The Right Lesson To Learn From Thalidomide ... a 1960's tranquilizer

[Guest guest]

thalidomide (as it turned out) does not cause birth defects in

rats.

The Right Lesson To Learn From Thalidomide

B. , M.D.

http://w3.aces.uiuc.edu:8001/Liberty/Tales/Thalidomide.Html

---------------------------------------------------------------------

-----------

The Food and Drug Administration was originally (early in this

century) charged with establishing the purity and safety of foods

and drugs. As such, it was tolerable, and even did a certain amount

of good in acting as policeman against certain types of actions

which we all agree constitute " fraud " (i.e., putting horsemeat in

the hamburger, putting sugar instead of antibiotic in the antibiotic

pills, etc.)

But then, and the late 1950's and early 60's, something horrible

happened, both to the citizen and to the State. In Europe, a drug

called thalidomide was marketed as a tranquilizer. In America, the

FDA official in charge of the American " new drug application " for

thalidomide (Nov., 1960) was a woman physician (Francis Kelsey,

M.D.) whose physician/pharmacist husband did not like the way

routine pharmacologic tests had been done on thalidomide. Dr. Kelsey

was also concerned about some medical reports in late 1960 that

thalidomide might cause neuropathy in some of its users. Neither of

these concerns was fatal for the thalidomide application, but

together they were enough to hold up the FDA's approval of

thalidomide for a year. Since neither problem had anything to do

with birth defects, it was only by the sheerest chance that the red-

tape in these matters caused introduction of thalidomide to be

delayed in the U.S. until it began to be suggested in late 1961 that

thalidomide was a dangerous drug for pregnant women. In the end, the

association between thalidomide and birth defects was discovered in

Europe, not America -- and certainly was not discovered by the FDA.

Despite this, on August 7, 1962 a grateful President F. Kennedy

awarded the Distinguished Federal Civil Service Award to Dr. Kelsey,

who by this time was beginning to make (in retrospect) statements

about how she had been concerned with the reproductive safety of

thalidomide all along.

However much we all like heroic tales and medals, there is actually

very little in the record to bear out the official heroic version of

the thalidomide story. Upon careful examination it appears that no

reproductive tests were done at all on thalidomide before 1961, nor

indeed did the FDA ask for any. In fact, it appears that even had

any pre-marketing reproductive tests of thalidomide in rats been

done, they would have *still* have shown negative results, for

thalidomide (as it turned out later) does not cause birth defects in

rats. We now know that it would have taken a much more exhaustive

set of animal tests to catch thalidomide than was routinely used

anywhere in 1961. An honest reading of the facts thus forces the

conclusion that (questions of luck aside) Dr. Kelsey's medal was

awarded basically for being a delay-causing bureaucrat and thereby

allowing Europeans to serve as first-class " guinea pigs " for

Americans, in a case where (quite literally) guinea pigs themselves

would not have done an adequate job. Dr. Kelsey's medal was soon to

become an excuse for much self-congratulation regarding FDA policy,

without much thought being given to what the consequences of a de-

facto U.S. marketing delay policy might be, if applied to all new

drugs across-the-board.

And there was other fallout. In 1962 the thalidomide disaster gave

unexpected new life to several stalled bills on capitol hill which

proposed to give the FDA power over not only safety, but also the

_efficacy_ of new drugs. There was a some irony in this, since the

thalidomide disaster itself was of course an issue of safety, and

had nothing at all to do with efficacy (the bills were themselves

introduced before anyone had heard of thalidomide). Unfortunately,

however, the fine distinction was lost on congress, which only knew

that the FDA seemed to be a good thing and should therefore be made

bigger. In 1962 the so-called " Kefauver Amendments " to the Food,

Drug and Cosmetic Act were passed into law, giving the FDA new broad

powers, and thus the bloated and mutated regulatory agency that we

know today was born. Thalidomide, as it turned out, proved to be a

monster--producing drug in more ways than one.

