Saturday, January 22, 2011

Americans wait longer for life-saving drugs

The 1962 Kefauver-Harris Amendments have killed a lot of people

How could regulations, which were passed to protect the American public, actually do more harm than good? To answer that question, we must first examine what changes the amendments made in drug development.

A pivotal provision of the amendments concerned the approval process. Prior to 1962, a manufacturer would submit data on a new drug and the FDA had six months to respond. In the absence of FDA concern or questions, marketing could begin. However, the amendments required FDA examiners to actually sign off and approve each New Drug Application (NDA), as a testament to the safety and efficacy of the new drug.

Of course, since no drug is totally safe and efficacious, FDA personnel risked censure by Congress if unexpected side effects, which occur with all drugs, were severe enough to attract public attention. To protect themselves, therefore, regulators began demanding more and more testing, so that they could show “due diligence” in the event they were asked to defend an approval.

In addition, the FDA was given oversight of pharmaceutical advertising, manufacturing, and labeling. The FDA determined which animal safety studies had to be performed prior to testing a new drug in people. Consequently, manufacturers had to do more animal experimentation, perform more quality control work, negotiate every word of advertisements and labels with the FDA, and send literally truck loads of data to the FDA.

One of the primary provisions of the Kefauver-Harris amendments was, of course, the senator’s requirement for “substantial evidence of efficacy.” The FDA decided that giving doctors samples of drugs and getting their evaluation was not enough evidence of effectiveness. Based on the amendments, the FDA began requiring that drug companies perform two U.S. studies that were “double-blind, placebo-controlled.” In other words, some patients would receive the test drug and some would receive an identical “sugar” pill. The capsules or tablets would carry a number, not a name, so that neither patient nor doctor would know what was taken. When the study was done, the code would be broken.

Even if more patients were helped by the drug instead of placebo, it would only be considered effective if the results were “statistically significant.” Because we are not genetically identical, an inactive drug could appear effective simply because one group was going to heal faster naturally than the other.

Therefore, statisticians look for big differences between placebo groups and drug treated groups. When this difference is big enough to have 95% certainty that the drug effect isn’t simply due to chance, we call that “statistically significant.” By requiring two studies with 95% certainty, the FDA set a high standard for new drugs to meet.

Of course, meeting all of these new requirements took time. As you can see from Figure 2, drug development times, which were about 4 1/2 years between 1948 and 1961 started rising dramatically after the amendments were passed. Development times, as used here, are the years between the first time the drug is made (compound synthesis) and FDA approval. How do we know that the increase in development time was due to the 1962 amendments and not some other factor? The time for the FDA to review new drug applications went from about 7 months pre-amendment to an average of 29 months in the years 1963-1969. The extra time taken for the FDA to review the new studies it required was greater in the late 1960s than the time needed to do the studies themselves!

Clearly, the regulators were concerned about the new visibility that the 1962 amendments had given them. They were asked to do the impossible: approve only safe and effective drugs. They did the next best thing. They still approved new drugs, but required more and more expensive studies, driving the cost of development up and raising drug prices.

Figure 2. Average development time of new drugs (known as new chemical entities or NCEs) before (blue bars;) and after (red bars;) passage of the 1962 Kefauver-Harris Amendments. The time saved by passage of the 1992 Prescription Drug User Fee Act is shown (pink bar) for the 1990-1999 period.

In addition, the FDA took more and more time to evaluate the studies, shortening the patent life of the new product. Manufacturers, who have to recover most of their costs before a drug goes generic, had fewer years to do so. Consequently, they raised prices even more.

Meanwhile, in Europe, regulations had not changed as much, even after the thalidomide tragedy. Consequently new drugs, although invented predominantly in the United States, were marketed first in Europe. Europeans had twice as many drugs in their pharmacies as Americans had!

One of these new drugs was propranolol, the first beta-blocker for heart disease. Because of the “drug lag,” propranolol entered the American market in 1968, three years after it had been available in Europe. One study performed in the 1980s estimated that propranolol was saving approximately 10,000 American lives per year. Consequently, at least 30,000 Americans died prematurely during the three-year delay in propranolol approval. This estimate may be low, since propranolol was not approved for its major uses, angina and hypertension, until 1973 and 1976 respectively.

Instead of being complemented for finally approving propranolol, the FDA was criticized by a congressional committee for exposing the American public to a drug with potential side effects. Given this negative feedback, it’s hardly surprising that the FDA increased its regulatory demands even further.


Dieting while pregnant can lower your baby's IQ

For once I agree with the official advice -- at the end of the article below

Expectant mothers who diet during pregnancy are putting their babies at risk of low IQs and behavioural problems, scientists say. A new study found that cutting back on vital nutrients and calories in the first half of pregnancy stunts the development of an unborn child's brain.

Although the study was carried out on animals, researchers says the same findings are likely to be true for women - and highlight the lifelong dangers to babies if their mothers don't eat healthily. Author Dr Thomas McDonald said: 'This study is a further demonstration of the importance of good maternal health and diet.

'It supports the view that poor diets in pregnancy can alter development of foetal organs, in this case the brain, in ways that will have lifetime effects on offspring, potentially lowering IQ and predisposing to behavioural problems.'

Past studies have shown that severe diets, famines and food shortages during pregnancy can harm unborn babies. But the new study looked at the sort of 'moderate dieting' typical of women in Britain and America.

The researchers compared two groups of baboon mothers at the a primate research centre in San Antonio. One group was allowed to eat as much as they wanted during the first half of pregnancy - while the other group was fed 30 per cent less - 'a level of nutrition similar to what many prospective mothers' experience, the researchers said.

Cells did not divide as much as they should and connections between neurons were not made.

Lack of nutrients interfered with the way brain cells connected in the unborn babies and altered the expression of hundreds of genes - many involved in cell growth and development, the researchers report in the Proceedings of the National Academy of Sciences.

Dr McDonald said foetal nutrient deficiency was a special risk for both teenage mothers and women who get pregnant later in life.

In teenage pregnancies, the developing foetus can be deprived of nutrients by the needs of the growing mother, he said. And stiffer arteries in older women reduce blood flow to the womb, reducing the flow of nutrients to the growing baby.

The scientists called for more research into links between maternal diet and their children's risk of autism, depression and schizophrenia later in life.

The study also challenges the widely held view that mothers can protect their unborn babies from poor diets in pregnancy, he said.

The baboon's brain developmental stages are 'very close' to those of human fetuses, the researchers said.

Dr Peter Nathanielsz, of the University of Texas Health Science Centre in San Antonio said: 'This is a critical time window when many of the neurons as well as the supporting cells in the brain are born.'

Guidelines from the Royal College of Obstetricians and Gynaecologists state: 'There is little evidence of harm in the first half of pregnancy - but in the second half concerns arise.'

However, it still advises women not to diet if they find they are pregnant.

Dr Patrick O'Brien, consultant and spokesman for the Royal College of Obstetricians and Gynaecologists said the study might not apply to women. 'All the studies in humans have not suggested that moderate dieting in the first half of pregnancy causes any problems,' he said. 'Our guidance is unchanged - that pregnant women should eat a healthy mixed diet and should avoid dieting, but also avoid "eating for two",' he added.


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