Off-label Use vs Off-label Marketing

Off-label Use and Off-label Marketing Are Different

Off-label use and off-label marketing, on the surface, sound similar but they are two distinct practices in the pharmaceutical industry and medical community.  Off-label use is a practice by which physicians prescribe an F.D.A-approved drug for an unapproved indication/dose/age/administration.  Sounds strange but off-label use has been widely and legally implemented in the medical community for a long period of time.  Off-label marketing, on the other hand, is a practice by a drug company to promote drug use in unapproved indications.  In other words, physicians are legally allowed to prescribe drugs for any purpose (based on their professional assessments), but companies are not allowed to promote drugs for unapproved uses by the F.D.A.

Off-label Use Example

An increasing number of antipsychotic drugs have been brought to market in recent years.  The earlier version of the antipsychotic drugs (aka typical or first generation antipsychotics) are mainly to treat schizophrenia, bipolar disorder, and delusional disorder.  Nowadays, more and more non-psychotic symptoms, like depression, anxiety, autism, obsessive compulsive, just to name a few, are treated more prevalently with newer version of antipsychotic drugs (aka atypical or second generation antipsychotics).  A recent research by groups at the Stanford University and University of Chicago showed that atypical antipsychotic drugs are prescribed frequently for non-FDA approved use that lack strong evidence to actually benefit patients.  This widespread post-market off-label use of the FDA-approved second generation antipsychotics needs to be monitored more closely should unknown side effects outweigh the benefits.  Aside from unproven benefits of off-label use, medicare and private insurance companies often deny coverage for off-label prescription.

Off-label Marketing Example

In September 2010, Novartis has agreed to pay a hefty $422.5 million fine for off-label marketing over six drugs (Trileptal, Diovan, Exforge, Sandostatin, Tekturna and Zelnorm).  One of the off-label marketing practices (blood-pressure drug Diovan) was revealed and kind of shocking as this marketing gimmick went too far that highlighted the unethical medical practices due to greed.

In recent months, Pfizer has been ordered to pay a $142.1 million fine for violating federal racketeering laws in the marketing of Neurontin (gabapentin), an anticonvulsant drug approved by the F.D.A. in 1993 for epilepsy indication.  Neurontin was marketed to be effective in treating bipolar disorder and migraines and was hidden for suicide risk.

On 28 February 2011, Elan Pharmaceuticals pleaded guilty of violating the Food Drug and Cosmetic Act for off-label marketing on its epilepsy drug Zonegran approved by the F.D.A. in April 2000.  Again, a hefty criminal fine of $97 million was paid.

Along the same line, several companies had faced serious legal and financial consequences from off-label marketing.  In the past few years, a handful of pharmaceutical companies had settled with federal government on their health care fraud, and here they are:

  • Pfizer: $2.3 billion
  • Eli Lilly: $1.4 billion
  • Allergan: $600 million
  • AstraZeneca: $520 million
  • Bristol-Myers Squibb: $515 million
  • Forest Laboratories: $313 million

Some Thoughts

One psychiatrist once told me that she has stopped using free pens given by drug companies as she later noticed that she wrote more prescriptions from the drug companies that brilliantly use their freebies to subconsciously influence a physician’s professional judgment.  How can a patient assure that a physician is not materialized in any way making prescription recommendation?  Is the drug prescribed based on the best interest/benefit for patient or off-label use for empirical reason or off-label marketing for kickback?  That said, with internet available at your fingertip, it is worth self-educating and doing due diligence on one’s prescribed drug.

Until next post, keep on reading and writing!!

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Avastin Hits the Breast Cancer Indication Wall

A Brief History of Avastin

Avastin (its generic name: bevacizumab) was developed by the biotechnology giant–Genentech (bought by Roche in March 2009), and was first approved by the U.S. FDA in 2004.  Avastin is a biologic antibody targeting “vascular endothelial growth factor” that involves in blood vessel formation.  By disturbing the blood vessel formation (a.k.a. angiogenesis) in tumors, the tumor cells lose nutrition and oxygen supplies and therefore die.  Avastin, in combination with intravenous 5-fluorouracil-based chemotherapy, has been used in treatment of several solid tumors, like metastatic colorectal cancer, metastatic kidney cancer, and non-small cell lung cancer.  In addition, in combination with paclitaxel (another chemotherapy drug), Avastin was used in treatment of metastatic HER2-negative breast cancer patients.  Unfortunately, the new clinical data from US trials showed that Avastin is not effective.  Based on the new scientific data, the FDA recently had decided to recommend removal of breast cancer indication from Avastin label.

Contrary Results of Avastin in Breast Cancer Treatment

Initially, I was grieved by Avastin’s failure of showing benefits in disease-related symptoms or survival to breast cancer patients.  But turn on my glass is half-full thought, at least Avastin is still valid in other treatment indications.  However, Genetech, the company marketing the drug doesn’t think so because the European Medicines Agency gave a green light to Avastin, arguing against FDA’s recommendation of Avastin removal from breast cancer indication.  Genentech will request a hearing with FDA by 18 January 2011.