Today, thirty years later, the cost of developing and marketing a

new drug in the United States has risen to an average of about a

quarter of a billion dollars PER DRUG. To make a long story short, a

large part of this money is regulatory cost. Not surprisingly, the

huge sums spent in drug development are reflected in the price which

the consumer pays when he/she picks up any prescription for a newer

drug. The reader who wishes to directly assess the regulatory cost

of the FDA is invited to shop for pharmaceuticals in Mexico, where

(except for packaging) the identical pharmaceutical product made by

the identical company can sometimes be had for as little as 1/5th

the U.S. price.

The FDA is responsible for high regulatory costs in money; the

regulatory cost in lives is more difficult to assess, but is

probably significant. The high cost of drugs has led not a few

impoverished patients to stop taking what the doctor ordered,

sometimes with expensive or even tragic results. Even worse, the

newest drugs now, as a rule, are available in Europe for years

before being available in the U.S., and in the interim many U.S.

patients almost certainly die for lack of treatment. One estimate,

for instance, puts the number of people who died of cardiac

arrhythmias, as the direct result of the historical FDA's multi-year

lag-time in evaluating beta-blocker drugs, in the hundreds of

thousands-- a number which, if correct, makes up for thalidomide

many times over.

It is important to understand that this situation arises via one of

the significant shortcomings of democracy. Politically, the FDA

comes under severe pressure for passing a drug which is later shown

to be unsafe, but (in an unbalanced way) comes in for much less

political pressure as regards the equally dangerous failure to

swiftly pass a drug which proves to be efficacious. This lack of

balance results from the fact that patients who die as the result of

a drug-reaction are seen to die because of the drug, but patients

who die as the result of lack of a drug (especially one which the

local docs are not familiar with) are seen to die of the *disease*.

Even if the local doctor understands the FDA's role in preventing

the patient from being properly treated, " Stenosis of the

Government " is not a medical diagnosis, and cannot be written on a

Death Certificate.

It is also important to understand that this situation arises

because of a certain laziness of the citizenry in understanding that

the decision of whether to take a specific drug for a specific

purpose, is only partly a scientific one. The reason for this is

that, even in the rare case where the probabilistic risks and the

benefits of " taking the drug vs. not taking it " have been fully

defined by science, the *balancing* of these risks and benefits is

still an ethical and moral decision, and one which varies wildly

from person to person, due to circumstance and personal preference.

To put it succinctly, the decision to try a new and possibly

dangerous treatment may well and properly be influenced by how much

pain the prospective treatment-taker is in, and even upon how soon

he or she can expect to die if nothing is done. Unfortunately,

however, these factors do not directly enter into decisions made in

Washington, basically because Washington is not in pain, and

Washington is not dying. If you are the patient with a serious

problem, therefore, you may expect that having a decision about your

treatment made for you in Washington is less likely to be

satisfactory, if for no other reason simply due to the fact that

they do not know you or your problems in Washington, and even if

they did know you, still could not care about your problems nearly

so much as you and your family do. Empathy is a function of

proximity; all physicians know this. It is an elementary principle

of medicine that nearly any displacement of medical decision-making

away from patient and physician in the direction of a place

thousands of miles away, is bound to result in needless suffering.

Thus, the FDA as it functions today is basically engaged in an evil

enterprise. To be sure, the people who run the FDA may not be evil

people (though perhaps some are) but unfortunately, this does not

change the facts about the FDA's generally negative impact upon the

world.

The FDA, it must be remembered, is in the game for the political

power, not for the benefit of the citizenry. This is a fact which

comes across in many issues, large and small:

In large health issues, the FDA is known to bow to political

pressure if it is massive enough (i.e., the AIDS lobby), but there

are very few fatal diseases in which those struck by the disease are

characteristically young and full of energy (which can be used for

lobbying) for many years before they succumb. The FDA as an

institution is thus free to remain firmly entrenched to retard

development of treatments for hundreds of equally deadly diseases

which have smaller or weaker groups of victims, by comparison with

AIDS. Alzheimer's disease patients, for instance, do not ACT UP.

