The FDA, speed, and thalidomide
Articles like this one accuse the FDA of unnecessary slowness in approving diagnostic techniques, treatments, and vaccines:
Pandemic vaccines and drugs don’t move through the FDA approval process faster. Instead, drug- and device-development times actually increased more than 70 percent over the past decade because the FDA keeps demanding more studies and more data using outdated techniques.
It’s easy to blame the FDA, and as a federal agency I’m sure there’s plenty to blame. But don’t forget that the American people demand (and I mean exactly that: demand) contradictory things from new drugs, treatments, and vaccines: speed of development and use, and absolute safety. And if we don’t get that “absolute safety” part, we’ll sue the pants off you.
Well, those are contradictory demands. You can’t ordinarily get both. In fact, absolute safety, to the degree that people seem to be demanding it these days, is not possible even with a very slow development of the drug, treatment, or vaccine. Many problems only reveal themselves over time, and every treatment will have some problems for someone.
I am old enough to remember that America dodged the thalidomide bullet that hit Europe. It was through this more-cautious approach of the FDA:
In September 1960, Dr. Kelsey was a newly appointed member of the Food and Drug Administration (FDA). Her very first assignment was to review the application for the drug Kevadon. Synthesized in 1954 and introduced to the market on October 1, 1957 in West Germany, the drug””known there by the name Thalidomide””was hailed as a wonder cure for insomnia. Non-addictive and non-toxic, Thalidomide induced sleep and was prescribed as a sedative that promised no side effects. As its popularity grew, it soon became the drug of choice prescribed to pregnant women…
No side effects—at first. At least, not that anyone could see.
Of particular concern to Dr. Kelsey and her staff was one of the drug’s major selling points: unlike barbiturates which induced sleep but also induced death if taken in large quantities, Thalidomide could be ingested in large quantities, seemingly without toxic side effects. However, Dr. Kelsey recalled a study she conducted on rabbits as a young post-doctoral pharmacologist at the University of Chicago in 1942. Part of a team that was seeking to create a synthetic cure for malaria, Dr. Kelsey had noted that, although adult rabbits metabolized quinine rapidly, pregnant rabbits were less able to metabolize the drug and embryonic rabbits had no ability to metabolize the drug. Furthermore, Dr. Kelsey noted that the drug did indeed pass through the placental barrier between mother and developing fetus. Recalling those observations in reviewing the Thalidomide application, Dr. Kelsey was concerned that physiological changes such as pregnancy might change the absorption properties of Thalidomide, leading to harmful consequences.
Responding to Dr. Kelsey’s requests for more clinical proof of the drug’s safety, Richardson-Merrell submitted additional evidence, but she again rejected the application on the grounds that the reports were testimonial””not clinical””in nature.
As autumn closed in on the Christmas holiday season””the most lucrative time of the year for the sale of sedatives””the pharmaceutical company, frustrated by the repeated and, in their view, unnecessary delays, began to pressure Dr. Kelsey with visits and phone calls to her superiors. Despite the increasing pressure, Dr. Kelsey remained steadfast in her demand for thorough clinical studies demonstrating the drug’s safety.
Recalling this story (not every detail, but the main outline), I tend to think of it when people trash the FDA for being too cautious about new drugs. However, in the past, whenever I’ve brought it up in such conversations, nobody had ever heard of it (that is, they’d heard of thalidomide, but not that it was not approved in the US, or why). In fact, people often misremember, and think that the bulk of the thalidomide babies were born in the US rather than Europe. What actually happened was this:
In the few years that the drug was on the world market, thousands of children were born with Thalidomide-related deformities. Many did not survive until their first birthday. Countless more miscarriages were traced to the use of Thalidomide. The damage in the United States, due to the work of Dr. Kelsey, was small by comparison, with 17 children documented to have Thalidomide-associated deformities. (During an investigational period, Richardson-Merrell had distributed more than 2.5 million Thalidomide tablets to more than 1,000 doctors who, in turn, gave Thalidomide to nearly 20,000 patients, several hundred of whom were pregnant women.)
It was one of the times that the US and the FDA—and its caution—were the stars.