Some Sticky Issues in FDA’s Decision on Avastin

In 2008, Avastin was granted “accelerated approval” for metastatic breast cancer treatment in combination with paclitaxel (called E2100 study).  Few years later, more science-based evidence from two clinical trial studies (named AVADO and RIBBON1) showed that Avastin did not benefit breast cancer patients.  Some patients claimed Avastin is helpful and are afraid the FDA’s decision will affect Medicare reimbursement because the annual spending of Avastin can reach $88,000, not many patients can afford such expensive treatment if Medicare doesn’t pay for it (or part of it).  You can read more on:

Until next post, keep on reading and writing!!  Happy New Year 🙂

Type 2 Diabetes Drug Faces Uncertain Future

Avandia is on The Hot Seat

Among a dozen diabetes medications, GlaxoSmithKline’s Avandia (rosiglitazone) has recently drawn scrutiny by the FDA due to adverse side effects on the cardiovascular system. To make matter worse, the company is being subpoenaed by the US Department of Justice over its development and marketing practices for Avandia over a decade.  In 28 October’s Nature reported that:

In its third-quarter earnings report released on 21 October, drug giant GlaxoSmithKline (GSK) revealed that it is being subpoenaed by the US Department of Justice over the company’s development and marketing practices for the diabetes drug Avandia (rosiglitazone). The company, headquartered in London, came under fire in July when a US Senate committee concluded that GSK had known about the drug’s heart risks for more than a decade without reporting them to regulators. GSK denied the charge. Sales of Avandia are currently restricted in the United States and banned in Europe.

Three Bad Luck Drugs in The Treatment of Type 2 Diabetes

Three similar diabetes drugs belonging to “thiazolidinedione” class, Troglitazone (Rezulin by Daiichi Sanyko Co.), Rosiglitazone (Avandia by GlaxoSmithKline) and Pioglitazone (Actos by Takeda Pharmaceuticals), help increase insulin sensitivity and are widely used in the treatment of type 2 diabetes.  Unfortunately, Rezulin was withdrawn from the U.S. market in 2000 due to hepatotoxicity.  Recently, Avandia was restricted for use in type 2 diabetes treatment due to increased heart attack and stroke risks.  Similarly, Actos was faced postmarket safety review of potential increased risk of bladder cancer.

Drug Effects Are Not That Easy to Study

From a biomedical scientist’s point of view, seeing those drugs crashed and burned is very frustrating.  On average, it costs ~$1.8 billion and 10- to 15-year timeframe to develop and bring a drug to market, let alone a possible withdrawal by FDA even after a drug goes on the market.  Why is it so hard to come out a safe and efficient drug?  In this case, I think the answers may lie in the undiscovered biological properties of cell membranes.  It’s been shown that small molecule’s perturbation to lipid bilayers (an essential component of cell membranes) can influence membrane proteins’ (e.g. ion channels, ion transporters, and receptors) functions.  The effects of above three famous bilayer-modifying molecules belong to “thiazolidinedione” class of drug acting as peroxisome proliferators-activated receptors gamma (PPARg) ligands that have multiple and profound effects on gene regulation, development, and metabolism.  In other words, these drugs somehow influence the cell membrane properties through complicated mechanisms, thereby causing functional changes of many unknown and unidentified targets.  In drug development world, the cost of “unknown” is very difficult to put a price tag on it.

Drug Development Business Seeks a Balancing Act Between Risks and Benefits

Again, no drug is perfect without any safety issue.  It’s a balancing act of the risks and benefits measurement and management.  When one drug flops, more will come; it is the failure we learn to make things better (hopefully)!

Until next post, keep on reading and writing!!

Fat Chance for Weight Loss Drugs

The Country in Desperate Need of Biggest Losers

Obesity has become a national image of the US population given that one in every three US residents (>72 millions) are overweight or obese. Compared with ~400 millions of overweight/obese human beings worldwide, 18% of them are in the US despite the fact that the US population only accounts for 4.52% of the entire population on earth.

Although it is fairly easy to tell if a person is overweight/obese, there is a scientific definition.  According to the Centers for Disease Control and Prevention, overweight is defined as the body mass index (BMI) is over 25 in an adult, whereas BMI greater than 30 is doomed obesity. Want to know your BMI? Click here to find out.  In addition to the severe distortion of body appearance by excess body fats, obesity can cause many notorious chronic diseases, such as diabetes, hypertension, heart attack, stroke, just to name a few (check this article to learn more diseases caused by obesity).

Losing is Simple But Not Easy

Obesity has created a huge market for biotech/pharmaceutical companies, from weight loss to lowering blood sugar, surgical fat removal to gastric bypass surgery.  Since obese patients are expected to rely on weight loss drug for a long period of time, it is conceivable that a FDA-approved magic pill can potentially become a cash cow for a pharmaceutical company.  Unfortunately, that magic pill is proved hard to find.  For instance, a fen-phen weight loss cocktail was recalled in 1997 due to serious heart and lung side effects.  On 8 October 2010, the FDA announced that Abbott Laboratories withdrew its 1997-approved weight loss drug Meridia off the market due to increased risk of heart attack and stroke.

During past few months, the FDA advisory committee had suggested “NO” to two companies developing weight loss drugs with unwanted side effects: Vivus’s Qnexa (phentermine and topiramate) and Arena Pharmaceuticals’s Lorqess (lorcaserin).  The next drug facing the FDA advisory committee, Orexigen and Takeda’s Contrave, is looking gloom given the recent FDA advisory committee’s tone on weight loss drugs.

Several companies with weight loss products still on the market are facing mixed sales records and potential side effects during aftermarket analysis.

  • GlaxoSmithKline: Alli
  • Roche: Xenical
  • Allergan: Lap-Band
  • Novo Nordisk: Victoza
  • Sanofi-Aventis: Lantus
  • Merck: Januvia
  • Eli Lilly/Amylin: Byetta

Go Back to The Basics

Although I am in the sickness industry (medical research to find the cause and cure for diseases), I really think the simplest way to reduce obesity incidence is to implement healthy diet and regular exercise promoted by the wellness industry.  Forget about that magic pill, eat right and sweat more!

Until next post, keep on reading and writing!!