Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 7, Num. 1, 2011, pp. 35-39

Journal of Cancer Research and Therapeutics, Vol. 7, No. 1, January-March, 2011, pp. 35-39

Original Article

Off-label use of anti-cancer drugs in India: To be or not to be!

Vikram Gota, Pankaj Patial

Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India

Correspondence Address: Vikram Gota, Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India, vgota@actrec.gov.in

Code Number: cr11008

PMID: 21546740

DOI: 10.4103/0973-1482.80455

Abstract

Keywords: Anti-cancer drugs, off-label, survey

Introduction

Any new drug is labeled for an indication, dose and route of administration by drug approval authorities called on-label. Use of a drug outside the terms of its official labeling is referred to as off-label. ^[1] Several factors contribute to the high prevalence of off-label use in oncology. Off-label use of chemotherapy is higher for patients with multiple comorbidities, those who have advanced disease, and those for whom treatment is intended to be palliative. ^[2] Interest in new medical discoveries and a booming economy resistant to cost constraints may also contribute to this practice. ^[3] The availability of novel combination regimens with either better efficacy or reduced risk of adverse events is likely to lead to high off-label drug utilization. Quite often, the results of the clinical trials that lead to drug labeling are not generalizable to populations outside carefully selected and tightly managed study groups. As a result, uncertainty about the "best" therapeutic option is frequently encountered in oncology decision making. Given the lack of data and high level of uncertainty, the pervasiveness of off-label use of oncology-related drugs is not surprising. Ever expanding knowledge of tumor biology may promote off-label use through the discovery that many diseases contain similar therapeutic targets. For example, the use of rituximab to treat diffuse large cell lymphoma and Waldenstrom′s macroglobulinemia rests on the knowledge of CD20 and its role in the pathogenesis of these two cancers. Moreover, pharmaceutical companies do not favor conducting large randomized trials to extend the labeling once a drug is approved because conducting clinical trials is expensive. For example, industry sponsored trial of aspirin will never happen in spite of overwhelming evidence of inflammation in the pathogenesis of cancer. Rather, they would encourage off-label use based on results of small investigator initiated trials, which tend to become standard care over a period of time. Many off-label indications are already accepted and even reimbursed by insurance companies. ^[4]

Oncologists′ freedom to prescribe drugs off-label carries important advantages. 1) It offers hope in the palliative setting, particularly when approved treatments have failed. 2) It offers the patients and physicians earlier access to potentially valuable medications and allows physicians to adopt new practices based on emerging evidence. 3) It could be the only available option for very rare cancers or those of unknown primary site. 4) It enables oncologists to generate proof-of-concept data in a non-trial setting which could pave the way for a future randomized controlled trial. There is also a flipside to this. 1) Expanding usage of off-label chemotherapy without strong evidence of safety and effectiveness may do more harm than good. 2) When newer, more expensive drugs are used off-label, it increases health care costs unnecessarily. 3) It undermines the incentives for manufacturers to perform rigorous studies and instead subtly encourages them to game the system by seeking approval for secondary indications for which clinical trials are less complicated and less expensive. 4) Off-label use may discourage evidence-based practice.

Several estimates are available for the prevalence of off-label use of drugs in cancer, mostly from the USA. A recent study of 28 oncologists and 12 oncology practice managers in geographically diverse areas pinpointed more than 50 physician-administered anticancer therapies used off-label for a variety of diagnoses. The study found that the top five drugs used in oncology practices represent almost 50% of the total number of mentions of physician-administered drugs used off-label. ^[5] A retrospective survey on the use of rituximab showed that 75% of rituximab prescriptions in a National Cancer Institute (NCI) designated comprehensive cancer center was for off-label indications. ^[3] A large study conducted in the USA revealed that 33.2% of chemotherapy, including hormonal therapy, administered by oncologists was being used off-label. ^[6] The prevalence of this practice in India is not well documented.

Materials and Methods

We conducted a survey in March 2010 to understand the extent of off-label use in oncology practice in India. A list of 10 anticancer drugs was prepared and oncologists were requested to fill in all the indications for which a given drug was used in their center. Drugs commonly used in oncology practice and those with level 2 or 3 evidence for off-label indications were selected for the survey. Ten centers were identified, one each from Kerala, Tamil Nadu, Karnataka, Andhra Pradesh, Delhi, Gujarat, West Bengal, Bihar and two in Maharashtra. One oncologist from each of these centers was contacted by phone or email and explained about the survey. The questionnaire (list of drugs) was sent to them by email if they agreed to participate in the survey. A reminder was sent to those oncologists who did not respond within a week. The survey concluded 2 weeks after the reminder was sent, and those who did not respond within this time period were considered non-responders. The labeled indications of each drug were obtained from the Food and Drug Administration (FDA) website. FDA labeling has universal acceptance and therefore it was chosen as the basis for on-label use. Off-label use was categorized as those recommended in the National Comprehensive Cancer Centre Network (NCCN) guidelines and those without.

