What does happen to drugs following public release?

A recent JAMA study combining researchers from the U.S. and France looked at the “future” of FDA approved drugs from 2001 to 2010. It found almost a third (32%) experienced a “post market safety event” over eleven years.  Only three out of 222 drugs were  withdrawn from use.  But about 30% either got a “black box” warning or a “safety communication” letter.

You learn a lot about drugs when you start using them.

How Drugs Get Approved

Approved drugs go through a tight gauntlet.  About 90% of actively studied drugs never achieve approval.  Until recently, when the fruits of biotechnology finally bore fruit, fewer drugs were approved year by year for quite a long time.

Yet approved drugs are generally studied for generally short periods. Antidepressants, for example, may only be only put through clinical trials of  weeks or months – and then be used for years or decades.  Perhaps more important, drugs are often studied in subjects who possess  “one problem” rather than the many, concurrent diseases found in the older population, who use the most drugs. Statistically it is far easier to study drugs among people with a single diagnosis. That may not tell you, however, how they’ll work in the patients who end up actually using them.  When people have multiple diagnoses they are often prescribed multiple medications.   Those kinds of drug interactions are not actively studied under most FDA protocols.

In short, drugs are used in very different populations than the “pure,” often younger groups in which they are studied for original efficacy.

Yet overall things are far better than they used to be.  In the past, drug companies could hide a lot of their data.  As British epidemiologist Ben Goldacre has pointed out, only 51% of paroxetine’s (paxil) clinical trials demonstrated it performing better than placebo.  Yet the data original presented to the FDA showed 94% of the trials as “successful.”  The FDA is much more cautious than it once was.  Still, much of their funding comes from drug companies.

For political and economic reasons, you can go just so far in assaying risk.

What the Study Showed

Not all drugs are equal.  Certainly not once they go “post-market.”

Among the drugs that later gained black box warnings and safety letters, psychotropics stood out.  The odds ratio for safety warnings was nearly 4 to 1.  The brain is a very complicated place, and many neurologically active drugs produce side effects that are not immediately obvious.

Drug companies know this well.  Johnson and Johnson alone paid $2.2 billion in criminal and civil fines for “overpromoting” risperidone (risperidal) to children and the elderly. Other drug companies paid up similarly hefty sums.   These drugs created far more obesity, hypertension, and diabetes than originally advertised.  Yet overall profits from these medications dwarfed the billions in fines.

Biologics also have a higher rate of safety and black box warnings post-release.  This is not a surprise.  Drugs like monoclonal antibodies are interacting with the immune system in novel, not very well understood ways. The immune system itself may be compared with the brain for its many levels of complexity. Even very tightly “targeted” medications impact the entire immune cascade of response.

Last, drugs that were approved early because of perceived public health need, or approved very late in the allowed timeframe for acceptance, also demonstrated  more problems later on.

What This All Means

Drugs do many things.  Much of what they do is unknown. Researchers still don’t understand how alcohol produces its many effects, and we have at least five thousand years of clinical experience with booze. The body possesses many layers of information and information integration of which we are unaware.  So it’s reasonable to expect “unexpected” effects for drugs over time.  That these occur more commonly among psychotropic or immunological drugs is perhaps predictable.

Yet FDA approval is greatly prized.  It means far more than profits to companies.  It also means respect.  People believe the FDA only approves drugs it knows to be safe.

So finding a third of them developing post-marketing problems is troublesome.

Fortunately, there is quite a bit than might aid the situation.  Big Pharma is now tightly connected with Big Data.  National health systems in Europe can fairly readily look at the problems drugs produce over time.  The will is there. The money may not be.

The situation in the US is more difficult.  Our remarkably fragmented and inefficient health care “system,”  compounded by insecure health record keeping maintained in closely contained information silos, makes long term monitoring difficult.  A national health system, even a single national payer form, might make it easier to monitor things when they go bad.

Yet large American populations can be checked. Operations like Kaiser can track their patients over rather long periods of time.

Yet ultimately someone has to pay.  It can be the public, directly, through FDA or HHS money.  Or it can be as if often is today, through happenstance.

As in many public health arenas, it’s better to know than not to know.  It took decades for clinicians to realize that ultrasound treatment of gallstones fostered diabetes.

Big data is ready and waiting.  If the security and privacy issues can be worked out, outfits like Google and Apple would no doubt love the data sets.

To fully survey drugs and their effects, however,  politicians will need to cross companies that may not want that information public.

We know how that plays out.