FDA Approval: The Mighty Drug Label

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In the first two articles for our educational series on the U.S. Food and Drug Administration (FDA), we covered what the FDA is about, and what it means when an approved drug is used off-label. We now dive into Part 3 of our continuing series: The drug label.

The CDER and the FDA

The Center for Drug Evaluation and Research (CDER) is part of the U.S. Food and Drug Administration (FDA), and is responsible to evaluating and monitoring new drugs before they can be sold. CDER monitors both prescription and over-the-counter brand name and generic drugs to ensure they work correctly and that their health benefits outweigh their known risks.

Drug companies seeking approval for a drug must conduct their own research, and then provide their test findings to CDER, where a team of salaried physicians, toxicologists, chemists, statisticians, mathematicians, pharmacologists, project managers, and other scientists review the company’s data and proposed labeling. It should be noted that it is up to the drug company’s discretion on what they report to CDER. We assume they report the good, the bad and the ugly but one has to question if this is reality when the drug company has much at stake in the approval process. Indeed, many recent cases suggest not all data are provided, Vioxx, Bextra the most notable.

In the perfect world, the CDER team will conduct its independent and unbiased review to give the drug approval for sale, noting CDER does not test the drugs, but does its own limited research into a drug’s quality, safety and effectiveness as part of its responsibility to consumers. In the real world we see evidence that this is not a fail-proof system as there have been a bevy of recent cases where drug companies have not submitted all of their data. In the quest for approval, they submit only positive data and/or falsified data.

FDA Ethics

All FDA employees are subject to the following ethical standards, noting that this is in an ideal world:

  • Financial disclosure prohibiting certain employees from holding a financial interest in a significantly regulated company, whereby more than 10% of the firms products or income are derived from products or services regulated by the FDA.
  • Federal Conflict of Interest Statutes: The Federal conflict of interest statutes assure that Government employees conduct Government business effectively, objectively, and without improper influence. These statutes govern representational activities, financial interests, outside compensation, and use of official information by Government employees.
  • CDER Manual of Policy and Procedures: Outside Activities: FDA Conflict of Interest Regulations require advance administrative approval prior to an employee participating in certain outside activities, whether paid or unpaid.
  • FDA Ethics Program – Post Employment Restrictions: FDA employees are subject to certain restrictions after they leave Federal service

Drug History and Other Public Information

Anyone can search for FDA approved drug products at Drugs@FDA to look up official information and find:

  • Labels for approved drug products
  • Generic drug products for an innovator (brand name) drug product
  • Therapeutically equivalent drug products for an innovator (brand name) or generic drug product
  • Cnsumer information for drugs approved from 1998 on
  • All drugs with a specific active ingredient
  • The approval history of a drug

Off-label Versus New Approvals

Over the lifespan of an approved drug, new medical evidence often points to new uses for an already approved drug. Sometimes the drug is used off-label for these conditions – see my article,”Going off on the off-label trail” for details. Alternatively, a company may wish to gain official approval to use the drug in a new way for a new condition. To gain approval, the FDA requires additional studies to for each new use. It is up to each drug company to decide whether or not to target approval for new uses, with the target payoff being the ability to market and get a higher return on its investment than off-label use.

BOTOX® and the FDA

One such company that has been successful in this venture is Allergan with its blockbuster drug BOTOX® (onabotulinumtoxinA). BOTOX is widely known as an aesthetic treatment for facial wrinkles, however it was initially approved by the FDA in 1989 to treat blepharospasm (eyelid spasms) and strabismus (visual problem in which the eyes are not aligned properly and point in different directions, aka crossed eyes). Allergan then sought and received FDA approval for the following:

  • Year 2000: BOTOX® therapy for cervical dystonia to reduce the severity of abnormal head position and neck pain.
  • Year 2002: BOTOX® Cosmetic (onabotulinumtoxinA) – the same formulation as BOTOX® – with dosing specific to moderate to severe frown lines between the brows.
  • Year 2004: BOTOX® for severe underarm sweating when topical medicines don’t work well enough.
  • Year 2010: BOTOX® therapy for increased muscle stiffness in elbow, wrist and finger muscles with upper limb spasticity, and BOTOX® for the prevention of headaches in adults with Chronic Migraine who have 15 or more days each month with headache lasting 4 or more hours each day in people 18 years or older.
  • Year 2011: BOTOX® to treat leakage of urine (incontinence) in adults 18 years and older with overactive bladder due to neurologic disease who still have leakage or cannot tolerate the side effects after trying an anticholinergic medication.

The word “botox” stirs up negative connotations; rat poison and over-plasticized vain men and women with frozen faces. In reality, it’s a two-chain polypeptide protein and neurotoxin produced by a purified form of bacterium Clostridium botulinum. It works by relaxing the contraction of muscles by blocking nerve impulses, resulting in muscles that can no longer contract. It was discovered by scientists in the 1950s to reduce muscle spasms, further studied as a treatment for crossed eyes in the 1960s and 1970s, and subsequently recognized by Allergan in the late 1980s for its potential multiple medical uses. Allergan has worked with the FDA to follow the process, but has also been in the hot seat with a 2010 settlement when it was charged with illegally promoting and selling the drug for unapproved uses.

FDA Framework is Not Perfect

The FDA provides a framework for reviewing products before they hit the market. It is not perfect and as we have seen in recent years, likely requires a large overhaul. Ultimately, however, the responsibility for our health and healthcare decisions lies with each of us. Do yourself a favor, explore the FDA and other medication websites. Learn about the medications you use. Do the research. Your health depends upon it.

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