That doesn’t mean it’s always a good idea to go so slowly, or that the FDA’s caution hasn’t grown too great since then. I don’t know; I don’t pretend to be an expert on whether the FDA is using the right standards or not at this point. But ever since I learned some of the details of the thalidomide days (I was too young to fully understand it when it happened), I have been cautious about condemning the FDA’s caution.
I’d offer that there’s no right or wrong answer, but a series of ad hoc particulars. If it were crucial to stave off an imminent global pandemic of ebola or polio or smallpox, perhaps it would make sense to speed up the process and take that risk.
The thalidomide example was for a sedative — a crummy sedative. That it couldn’t wait some short while longer while further questions were answered, especially serious questions based upon Dr. Kelsey’s own former research, is nonsense. It would be like rushing to market with Viagra — side effects be damned.
Bravo to Dr. Kelsey, however belated. The woman has sand! Where have such professionals gone?
n.B., and apparently she is still alive.
http://en.wikipedia.org/wiki/Frances_Oldham_Kelsey
I am a “DES daughter” – my mom was given the DES drug during pregnancy to reduce the chances of having another miscarriage.
So, she had me, but I have a greater risk of cervical cancer. Since my first abnormal test result was when I was 16 years old, that is a LONG lag time to find out cause and effect of a drug.
I can understand the need for adequate review. However, if a person is deemed terminal with cancer or some other issue, I have no problem with trying experimental drugs or “off-label” trials. At that point, it is life or death and if I am willing to sign a waiver, what the heck.
Part of ACA was the issue of “death panels” as well as the possibility of required discussions between doctor and patient on end of life care option. So, if I am very sick and the government wants me dead sooner than later, why can’t I volunteer to be the test subject for a medicine. What’s the difference between doctor assisted suicide via a sleep drug and one with an experimental drug?
With the issue of blood plasma donations for Ebola, it seems if my chances are 70% death, I would be willing to give a transfusion a try.
BTW – can the antibodies be separated out so that the risk of blood interactions is reduced? And, is there a point in the disease progression that care should be limited to comfort? I read that Duncan was put on dialysis and had a breathing tube put in, which increased risk to care givers.
T; Liz:
Yes, that’s why they allowed Brantly to have an experimental drug. He was thought to be dying, and (and this was important) because he is a physician, he could give informed consent. Short of someone dying (and a physician, too), they are gunshy because of lawsuits. There’s the “first, do no harm” thing.
Yes, Kelsey is quite a person, apparently. I read about her a while back. She also had a family and kids while she was doing all of this a half-century ago.
Interestingly thalidomide has since been approved for the treatment of other conditions.
LondonTraveler:
Yes, it’s only bad in pregnancy. It’s still banned in pregnancy. Woman (who are of child-bearing age) taking it have to have weekly pregnancy tests, and men must use condoms to avoid getting the drug into the woman’s system if pregnant.
Off Topic, but related to previous posts re the CDC actions….
I had a nice conversation with the Emergency Management Director of my town. They are very active with the state and county re pandemic preparation. He mentioned that the city’s manual for handling pandemics is about 8″ thick and has been in existence for years.
I mentioned that I had first looked on the city’s website and found nothing, which prompted the call to him. When I suggested putting up a page on the city website, he thought it was a good idea and promised to follow up on the idea. I don’t think he wants the rest of the community to be calling him! I stressed the importance of tracking individuals and protecting the first responders and he said that the 911 operators had already been trained on increasing questions re health issues.
One question he didn’t have an answer to was if the soldiers returning from WA will be in isolation on base for a period of time. I suggested that he needs to ask that of the state/federal people.
So – check with your local officials on their readiness for a pandemic. Here is a page from my state’s website. I checked a few other states and did not see anything.
http://www.ok.gov/health/Organization/Office_of_Communications/News_Releases/Situation_Updates/Surveillance_and_Preparedness_for_Ebola_Virus_Disease/
And a page from a local hospital:
http://integrisok.com/ebola-virus-disease/preparedness
Both sites had something on the main page and the info pages have been updated since I started looking at them. So, I know that the risk is low, but I am feeling more at ease that my state/city will be prepared for a pandemic. Of course I already knew that Oklahoma can deal with bombings, tornados, wildfires, floods as well as the occasional tropical depression and earthquakes. So, we’ll do OK with the flu or Ebola.