In small health issues the FDA's basic unconcern for health is

neatly illustrated by the fact that the FDA will not permit any

information about the possible dangers or side-effects of particular

herbal preparations to be printed on the bottle label, even though

such warnings might do much good. This is because the FDA does not

want to set the precedent of providing usage information of any kind

on herb bottle labels. The safety of the consumer is secondary to

the politics of the issue.

A full discussion of the FDA's many failings on specific issues is

beyond the bounds of this essay, but there is room for a last

informative illustration. For more than ten years the FDA has

zealously prohibited vitamin companies from making claims about the

ability of the B vitamin folic acid to prevent certain birth

defects, even while evidence in favor of this hypothesis mounted

year by year. Finally, this year (1992) the American Society of

Pediatrics, in the face of overwhelming scientific evidence,

formally recommended that all women of childbearing age (whether

known to be pregnant or not) routinely take a folic acid supplement

pill. Incredibly, as of this writing, the FDA will still not permit

vitamin manufacturers to inform the public of this on the bottle

label (!) Since there now appears no place the FDA can hide on this

issue, however, it now seems likely that, rather than admit a health

claim for a vitamin pill, the FDA will instead soon *mandate* adding

folate to white flour, as part of the enrichment process. We thus

seem likely to go very soon from a situation where manufacturers are

prohibited from telling of the benefits of the vitamin, to one in

which manufacturers are *obligated* to add it to your food without

your request (perhaps still without being allowed to tell you why).

Going from " prohibited " to " required " without going through the

intermediate state of individual choice is a nice illustration of

the way our government thinks, to be sure, but in the meanwhile,

until all this is sorted out and everyone is forced into

the " correct " mode, more children will surely be born deformed

because their parents meanwhile lacked information on

supplementation. Once again, however, the mission of the FDA is

power, not the prevention of birth defects. Anyone who still thinks

otherwise did not learn the right lesson from thalidomide.

---------------------------------------------------------------------

-----------

May be reprinted without permission, if reprinted whole.

© 1992 B. , M.D.

Compuserve 71450,1773

310 825-1927

[Guest guest]

thalidomide (as it turned out) does not cause birth defects in

rats.

The Right Lesson To Learn From Thalidomide

B. , M.D.

http://w3.aces.uiuc.edu:8001/Liberty/Tales/Thalidomide.Html

---------------------------------------------------------------------

-----------

The Food and Drug Administration was originally (early in this

century) charged with establishing the purity and safety of foods

and drugs. As such, it was tolerable, and even did a certain amount

of good in acting as policeman against certain types of actions

which we all agree constitute " fraud " (i.e., putting horsemeat in

the hamburger, putting sugar instead of antibiotic in the antibiotic

pills, etc.)

But then, and the late 1950's and early 60's, something horrible

happened, both to the citizen and to the State. In Europe, a drug

called thalidomide was marketed as a tranquilizer. In America, the

FDA official in charge of the American " new drug application " for

thalidomide (Nov., 1960) was a woman physician (Francis Kelsey,

M.D.) whose physician/pharmacist husband did not like the way

routine pharmacologic tests had been done on thalidomide. Dr. Kelsey

was also concerned about some medical reports in late 1960 that

thalidomide might cause neuropathy in some of its users. Neither of

these concerns was fatal for the thalidomide application, but

together they were enough to hold up the FDA's approval of

thalidomide for a year. Since neither problem had anything to do

with birth defects, it was only by the sheerest chance that the red-

tape in these matters caused introduction of thalidomide to be

delayed in the U.S. until it began to be suggested in late 1961 that

thalidomide was a dangerous drug for pregnant women. In the end, the

association between thalidomide and birth defects was discovered in

Europe, not America -- and certainly was not discovered by the FDA.

Despite this, on August 7, 1962 a grateful President F. Kennedy

awarded the Distinguished Federal Civil Service Award to Dr. Kelsey,

who by this time was beginning to make (in retrospect) statements

about how she had been concerned with the reproductive safety of

thalidomide all along.

