FDA Procedures - How the FDA Drug Approval Process Works

FDA Procedures - How the FDA Drug Approval Process Works

Drugs » FDA Procedures How the FDA Drug Approval Process Works

FDA Procedures How the FDA Drug Approval Process Works

The FDA is responsible for overseeing the evaluation of drugs in the United States and for granting approval prior to their being placed on the market. Their decision is based on evidence provided by the sponsor (i.e., drug manufacturer) that the prescription or OTC drug is safe and effective.

How the FDA Approval Process Works:

The FDAs approval process is the most rigorous worldwide and has long served as the gold standard.

The drug sponsor submits very extensive documentation supporting its claims for drug effectiveness and safety to the FDA. Its not unusual for the FDA to require additional evidence or documentation. The FDA might also require the manufacturer to revise its claims of effectiveness or cautions associated with the drugs use.

In the case of controversial drugs, FDA approval or disapproval-which may take a year or longer after initial documentation has been submitted-will bring forth its critics. The sponsor and its supporters will likely argue that the FDAs demands for proof of safety and effectiveness are unreasonably excessive.

They result in inordinate delays that are keeping valuable drugs off the market and unavailable to treat countless of Americans who are needlessly suffering and dying. Drug safety groups, by contrast, will argue that the FDA has overlooked or minimized potentially dangerous side effects or weak evidence establishing effectiveness. They will argue for additional patient trials and might even claim that the FDA  decision has been influenced by political considerations.

What kind of adverse effects-risks-are reasonable for a drug to be approved? There is no simple one-size-fits-all answer. The risks must be balanced against its benefits and the condition that is being treated.

Suppose the new drug is intended to treat a rather simple, non-life-threatening disorder, for which there are many good, safe drugs available. Few, if any serious side effects would be acceptable. But what if the disease is a grave one, with an ominous prognosis, and for which there are few reasonably effective, but not very safe, medicines? Here, any new drug, even one with weighty side effects, might be as good as existing drugs and may be even better.

In response to industrial, consumer, and political pressure, the Dietary Supplement Health and Education Act (DSHEA) was enacted by Congress in 1994. Dietary supplements were classified as foods and not medicines and are not subject to FDA requirements for drug approval.

Life was much easier for drug manufacturers some 100 years ago. If they wanted to claim that their medicine cured diabetes, heart disease, baldness, impotency, female problems, and consumption and was completely safe, they simply did so. Such claims were boldly proclaimed on the medicine bottle label or in their newspaper ads. No trials were conducted. Evidence supporting claims were based on testimonials provided by doctors or satisfied users.

How could our forebears have been so gullible to believe these outrageous claims? Until the late nineteenth century, scientists, doctors, and, of course, the general public had little understanding of what caused disease .

Good health was believed to depend on a balance among the different parts of the body.

This balance was between the flow in of nutrients and flow out of excrements (feces, urine, menstrual flow, sweat). Consistent with this belief was the view that medicines were needed to treat symptoms by reestablishing a healthy balance, not by correcting the underlying cause of those symptoms.

The authority of the FDA and laws enacted in response to drug disasters have evolved slowly to protect us against unsafe and ineffective medicines. They have progressed from:

Requiring proof of safety prior to their marketing (1938).

During the early days, doctors used purging, puking, bloodletting, and blistering to reestablish balance in the body. From the nineteenth century until the early 1970s cathartics were the most popular category of drugs found in patent medicines drugs

that reestablished the balance by cleaning the bowels.

Phase 3 clinical trials are meticulously managed by the sponsor, usually the drug manufacturer. Potential subjects for drug trials are carefully selected (or excluded) based on predetermined criteria. The clinical investigators control the doses of the test drug taken, ensure that the drug is in fact taken and when it is taken, and know whether any other drugs are being used.

By contrast, after the drug has been approved, all bets are off with respect to how, for what, and to whom the drug is prescribed. In this real-world environment, and only after the drug has been taken by tens or hundreds of thousands of patients, can the true benefits and actual risks of the medicine be assessed.

The FDA has no authority over how doctors practice medicine, including how they prescribe drugs. After a drug has been approved for a specified medical condition, doctors are legally able to prescribe it for any condition. It is estimated that 40 percent of all prescriptions are written for off-label, non-FDA-approved uses.

During phase 4; called post-marketing drug surveillance, the drug sponsor is required to provide the FDA with any reports of adverse drug reactions. Doctors and pharmacists may also do so, but on a voluntarily basis. Only some 10percent of all reactions are ever reported.

Depending on the nature or frequency of these adverse effects, and whether they outweigh the drugs potential benefits, the FDA can order the sponsor to increase the warnings contained in the prescribing information or demand removal of the drug from the market.

Serious adverse drug reactions may only be fully recognized years after a drug has been marketed. In the 25-year period between 1975 to 1999, 548 new drugs were approved and marketed. Of these, 16 were subsequently withdrawn from the market and 40 received a black box warning.

