are the public since we miss out on cheap effective drugs because the regulations make them too expensive to produce for most diseases and people.
US is really lucky to have FDA.
Actually you would see far fewer ads since you would remove the ability and need for advertising. The reason drugs are advertised now is because the drug companies have so few new drugs to sell (no drug off-patent is ever advertised). They need to maximise the returns from the few drugs they have to sell. If hundred of new drugs came out each year then mass marketing would not work since the market for each drug would be too small.
Yes there would be more “ineffective” drugs, but if you and your doctor had the choice of dozens of drugs for your disease which one would you choose - the one for which had no evidence that it worked, or the one where the drug company has scientific evidence? Even if they did not need to do trials for the approval process, pharmaceutical companies would still do them to convince doctors and patients.
Also, they have an analysis of the advertising aspect.
In other words, Dr. Pepine thought that the FDA restrictions preventing the advertising and promotion of aspirin for heart attack patients were responsible for the deaths of tens of thousands of people.
In other words, if a company wants to make money, it can randomly pick 4 non toxic compounds, and apply for FDA approval for treating of pancreatic cancer through click-trial, in average the company would get 4*0.279 ~=~ 1 compound approved and then market the medicine to the world that the medicine is effective.
They give weight/cost to type I and type II error, and their whole analysis can be changed if the weights changed.
I would treat the paper as a research-toy, self fulfillment. Try to change policy based on the paper would be absurd.
A better approach would be to not have any effectiveness trials at all and just collect good data on all patients using the drug. If a drug really worked it would become obvious the more patients used the drug, while if it was worthless this would also become obvious. A new drug would start out unknown with only the most desperate trying it and overtime we would learn more and more about its effects and side-effects.
This bayesian approach was not possible in the past, but with modern technology it is now. We would get better drugs with better known side-effects at far lower costs.
So, how does the FDA deal with this issue today? Suppose the scientists wanted to market (some flavor) of jelly beans as a drug to cure acne (instead of to cause it), and they test 20 flavors and get evidence at p < 0.05 that white jelly beans cure acne. Or 1000 flavors and evidence at p < 0.001.
Does the FDA look for a causal mechanism that would make the drug effective? Or are the companies afraid to market things that they genuinely suspect are ineffective because they'll eventually get sued? Or is the FDA's effectiveness standard so strong that you just can't cost-effectively game it like this today? (The last possibility seems a little bit unlikely.)
As far as I know nobody has ever been sued over a drug that didn’t work. From a purely legal perspective you would better selling a sugar pill than a real drug that worked and caused 1 in 100,000 people to drop dead.
2. The full clinical trials still cost hundreds of millions of dollars.
Which is only one of two possibilities, and hence, it cannot be 'the probability the drug is approved by the FDA', for the same reason that 'a p-value of 0.05' does not mean '95% probability the drug works'.
Pre-clinical only requires that you show a drug is not toxic and has a potential benefit. Most drugs fail because they are either toxic or don't do anything.
Why would you loosen those regulations?
The bigger problem is you can’t show either of these with preclinical testing. If you could then there would be no need for human testing.
The reality is most of preclinical testing outside of certain drug classes (e.g. antibiotics) is not that helpful for knowing if a drug will cause problems in humans or will even work. It has got so bad that most drugs on the market would not get through current preclinincal testing requirements.