However much we all like heroic tales and medals, there is actually

very little in the record to bear out the official heroic version of

the thalidomide story. Upon careful examination it appears that no

reproductive tests were done at all on thalidomide before 1961, nor

indeed did the FDA ask for any. In fact, it appears that even had

any pre-marketing reproductive tests of thalidomide in rats been

done, they would have *still* have shown negative results, for

thalidomide (as it turned out later) does not cause birth defects in

rats. We now know that it would have taken a much more exhaustive

set of animal tests to catch thalidomide than was routinely used

anywhere in 1961. An honest reading of the facts thus forces the

conclusion that (questions of luck aside) Dr. Kelsey's medal was

awarded basically for being a delay-causing bureaucrat and thereby

allowing Europeans to serve as first-class " guinea pigs " for

Americans, in a case where (quite literally) guinea pigs themselves

would not have done an adequate job. Dr. Kelsey's medal was soon to

become an excuse for much self-congratulation regarding FDA policy,

without much thought being given to what the consequences of a de-

facto U.S. marketing delay policy might be, if applied to all new

drugs across-the-board.

And there was other fallout. In 1962 the thalidomide disaster gave

unexpected new life to several stalled bills on capitol hill which

proposed to give the FDA power over not only safety, but also the

_efficacy_ of new drugs. There was a some irony in this, since the

thalidomide disaster itself was of course an issue of safety, and

had nothing at all to do with efficacy (the bills were themselves

introduced before anyone had heard of thalidomide). Unfortunately,

however, the fine distinction was lost on congress, which only knew

that the FDA seemed to be a good thing and should therefore be made

bigger. In 1962 the so-called " Kefauver Amendments " to the Food,

Drug and Cosmetic Act were passed into law, giving the FDA new broad

powers, and thus the bloated and mutated regulatory agency that we

know today was born. Thalidomide, as it turned out, proved to be a

monster--producing drug in more ways than one.

Today, thirty years later, the cost of developing and marketing a

new drug in the United States has risen to an average of about a

quarter of a billion dollars PER DRUG. To make a long story short, a

large part of this money is regulatory cost. Not surprisingly, the

huge sums spent in drug development are reflected in the price which

the consumer pays when he/she picks up any prescription for a newer

drug. The reader who wishes to directly assess the regulatory cost

of the FDA is invited to shop for pharmaceuticals in Mexico, where

(except for packaging) the identical pharmaceutical product made by

the identical company can sometimes be had for as little as 1/5th

the U.S. price.

The FDA is responsible for high regulatory costs in money; the

regulatory cost in lives is more difficult to assess, but is

probably significant. The high cost of drugs has led not a few

impoverished patients to stop taking what the doctor ordered,

sometimes with expensive or even tragic results. Even worse, the

newest drugs now, as a rule, are available in Europe for years

before being available in the U.S., and in the interim many U.S.

patients almost certainly die for lack of treatment. One estimate,

for instance, puts the number of people who died of cardiac

arrhythmias, as the direct result of the historical FDA's multi-year

lag-time in evaluating beta-blocker drugs, in the hundreds of

thousands-- a number which, if correct, makes up for thalidomide

many times over.

It is important to understand that this situation arises via one of

the significant shortcomings of democracy. Politically, the FDA

comes under severe pressure for passing a drug which is later shown

to be unsafe, but (in an unbalanced way) comes in for much less

political pressure as regards the equally dangerous failure to

swiftly pass a drug which proves to be efficacious. This lack of

balance results from the fact that patients who die as the result of

a drug-reaction are seen to die because of the drug, but patients

who die as the result of lack of a drug (especially one which the

local docs are not familiar with) are seen to die of the *disease*.

Even if the local doctor understands the FDA's role in preventing

the patient from being properly treated, " Stenosis of the

Government " is not a medical diagnosis, and cannot be written on a

Death Certificate.