Results and Discussion

Nine out of 10 centers agreed to participate in the survey. Four centers responded to the questionnaire, two from West zone and one each from North and South zones. Five centers did not respond, even 2 weeks after the reminder was sent. Six out of 10 drugs were used for off-label indications. The number of off-label indications for which these drugs were employed in the four centers that responded to the survey is shown in [Table - 1]. All off-label usage was in accordance with the NCCN recommendations, except for gemcitabine which was used in one center for treating sarcomas and hepatocellular carcinoma based on phase II data. Lack of affordable options for these cancers encouraged the oncologist to use this drug for off-label indications. The pooled data from the four centers is shown in [Table - 2].

The survey has some obvious limitations. The number of responders was too few (40%) to draw meaningful conclusions. Thus, the findings of this survey cannot be considered representative of off-label prescribing practices in oncology across the country. Secondly, responders might have been reluctant to discuss off-label practices in spite of an assurance to keep their identity strictly confidential. Finally, the responses included broad terms like lymphoma, breast cancer, etc., without specifying the stage of disease, intent of therapy (curative or palliative) or the line of treatment (de novo or salvage), which made it difficult to assess the correct use of these drugs as per labeling. Besides, our survey failed to address the dose and route of administration of drugs, which are also important for qualifying treatments as on-label. In spite of the lacunae, the survey gives an indication that oncologists in India could be carrying a very defensive approach toward treating their patients and not willing to consider evidence outside the generally accepted guidelines of the NCCN while administering drugs off-label. The fact that off-label use is still a gray area where the law has not taken a firm stand has not helped matters.

Off-label use is not uniformly regulated across the globe. It could be as liberal as in Japan where a new drug application permits the approval of off-label usages without clinical trials. ^[7] In some countries, such as France, drug agencies that regulate marketing prohibit dissemination of information on off-label use. The European Medicines Agency (EMEA) is more receptive to off-label practice by proactively supporting clinical trials of off-patent drugs for off-label indications, especially in children. For example, they promote specific clinical trials which fall within the priority list that is prepared from a public health perspective for studies into off-patent pediatric drugs. ^[8] These studies would be funded by the European Union (EU) through the FP7 Health-Research Community Program and, although not obligatory, are likely to contribute to the development of Pediatric Use Marketing Authorization (PUMA). ^[9],[10] Moreover, the European Society of Medical Oncology (ESMO) has suggested a search for new regulatory mechanisms that could permit extension of drug labels beyond the initiative of the manufacturers. ^[11] The FDA also encourages studies in pediatric population, providing the sponsor with an additional 6 months of marketing exclusivity. ^[9] This incentive has led to enhanced understanding of the pharmacology of drugs in children.

In the USA, dissemination of medical journal articles is governed by the Good Reprint Practices Guidance published in January 2009 which imposes significant constraints on the promotion of off-label use of approved drugs. ^[12] These restrictions state the following: (1) the medical or scientific article must be published by an organization with an independent editorial board; (2) the journal article must be peer-reviewed; (3) the information in the article should address "adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate safety and effectiveness"; (4) the article must not be false or misleading; (5) the use discussed in the article must not pose a significant risk to public health; (6) financial interest disclosures accompanying the article must be prominently displayed; (7) the article should be disseminated along with the product′s approved label; and (8) sales people distributing the material should not discuss the article. Manufacturers′ full compliance with these guidelines might provide much-needed consumer protection and a measure of balance to how off-label uses are presented to physicians.