A black box warning sounds ominous and it is. These represent the most serious warnings placed on prescribing information for prescription drugs. These warnings highlight special problems relating to drug safety, particularly those leading to deaths or

Recent examples include antidepressants promoting suicidal thoughts in adolescents and children and the strong abuse potential of OxyContin.

According to an article in the Journal of American Medical Association, K.E. Lesser and colleagues found that half of the 16 drugs withdrawn were pulled within the first 2 years. But only half of the serious adverse drug reactions were discovered within seven years after the drug had been marketed.

The most common of these included liver, blood, and cardiovascular toxicity, and serious risks when used during pregnancy.

In recent years, a number of high-profile, widely used, and effective medications have been withdrawn from the market after causing fatalities. These include

Baycol, a cholesterol-lowering drug, which caused muscle toxicity.

Bextra and Vioxx, painkillers for osteoarthritis, which caused increased risk of stroke and heart attack.

Fen-Phen, an appetite suppressant, which caused heart and lung toxicity.

Propulsid, a nighttime heartburn treatment, which caused abnormal heart rhythms .

Rezulin, an anti-diabetic drug, which caused liver toxicity.

Seldane, an antihistamine for allergies, which caused heart toxicity.

Although many people take great pride in wearing the latest fashions and owning the newest auto mobiles, being prescribed the newest drugs might not be wise or safe.

Your doctor should probably avoid using the latest drugs when older, equally effective drugs are available. There is great wisdom in an old adage that advises doctors to be neither the first to use a new drug nor the last to discard the old.

Why werent these adverse effects detected during phase 3 clinical trials? To answer this question, we must look at the number of subjects participating in a clinical trial. If testing a common condition, such as osteoarthritis, high blood pressure, or insomnia, it is relatively easy to find plenty of subjects.

However, finding a sufficient number of willing subjects for rare diseases that only affect a few thousand people a year can be a major problem.

The second issue relates to the incidence of side effects. If the phase 3 study involves 2,000 subjects, it is easy to detect an unusual side effect that occurs in 1 percent (or 20) of the subjects. But what if the side effect is rather rare and occurs in only 1 of every 5,000 subjects? It would be very unlikely to be seen in a trial of only 2,000 subjects. After the drug is approved and is used by hundreds of thousands of patients, the number of affected people will be greatly increased.

When doctors are trying to select the best medicines for their patients, they read reports of clinical trials that appear in distinguished journals. Published studies describing the effectiveness of a drug are also an important tool used for marketing purposes. These reports have long been assumed to be honestly and objectively written and to include both positive and negative results about the drug studied.

In 2004, a number of antidepressant-making drug companies were accused of selectively releasing information and publishing studies about their drugs that only showed their positive aspects. They concealed other results-those that failed to show their drugs to be better than placebos or that some antidepressants increased the incidence of suicidal thoughts of children and teenagers.

One of the basic principles of the scientific method is to look at all the results of a study and then draw conclusions based on one valuation of the results.

Its not appropriate (or ethical) for scientists to cherry-pick-that is, include only favorable results, while purposely discarding unfavorable or negative ones.

Similarly, it was uncovered in 2005 that companies hid other clinical trial results that indicated that their COX-2 inhibitor painkillers might increase the risk of stroke and heart attack.

Doctors and patients were appalled and furious. They argue that it is much more difficult for a company to hide the results of a clinical drug trial if it announces, in advance, that it is conducting such a study and are informed of what the study is trying to determine and how many patients are in the study.

That way, if a study starts with 2,000 subjects, and the published results only account for 1,000, consumers will know to ask what happened to the others.

Not all clinical trials are conducted to assess drug safety. Many evaluate drug effectiveness for the treatment of conditions and often to compare their effectiveness with other drugs.

Sales of prescription drugs require convincing doctors and the public that their medicine is better (i.e., safer and more effective) than competing drugs. Doctors and pharmacists are receiving increased instruction on how to better analyze and interpret the results of clinical trials to permit them to draw their own conclusions.

In 2005, the National Institutes of Health setup a user-friendly website, www.clinicaltrials.gov, that tracks many clinical studies.

Some companies have been more forthcoming with information than others.You might want to log onto check whats new with any diseases or drugs youre tracking.

The development of medicines that save lives and improve the quality of our lives is very expensive but can be very profitable.

The FDA evaluates the results of animal (preclinical studies) and human (clinical) studies to determine the safety, effectiveness, and labeling prior to approving prescription and drugs for marketing.

Phase 3 human studies use double-blind, placebo controls to evaluate the effectiveness of test drugs.

Phase 4 studies (post-marketing surveillance) are intended to detect adverse effects after the drug is used in real-life conditions in large numbers of patients.

The selective disclosure of information on marketed drugs has undermined the confidence of the medical community and public in the integrity of some pharmaceutical companies.

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