The FDA has an impossible task. You can’t prove something is safe. Something that is safe causes no harm and you can’t prove a negative. Even something as widely used as penicillin occasionally causes a potentially fatal allergic reaction.
Even with all the safe guards in place, drugs are marketed and then withdrawn because of the side effects. This is probably going to be the pattern for years to come. Most drugs have so many effects on the body that it takes extensive studies to discover all the effects.
An example, for a time cox-2 inhibitors were popular to treat pain and inflammation with limited gastrointestinal symptoms. After the medications were on the market an unexpected pattern emerged in which people taking cox-2 inhibitors had an increased incidence of strokes and heart attacks and most of the cox-2 inhibitors were removed from the market. Now we find that like thalidomide, cox-2 inhibitors are beneficial in some tumors.
I don’t blame the FDA for the problems we have in our drug supplies. They are doing a reasonably good job at screening new drugs. It is an expensive but necessary step before the drugs are marketed. We need to look elsewhere for the problems.
Anyone who watches commercial TV for any length of time will hear commercials by trial lawyers asking them to come in as soon as possible for a lawsuit against one of the evil drug companies who put out a dangerous produce. These commercials are almost all directed against companies who produce drugs which have been thoroughly tested by the FDA and are considered safe. If a statistical aberration is later discovered, as an increase of bladder cancer for example, even if the increased risk is only slight, every individual who has taken the drug and gets bladder cancer no matter what other risk factors the person might have is asked to join the suite. If only one in one hundred bladder cancers in the group is actually caused by the medication, there is no way to tell which tumor is the one which is due to the medication so the courts assume they are all caused by the medication. Litigation may be a boon to trial lawyers who contribute gobs of money to politicians who will support the lawyers incomes but it drives the cost of medication through the roof.
This problem is particularly severe for vaccines. The people whose lives are saved or who live lives free from complications from the diseases the would have contracted if the vaccine were not available are invisible. No one knows who is the one who is alive because of the vaccine. On the other hand, everyone sees the sad case in which a patient has disabilities which the parents are convinced were caused by the vaccine. Because it is hard to disprove a negative, scientists can tell the parents that the vaccine probably did not cause the problem, (often autism) but the parents are certain that someone is responsible for their child’s disabilities and they soon convince themselves that it is the vaccine. Of course trial lawyers are always waiting to shower the family with money if the courts will consent. According to my memory, for a time no vaccines were manufactured in the USA at all. I’m not sure what the status is now but it is probably not much better.
Finally we have the politicians who exploit the situation for themselves. Trial lawyers are often very wealthy and have ways to transfer huge amounts of money to the politicians – especially Democrat politicians. They in turn pass laws which make it easier to sue the drug companies and to collect massive awards. This drives up the cost of drugs. The same politicians then use the high cost of drugs to attack the pharmaceutical companies. Sure enough, when one compares the cost to actually manufacture drug with the selling price there is a large mark up. That mark up goes to the costs which the politicians have imposed on the pharmaceutical companies, but of course the politicians don’t ever make the connection between the demands they place on the companies and the high cost of medication.
The end result is that many pharmaceuticals have not been manufactured and many people are suffering needlessly because the needed drugs which could have been produced for them don’t exist. Drugs which don’t exist but should exist are invisible, so politicians ignore them since it is difficult to demagogue an invisible problem. It is just when we are confronted with a deadly disease like Ebola that people suddenly wake up to the problem. Of course there are much more serious problems lurking out there which could kill thousands or millions of Americans soon. One is multi-drug resistant Tuberculosis which is now being disseminated around the country by Obama’s unscreened illegal aliens. The other is multi-drug resistant bacteria of other types such as MRSA.
Yea, things were better back when Eisenhower was president.
The last I read, thalidomide is devastating because it’s manufactured as a racemic mixture.
http://www.masterorganicchemistry.com/2012/05/23/whats-a-racemic-mixture/
Only one of the enantiomers causes the medically desired effects.
