As many would know, prescribing any medicine for disease conditions that are not approved by the drug approving authorities while granting its marketing approval, is generally termed as ‘off-label’ use of drugs.

It is also a usual practice in most of the regulated markets of the world that once the drug regulators give marketing approval of a medicine, which is indication-specific, physicians are free to prescribe these as they deem necessary. However, the drug manufacturers can seek prescription support from the doctors only for the indications as approved by the appropriate government authorities.

Even the USFDA had articulated, “the best way to address any concerns that the information about those (off-label) uses is not reaching medical practitioners is to get those uses in the labeling. We believe that the risks of allowing drug companies to distribute journal articles and other information about off label uses far outweigh any benefits.”        

Since long, most of the drug regulators across the world, including the Drug Controller General of India (DCGI) have prohibited the sales promotion for unapproved uses of drugs to doctors. Nevertheless, the practice continues ignoring its serious consequences.

Monitoring of ‘off-label’ use is challenging: 

Monitoring of off-label use of medicines is quite challenging too by the drug regulators, especially in India, where post marketing surveillance is generally just on paper.

In this regard, a recent research study that I shall refer to below in this article, has quite appropriately suggested, “Future electronic health records should be designed to enable post market surveillance of treatment indications and treatment outcomes to monitor the safety of on and off-label uses of drugs.”

As India intends to move towards the ‘Digital’ space, this suggestion would be quite implementable by the DCGI, as the ‘Smart Cities’ start coming up.

Some examples of extensive off-label usages: 

According to the study done by a team of experts in medical information – Iodine, using the top drugs by number of monthly prescriptions, the following is a list of 4 medications with surprising off-label uses:

Drug	Approved Indication	Off-label Indication
Abilify (Aripiprazole)	Schizophrenia, Bipolar Disorder, Major Depressive Disorder (adjunctive), Autism-related Irritability, Agitation associated with Schizophrenia or Bipolar Mania, other	Insomnia
Lyrica (Pregabalin)	Management of: neuropathic pain associated with diabetic peripheral neuropathy, post herpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury; adult patients with partial onset seizures (adjunctive)	Anxiety
Namenda (Memantine)	Moderate to severe dementia of the Alzheimer’s type	ADHD, OCD
Synthroid (Levothyroxine)	Low thyroid hormone levels, some types of goiters, management some types of thyroid cancers	Depression

Off-label use and increasing risks of drug safety: 

In its November 02, 2015 online issue, JAMA Internal Medicine published an article titled, “Association of Off-Label Drug Use and Adverse Drug Events (ADE) in an Adult Population.” The objective of this study was to monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population.

This particular study assumes importance, as off-label use of prescription drugs without strong scientific evidence has been identified as an important contributor to preventable Adverse Drug Events (ADEs), especially in children. However, despite concerns in this regard, no systematic investigation on the effects of off-label drug use in adult populations is being performed, regularly.

The detail analysis of this study reveals that not only is the benefit of off-label prescription is uncertain, but the risks of ADEs could make the ‘risk-benefit ratio’ quite unfavorable. So much so that in a large number of cases, no drug treatment will be a much better option.

According to the authors, the risk for ADEs grew as the number of prescription drugs the patient used increased. For example, patients using eight or more drugs had more than a 5-fold increased risk for ADEs compared with patients who used one to two drugs.

The study involving 46,021 adult patients, receiving 151,305 prescriptions between January 2005 and December 2009 was done in Canada. Of those prescriptions, more than 10 percent were prescribed for off-label use. Interestingly, out of that group, more than 80 percent prescriptions were for off-label uses without any robust scientific evidence supporting the use.

Based on the findings the researchers concluded that off-label use of prescription drugs is associated with ADEs.

The article suggested:

• Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence.

• Future electronic health records should be designed to enable post market surveillance of treatment indications and treatment outcomes to monitor the safety of on and off-label uses of drugs.

Pharma industry strongly opposes off-label use, when it suits them:

Interestingly, pharma industry vehemently opposes off-label use of drugs, when it suits them.

To give just a couple of examples, recently a new law that permits prescribing of drugs for off-label uses in France has reportedly been strongly opposed by the pharmaceutical industry in Europe.

Pharma trade associations argue, “the above move of France is directly in opposition to European Union’s laws that prohibit member states from supporting off-label use for economic purposes, and is a trend that undermines the current regulatory framework and could put patients’ health at risk.”

Besides France, they have also submitted a complaint against Italy to the European Commission over the country’s new off-label rules.

Common methods followed for off-label marketing:

The other side of the story is that, reportedly many pharma companies continue promoting off-label uses of drugs aggressively, for significant commercial gains.

According to ‘The Centers for Medicare & Medicaid Services (CMS) – a federal agency within the United States Department of Health and Human Services, some of the off-label drug promotion methods of the pharmaceutical companies are as follows:

• Paying incentives to sales representatives based on sales for off-label use

• Paying kickbacks to physicians to prescribe drugs for off-label use

• Disseminating misleading posters promoting off-label use

• Paying physicians:

- To pretend to be the authors of articles about off-label uses when the articles were actually written by manufacturers’ agents

- To serve as members of “advisory boards” promoting off-label use

- To travel to resort locations to listen to promotions about off-label use

- To give promotional lectures in favor of off-label use to fellow practitioners

• Publicizing studies showing efficacy of off-label uses, while suppressing studies showing no efficacy.

