Legally speaking

Legally speaking

In the absence of firm guidelines and consistent monitoring, off-label use of drugs by patients has increased tremendously. Aashruti Kak lays down the pros and cons of off-label drugs promotion and the need for formal regulations on that front

Off-label use of approved drugs has been in question for decades now. While doctors can prescribe drugs for uses other than those approved by the FDA, drug makers themselves cannot promote or advertise their products for such uses.

In 2000, the Washington Legal Foundation, an organisation that champions free market principles, limited and accountable government, individual rights, business civil liberties, and legal ethics, won a lawsuit against the US Food and Drug Administration (US FDA) for denying the industry its First Amendment right by regulating its off-label promotions. The judgement that year allowed pharma manufacturers to distribute independent, scientific publications on off-label uses of their drugs to doctors.

Now, nine years later, the US FDA has formed confirmed guidelines that allow companies to promote their drugs for unapproved uses through the distribution of peer-reviewed journals about off-label uses. However, many policy analysts world over believe that these guidelines are more like recommendations to pharma companies, rather than a formal regulation, and many also believe that the US FDA is washing its hands off of the burden of regulating off-label marketing practices and handing it over to the companies. The existing US FDA policy on marketing off-label uses of drugs takes after the FDA Modernization Act of 1997, which lightened the restrictions on drug promotions, however, it is still against direct promotion of products for unapproved uses. Hitesh Gajaria, Sector Head-Pharmaceuticals, KPMG, says, “This is not a sudden change in perspective. Distribution of journal articles about off-label drug use has been allowed and widely-practiced previously also. However, the law for the same expired in 2006 and companies have since lobbied to renew it.”

The above guidelines are an absolute version of the draft about Good Reprint Practices (GRP), which were first issued in February 2008. According to a Sun Pharmaceuticals spokesperson, through the GRP for the distribution of medical journal articles and medical or scientific reference publications on unapproved new uses of approved drugs and approved or cleared medical devices, the US FDA is permitting to print off-label uses in journals with a lot of restrictions. He says that this guidance states that US FDA’s policy on promotion of drugs for unapproved use has not changed, however in the light of advancement of public health, such information could be printed in journals as letters to the editor, abstracts of publication, and reference publications that contain little discussion with some investigative data. “The FDA also describes how this information could be given/disseminated to physicians and that it should be essentially separate from promotional literature. Also, the journal reprints or publication should be accompanied by certain statements, for example, ‘the Author of such articles should not be known to manufacturer as having financial interest in the product or receiving compensation from manufacturer,” he added.

In detail, the terms and conditions of the guidelines state that sales representatives of companies are not allowed to discuss the peer-reviewed article with a doctor during the sales visit. Also, the article must be published by an organisation having an editorial board that has experts in the subject under review, and not as a form of a special supplement sponsored by the manufacturers. Needless to say, the information in the article must be whole and not influenced by the manufacturer in any way. Most importantly, the article must have a permanent disclaimer announcing that the uses in discussion are not approved or endorsed by the US FDA. “The US FDA clearly specifies how a company can make known its off-label drug uses to the doctor without in any way manipulating any information contained in the journal and that the review is undertaken by an expert board of the organisation publishing the article and is in no way influenced by the manufacturer,” informs Gajaria.

Loopholes and fallout

“The biggest issues that surface in promotion of off-label drug uses pertain to the availability of adequate data on the safety and efficacy of the drug. It also raises concerns about ethical and moral responsibilities of doctors while providing the highest quality of care to their patients”

– Hitesh Gajaria Sector Head-Pharmaceuticals


“In any country, off-label use of drugs is an issue between the company, the physician and the patient. It’s a grey area, where there are no well laid guidelines. And any authority like the US FDA would not take knee jerk reactions; they would have deliberated amongst themselves, consulted experts, weighed their options regarding the risk-benefit ratio and then taken the decision”

– Dr Surinder Singh
Drug Controller General of India (DCGI)

But the above drafted guidelines seem to have two big loopholes-firstly, drug manufacturers need not limit the promotion of off-label uses to the drugs and indications that they are working on for US FDA assessment. Secondly, there is no compulsion for the US FDA to review the peer-reviewed journals that will be distributed. Keeping these in mind and the fact that the US FDA has lowered its guard and considerably reduced the legal burden of pharma companies with regards to off-label uses of their drugs, the impact on consumer safety and public health can be variably huge.

Gajaria avers, “This is a complex issue. It immediately raises concerns about how rigorous the studies published in peer-reviewed journals are, as compared with the FDA’s drug approval process. However, it is also important to take into consideration the fact that it is almost impossible to identify all uses of a drug when it is in the process of approval for the first time and the time involved in getting approvals for a new indication is considerable. More importantly, allowing the doctor the choice to prescribe drugs for an off-label use can bring in benefits such as innovation in clinical treatment, especially in cases where the conventional mode of treatment has been ineffective. It provides doctors faster access to potentially valuable medications. Hence this is a positive move.”

The Indian parallel

If it is a new drug (under four years) then it falls under the Drug Contoller General of India (DCGI). More than four years, it goes under the State drug regulatory authority, which controls the manufacture, sale and distribution of that drug. Dr Surinder Singh, DCGI, explains, “Off-label uses of drugs are not at all regulated in our country, even internationally there are no concrete regulations governing them. Off-label use of a drug is mainly a prerogative of the clinician. If companies are promoting their drugs for unapproved uses, then it’s a contravention of the law and that is when we are bound to take action under the Drugs and Magic Remedies (Objectionable Advertisements) Act 1954.” But according to him, at the moment there is no inception of a rule related to this issue.