It is also important to understand that this situation arises

because of a certain laziness of the citizenry in understanding that

the decision of whether to take a specific drug for a specific

purpose, is only partly a scientific one. The reason for this is

that, even in the rare case where the probabilistic risks and the

benefits of " taking the drug vs. not taking it " have been fully

defined by science, the *balancing* of these risks and benefits is

still an ethical and moral decision, and one which varies wildly

from person to person, due to circumstance and personal preference.

To put it succinctly, the decision to try a new and possibly

dangerous treatment may well and properly be influenced by how much

pain the prospective treatment-taker is in, and even upon how soon

he or she can expect to die if nothing is done. Unfortunately,

however, these factors do not directly enter into decisions made in

Washington, basically because Washington is not in pain, and

Washington is not dying. If you are the patient with a serious

problem, therefore, you may expect that having a decision about your

treatment made for you in Washington is less likely to be

satisfactory, if for no other reason simply due to the fact that

they do not know you or your problems in Washington, and even if

they did know you, still could not care about your problems nearly

so much as you and your family do. Empathy is a function of

proximity; all physicians know this. It is an elementary principle

of medicine that nearly any displacement of medical decision-making

away from patient and physician in the direction of a place

thousands of miles away, is bound to result in needless suffering.

Thus, the FDA as it functions today is basically engaged in an evil

enterprise. To be sure, the people who run the FDA may not be evil

people (though perhaps some are) but unfortunately, this does not

change the facts about the FDA's generally negative impact upon the

world.

The FDA, it must be remembered, is in the game for the political

power, not for the benefit of the citizenry. This is a fact which

comes across in many issues, large and small:

In large health issues, the FDA is known to bow to political

pressure if it is massive enough (i.e., the AIDS lobby), but there

are very few fatal diseases in which those struck by the disease are

characteristically young and full of energy (which can be used for

lobbying) for many years before they succumb. The FDA as an

institution is thus free to remain firmly entrenched to retard

development of treatments for hundreds of equally deadly diseases

which have smaller or weaker groups of victims, by comparison with

AIDS. Alzheimer's disease patients, for instance, do not ACT UP.

In small health issues the FDA's basic unconcern for health is

neatly illustrated by the fact that the FDA will not permit any

information about the possible dangers or side-effects of particular

herbal preparations to be printed on the bottle label, even though

such warnings might do much good. This is because the FDA does not

want to set the precedent of providing usage information of any kind

on herb bottle labels. The safety of the consumer is secondary to

the politics of the issue.

A full discussion of the FDA's many failings on specific issues is

beyond the bounds of this essay, but there is room for a last

informative illustration. For more than ten years the FDA has

zealously prohibited vitamin companies from making claims about the

ability of the B vitamin folic acid to prevent certain birth

defects, even while evidence in favor of this hypothesis mounted

year by year. Finally, this year (1992) the American Society of

Pediatrics, in the face of overwhelming scientific evidence,

formally recommended that all women of childbearing age (whether

known to be pregnant or not) routinely take a folic acid supplement

pill. Incredibly, as of this writing, the FDA will still not permit

vitamin manufacturers to inform the public of this on the bottle

label (!) Since there now appears no place the FDA can hide on this

issue, however, it now seems likely that, rather than admit a health

claim for a vitamin pill, the FDA will instead soon *mandate* adding

folate to white flour, as part of the enrichment process. We thus

seem likely to go very soon from a situation where manufacturers are

prohibited from telling of the benefits of the vitamin, to one in

which manufacturers are *obligated* to add it to your food without

your request (perhaps still without being allowed to tell you why).

Going from " prohibited " to " required " without going through the

intermediate state of individual choice is a nice illustration of

the way our government thinks, to be sure, but in the meanwhile,

until all this is sorted out and everyone is forced into

the " correct " mode, more children will surely be born deformed

because their parents meanwhile lacked information on

supplementation. Once again, however, the mission of the FDA is

power, not the prevention of birth defects. Anyone who still thinks

otherwise did not learn the right lesson from thalidomide.

---------------------------------------------------------------------

-----------

May be reprinted without permission, if reprinted whole.

© 1992 B. , M.D.

Compuserve 71450,1773

310 825-1927