Even the Uniform Code of Pharmaceutical Marketing Practices (UCPMP) of the Government of India does not allow such sales and marketing practices. But these all continue to happen, unabatedly.

A path much abused?

Although most of the drug companies publicly advocate self regulation to avoid unethical marketing practices, the situation on the ground is much different, across the world. 

The following are just a few examples of serious business consequences faced by some of the well-known global pharma and biotech majors, besides many others, from the United States Department of Justice, for alleged off-label promotion of drugs: 

• On November 4, 2013, Johnson & Johnson (J&J) was asked to pay more than US$ 2.2 billion to resolve criminal and civil liability arising from allegations relating to the prescription drugs Risperdal, Invega and Natrecor, including promoting for uses not approved as safe and effective by the USFDA and payment of kickbacks to physicians and to the nation’s largest long-term care pharmacy provider.  

• On July 30, 2013, Wyeth Pharmaceuticals Inc., a pharmaceutical company acquired by Pfizer, Inc. in 2009, agreed to pay US$490.9 million to resolve its criminal and civil liability arising from the unlawful marketing of the prescription drug Rapamune for uses not approved as safe and effective by the USFDA. 

• On December 19, 2012, Amgen Inc. pleaded guilty and paid US$762 million to resolve criminal liability and false claims allegations.

• On July 2, 2012 GlaxoSmithKline LLC (GSK) pleaded guilty and paid US$3 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of certain prescription drugs, its failure to report certain safety data, and its civil liability for alleged false price reporting practices. This resolution is the largest health care fraud settlement in the US history and the largest payment ever by a drug company, so far. 

• On May 7, 2012, Abbott Laboratories Inc. pleaded guilty and agreed to pay US$1.5 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of the prescription drug Depakote for uses not approved as safe and effective by the USFDA.  This resolution is the second largest payment by a drug company and includes a criminal fine and forfeiture totaling US$700 million and civil settlements with the federal government and the states totaling US$800 million.  Abbott also was reportedly subjected to court-supervised probation and reporting obligations for Abbott’s CEO and Board of Directors.

• On October 21, 2011, Pfizer Inc. agreed to pay US$14.5 million to resolve false claims allegations related to its marketing of the drug Detrol. 

• On June 10, 2011, Novo Nordisk was asked to pay US$25 million to resolve allegations of off-label promotion of Novoseven.

• On September 30, 2010, Novartis agreed to pay US$422.5 million to settle criminal and civil investigations into the marketing of the anti-seizure medicine Trileptal and five other drugs. The government accused Novartis of mislabeling, paying illegal kickbacks to health care professionals through speaker programs, advisory boards, entertainment, travel and meals. 

Hence, it appears that the path followed by many pharma players to inform the doctors about the judicious off-label use of drugs only in circumstances where approved treatments have failed, is being much abused. 

A conflict of interest? 

Many doctors believe that there is also a distinct upside for off-label use of drugs, as flexibility of a physician to prescribe drugs off-label offers important advantages too, especially in circumstances where approved treatments have failed. This is indeed true and indisputable.

However, the reality is, many pharma industry, in general, actively encourage off-label use of drugs for commercial benefits through expanded use of their respective brands.

Aggressive drug promotion for various off-label uses, reportedly being so widespread and indiscriminate, many physicians can’t even remember the approved indications of drugs. Hence, they do not necessarily go for off-label use only when approved treatments have failed.  In this context, on November 23, 2015, ‘The Wall Street Journal (WSJ)’ in an article titled, “Risk of Off-Label Uses for Prescription Drugs” reported as follows:

“A 2009 study published in the journal Pharmacoepidemiology and Drug Safety found that 1,199 physicians in a national survey were able to identify the FDA-approved indication of 22 drugs only about 55% of the time. The physicians surveyed included primary-care doctors and psychiatrists.” 

On the other hand, the patients generally expect that the prescribed drugs will be safe. They want to administer evidence based approved medicines. Some of them have even started expressing that these evidences must also be disclosed to them.

Hence, there seems to exist a clear conflict of interest in this matter between the patients, drug manufacturers and perhaps the doctors, as well.

Conclusion:

The magnitude of general off-label use of drugs is reportedly increasing and is likely to increase further, exposing patients to increased risks of ADEs.  Although the business consequences of getting engaged in this unwanted process indiscriminately could at times be quite adverse, in the balance of probability between slim chances of getting caught, and expected creamy return, many pharma players continue to feel that this risk is worth taking.

Therefore, the moot question that needs a pragmatic answer is, for patients’ safety, when the global and local pharma majors talk about prescriptions of only impeccable evidence based medicine, do they walk the talk?

By: Tapan J. Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.