He adds, “Sometimes indications have an evolution for which later on a particular drug could get an approval. And in any country, off-label use of drugs is an issue between the company, the physician and the patient. It’s a grey area, where there are no well laid guidelines. And any authority like the US FDA would not take knee jerk reactions; they would have deliberated amongst themselves, consulted experts, weighed their options regarding the risk-benefit ratio and then taken the decision.”

In India, under the Food, Drug, and Cosmetic Act (FDCA), a company must specify the intended uses of a product in its new drug application to the FDA. Before approving a drug, the FDA has to determine that the drug is safe and effective for the use proposed by the company. Once approved, the drug may not be marketed or promoted for off-label uses. In 2004, the Government of India had constituted a Committee to look into the aspect of off-label usage of drugs. The Committee, after extensive deliberations had authorised the Indian Medical Association (IMA) headquarters to draft a policy statement on off-label usage of drugs. Following this, IMA’s policy statement defined off-label use of a drug for indications or doses or routes of administration that are not included in the labelling approved by the Drug Controller General of India (DCGI). It also stated that for optimal patient care, it was imperative that registered medical practitioners have access to accurate and unbiased information about off-label uses of prescription drugs. IMA strongly supports the addition to approved labelling those uses of drugs for which safety and efficacy have been demonstrated.

According to the IMA, a registered medical practitioner may lawfully use an approved drug for an unlabelled indication when such use is based upon sound scientific evidence and sound medical opinion. But they also have the responsibility to interpret the information received from any source before making clinical decisions. Off-label prescriptions are to be written by competent doctors in the best interest of the patient. As per the association, off-label use of drugs is often the leading edge in patient care and research. In most instances they may even be the treatment of last resort. Because off-label prescriptions are legal, pharma companies have little incentive to obtain new indications for their approved drugs. But to justify their proposed off-label uses, companies must show evidence from clinical trials that the drug works for the new purposes, which is ultimately a process that consumes time and money.

Risks vs Benefits

The practice of off-label prescribing raises a number of legal and ethical issues, the most visible ones being the regulation of off-label prescribing by doctors and promotion by manufacturers. There is usually inadequate evidence supporting the off-label used of a drug in which the benefits outweigh the risks in order to seek approval of the US FDA. Hence, most companies may use off-label marketing as a way to avoid drug approval for indications other than the approved ones. The only bright side of off-label use of drugs is that it can save lives, especially in medical fields like oncology, where there are few effective treatments.

“The biggest issues that surface in promotion of off-label drug uses pertain to the availability of adequate data on the safety and efficacy of the drug. It also raises concerns about ethical and moral responsibilities of doctors while providing the highest quality of care to their patients,” opines Gajaria.

While off-label uses may be beneficial to people in certain ways, the patient population, even though wanting the newest therapies, is reluctant to go for them because of basic expectations like safe, affordable, and ‘evidence-based drugs’. In this tug of war between profits and patient health, even physicians root for their freedom to prescribe drugs that suit their patient’s needs as it would allow innovation in clinical practice in the face of failing approved treatments and orphan indications.

On the risk side of the matter, off-label use of drugs can overlook drug safety and efficacy. To top that, when newer drugs come into the market with off-label uses, they tend to be expensive, and play a big role in increasing healthcare costs. Instead of focusing on thorough clinical studies for new drugs, drug manufacturers can encourage seeking approvals for secondary uses of their drugs for which clinical studies are simpler and inexpensive as compared to the former, discouraging evidence-based practice in the process.

The use and promotion of such drugs has been challenged many a times legally. “One such example is that in 2003, a well known Indian pharma company initiated a promotional-cum-research programme by asking doctors to prescribe an anti-cancer drug to over 400 women as a fertility drug. It then revealed the doctors’ reports to other doctors as research, through its medical representative network. Following this, off-label drug prescription was prohibited in India, causing the IMA to launch a campaign to allow off-label prescription,” informs Gajaria. Singh informs that Letrozole was a drug brought out by Novartis, and had an off-label use initially in India, which now has a license in our country. In the West it still has a largely off-label use.

Other examples are of drugs like Genotropin, a human growth drug, which was promoted and sold by Pfizer as an anti ageing drug; Zyprexa (approved antipsychotic) which was promoted by Eli Lilly for Attention-Deficit/Hyperactivity Disorder (ADHD); and AstraZeneca’s Abraxis (cancer drug).

A balanced approach

Regulating authorities like the US FDA world over need to have an active role in developing evidence based practice, preventing companies from avoiding approvals and undermining their authority by flouting their rules. The authorities need to cater to all stakeholders (pharma industry, doctors and patients) by moving beyond corporate marketing. For instance, they should foray deeper into systematic collection of post marketing data to keep a record of all the risks and benefits of common off-label uses. They should also keep an eye out for any products that are in the market for off-label use that are not supported by strong evidence etc.

While there are patients desperate for early stage investigational drugs, there are others who want regulators to protect them from unsafe remedies. Regulators need to balance these expectations. Singh says, “When it comes to off-label use, the only thing that should weigh on the minds of regulators is the risk-benefit ratio.”

Gajaria agrees, “I believe that for every off-label drug use, a very clear risk-benefit trade-off is needed. That means the benefit to the patient from use of the drug must far outweigh the risk involved. The efficacy and safety of use has to be kept in mind. Off-label drug usage already exists in most parts of the world. With the US FDA laying down guidelines for the same, other countries may take cues and we may see this practice further increasing worldwide.”