In India, new treatments are approved by Drug Controller General of India (DCGI) but there are no specific guidelines over the use of off-label drugs. Marketing such drugs by pharmaceutical company is considered as contravention of the law and action is taken under the Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954. In 2004, the Government of India constituted a committee in Indian Medical Association (IMA) to propose guidelines on the off-label use of drugs. The guidelines put forward by IMA strongly recommended the off-label use of drugs for which safety and efficacy have been demonstrated, especially if such a use is based upon sound scientific evidence and sound medical opinion. The committee was of the opinion that therapeutic advances are often achieved at a rapid rate while progress through licensing authorities is slow, and therefore, the labeled indications may not reflect the current knowledge and may not include well-proven uses of a drug and may be over restrictive. The committee, however, put the onus of interpreting the information on the off-label use of drugs on the Registered Medical Practitioner. In spite of the IMA′s favorable stance on off-label prescribing, there is still no inception of a rule related to this issue. ^[13]

The concept of health insurance is still not widespread in India. Less than 10% of Indians have health cover. ^[14] In the USA, if an anti-cancer drug is being used off-label, the use must be supported to allow for reimbursement by health insurance companies. In November 2009, Centre for Medicare and Medicaid Services (CMS) expanded Medicare coverage to include off-label use of chemotherapy drugs in the USA. The CMS has identified certain drugs compendia to be used as references for off-label use of anti-cancer drugs and biologicals. ^[15],[16] In the absence of a compendium listing supporting off-label use, contractors may consider scientific evidence if published in one of the 26 designated peer-reviewed journals identified by CMS. Although Medicare contractors are required to provide coverage for accepted off-label uses published in the recognized compendia, they have discretion over coverage of off-label uses referenced in peer-reviewed literature. These measures by the CMS have further bolstered the right use of off-label drugs in USA, especially in the oncology sector.

For optimal patient care, oncologists should have access to accurate and unbiased information about off-label uses of prescription drugs. Since off-label prescribing is legal, pharma companies have little incentive to file for new indications for their approved drugs, whereas rigorous clinical trials would be required to justify their proposed off-label use. It is a no-win situation wherein companies are not willing to conduct further trials for new indications and at the same time are being forbidden to disseminate information that is generated by interested parties. Thus, oncology care will not be uniform throughout the country. The probability of a patient being offered an evidence-based off-label treatment would depend on the likelihood of the treating oncologist keeping abreast with emerging evidence. This deadlock could be broken by incentivizing drug development for newer indications either in the form of marketing exclusivity (as followed by the FDA) or funding clinical studies of off-patent drugs (as practiced by EMEA) or by adopting carefully defined policies that allow pharmaceutical companies to disseminate emerging evidence for newer indications so that new treatment regimens are adopted faster in clinics.

If employed judiciously, the benefits of off-labeled use far outweigh the risks. Therefore, it calls for legislations to streamline this practice. Instead of totally banning promotion of drugs for off-label indications, the law should take a middle path and try to regulate it. While the DCGI does not regulate the practice of medicine, and thus cannot regulate off-label prescription of drugs by physicians, it can surely regulate the promotion of off-label use by pharmaceutical companies. The Good Reprint Practices Guidance of FDA could be a good starting point. It imposes significant constraints on the dissemination of medical journal articles about off-label uses, but does not oppose it if done within the boundaries of the guidance. Fraudulent practices by the industry may still threaten this liberal stance, as in the case of Pfizer in 2009. The company was brought to book with a stringent penalty of $2.3 billion, the largest health care fraud settlement in the history of US Department of Justice. ^[17] Even the most reasonable guidance on promotion of off-label should not protect the manufacturers from state persecution when their promotional activities are fraudulent. Such a legal backing would ensure that legislations made in public interests are not misused by groups with vested interest. Finally, the system could be further streamlined by directing the insurance companies to cover off-label uses as long as they are supported by sound scientific evidence. Identifying drugs compendia as shown by CMS would encourage rational prescribing. Agencies like Indian Council for Medical Research (ICMR) should take a lead in this direction. On their part, oncologists should evaluate the published data and past clinical experience to assess the risk of such treatments. Off-label practice, although evidence based in its own right, can be further exploited to generate more concrete evidence by prospectively collecting safety and efficacy data of an approved drug for unapproved indications. This could be achieved in the form of a nationwide pharmacovigilance program with a central database or by incentivizing this process in a way that would not compromise the safety of patients receiving the drugs.

In conclusion, off-label prescription in oncology practice in this small survey of premier cancer centers in India was found to be very limited. However, the sample set may not be representative of the country. Off-label use of drugs has several advantages, and therefore, the government in close association with the DCGI should look at ways and means to streamline the practice. Such measure would enlarge the armamentarium for the treatment of cancer.

Acknowledgment

We are grateful to all oncologists who participated in this survey in spite of their busy schedule.

References

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