The other is actually a poison… which adults can sweep out of their systems… but which no fetus can.
http://en.wikipedia.org/wiki/Thalidomide
&&&&
I’ll not force you to read through all the details…
But the bad can be removed from the good by various chemical ‘tricks.’ { Said tricks are normal lab course material for organic chemistry. }
It turns out that MOST medicines are chiral. Separating the ‘twins’ from each other is rarely done.
I strongly suspect that MANY effective drugs are ‘lost’ this way. If there is ONE thing that Big Pharma does — it’s to skip past chiral testing.
Why?
Getting a drug down to enantiomerically pure status is brutally expensive — at lawsuit-proof levels.
If you didn’t already know: drugs are held to chemical purities that are entirely out of the range of normal chemistry.
Industrial chemicals are rated as being Technical grade… which is actually pretty pure.
Laboratory chemicals are limited to Reagent grade… which is mighty pure. Typically all relevant impurities are tested — and listed — right on the bottle.
Pharma grade is constantly adjusted UP towards the highest purity that is practical and available.
Attaining pharma grade separation out of a racemic blend is actually so brutally expensive that the entire matter is dropped.
Which is a shame. It stands to reason that countless drugs are near to hand… if only they were administered in enantiomerically pure form.
[ Side note: D & L has been replaced by R & S … ]
{ All ordinary (biologic) amino acids are L
{ All ordinary (biologically generated) sugars are D
The terms are resultant from optical properties: a torque/ twist is imparted upon light that passes through them when in solution. This is a remarkable effect that can only be appreciated in a laboratory setting.
One can establish just how enantiomerically pure a chemical is by its degree of ‘twist.’ (This value is specific to the chemical being examined.) A racemic mixture always has zero twist.
If any of this is new to you… you lucked out… and didn’t take first year organic chemistry.
G Joubert:
The US thalidomide FDA refusal story was mostly during the Kennedy administration, actually.
neo…
You write of 17 Americans…
Which is wildly against the odds…
My B-in-L’s brother is a child of Thalidomide.
The result is horrific.
blert:
I’m not sure what you mean by “wildly against the odds.” Do you mean it’s against the odds that you know someone who was affected by thalidomide? That’s certainly true.
But since there were only a few hundred pregnant women in the US who took thalidomide during pregnancy, the figure of 17 born affected isn’t so strange.
I remember travelingin Germanyy in the early 80’s; many cars with bumperstickers “A heart for children” . I asked; charity sticker for thalidomide babies.
neo…
My B-in-L’s brother was one of the VERY few hit by Thalidomide. (Inside the USA)
Until your sats I had no idea just how rare his circumstance was.
BTW, the Germans were permitting over-the-counter Thalidomide — circa 1957 !
The Thalidimide incident occurred prior the creation of the modern FDA. The FDA was created in response to the Thalidimide incident.
When the new FDA was created, the significant difference between it and its predecessor was not safety, but effectiveness. Prior to the modern FDA, the government didn’t require approval of effectiveness – only safety. This, despite the fact that Thalidimide didn’t have effectiveness concerns.
The “crisis” of Thalidimide created the atmosphere by which drug companies could lock in their position by requiring effectiveness approval. Effectiveness approval is far more expensive than safety approval. Thanks to the “Thalidimide” crisis, no non-patented treatment will ever be given approval (no matter how easy the safety standard is to reach). The costs of obtaining effectiveness approval are too high – and can’t be justified without a patent.
Vitamin D appears to be an exception to the above insight – as its widely used and tested for by MDs. But even in that case, no “effective” designation has ever been granted by the FDA.
The “caution” is really so they can be bribed and do the CYA.
The case of bad things creating infinite regulations is when mass murderers go around shooting people, which means everybody else will have to go under restrictions designed for insane serial killers.
Sensible policy requires that intelligent experts, like Dr. Kelsey, be allowed to make their own judgements. The relationship between risk and reward is always there, and may be difficult to quantify. Treatment of a probably terminal condition may militate for a more relaxed policy. A medical device which detects a dangerous condition but offers no personal risk might be placed on a very fast track for evaluation. The disquieting observation about the ‘Ebola Crisis’ is that political operatives rather than intelligent medical experts appear to be in charge. And that may become a formula for disaster.
I recall that Thalidomide was prescribed to relieve morning sickness during pregnancy.