Off-Label Cancer Drug Use -- Compendia in Need of Overhaul

Roxanne Nelson, BSN, RN

September 06, 2016

Cancer drugs are often used off label for indications that are not approved – but the system that covers the reimbursement for such use is inconsistent and needs to be overhauled, oncologists argue in an opinion piece published online August 25 in JAMA.

"Off-label use of oncology drugs is common, and in some cases, this use is supported by high-quality evidence demonstrating that the benefits outweigh risks for patients," said corresponding author Ethan Basch, MD, director of the Cancer Outcomes Research Program at the University of North Carolina at Chapel Hill (UNC) Lineberger Comprehensive Cancer Center and professor in the Division of Hematology/Oncology at the UNC School of Medicine.

"Unfortunately, there are also instances of off-label use when this is not the case," he told Medscape Medical News. "Given the substantial toxicities of cancer drugs, in the absence of clear evidence of benefits, giving these drugs may confer more harm than good, despite the best intentions of the prescribing physician. We owe it to patients to ensure that the risks they take on are worth it."

In the article, the authors argue that the process that is currently used to determine Medicare reimbursement for off-label use needs to be overhauled.

Specifically, they say, the problem lies with the five federally designated third-party drug compendia, which are privately owned pharmaceutical reference guides that are used by the Centers for Medicare & Medicaid Services (CMS) for decisions about off-label reimbursement.

CMS is required by law to provide coverage if the indication for an off-label cancer drug is supported by at least one of these compendia.

Private insurers may also use these compendia to inform their own coverage decisions.

The five designated compendia are the American Hospital Formulary Service (AHFS); National Comprehensive Cancer Network (NCCN) Drugs and Biologics; Clinical Pharmacology; Micromedex DrugDex; and Wolters Kluwer Clinical Drug Information Lexi-Drugs.

Each compendium has its own system for rating evidence and recommending therapies for different indications, but there are "substantial inconsistencies both between and within these resources," and in some cases, the quality of evidence used to determine off-label use is weak, the authors comment.

There is also limited transparency about how compendia are assembled and about conflicts of interest on the part of their contributors, all of which can lead to poor quality of patient care and high costs.

"As a community, we need both to generate evidence and to synthesize and evaluate this evidence to provide guidance to providers and payers," Dr Basch commented.

The compendia are relied upon to provide synthesis and evaluation of the evidence to support decision making, but unfortunately, they often fall short, which creates excess risk for patients, he explained.

"Generation of scientific evidence is a separate but related issue," Dr Basch added. "Better information in the compendia could provide the basis for determining areas where additional evidence generation is needed."

Inconsistency and Lack of Evidence

The authors note that a 2009 systematic review found that the quality of evidence cited in compendia for off-label cancer drug usage was less rigorous than the standards used to support drug approvals by the US Food and Drug Administration (FDA).

That review, which included 14 off-label indications of cancer drugs, found that there were substantial limitations in the level, quantity, consistency, and timeliness of evidence. Moreover, the evidence cited by the compendia was often not up to date and differed from that retrieved through independent search, as reported at the time by Medscape Medical News.

"This raises concern that payers may be compelled to cover inadequately proven treatments for which the risks outweigh benefits," write Dr Basch and his coauthors. "Despite the findings of this 2009 systematic review, this issue has not been addressed since then."

Erlotinib as an Example

In their article, Dr Basch and colleagues compare the off-label compendia listings for erlotinib (Tarceva, Genentech), which is currently approved by the FDA for non–small cell lung cancer and pancreatic cancer.

The off-label indications for erlotinib listed within recent versions of the compendia were compared, and the evidence cited for each indication was evaluated.

There were "persistent inconsistencies" between the compendia and "methodological weaknesses" in the analyses of the evidence, the authors note.

As an example, there is no off-label indication for the drug in the AHFS, but there is one in Clinical Pharmacology (for head and neck cancer), there are eight in DrugDex (colorectal cancer, newly diagnosed glioblastoma, recurrent glioblastoma, recurrent or metastatic head and neck cancer, renal cancer, non–small cell lung cancer, ovarian cancer, and prostate cancer), and there are three in NCCN (bone cancer, leptomeningeal metastases, and renal cancer).

The evidence cited to support these indications was weak in a number of instances, such a phase 1 trial, single-case reports, or small case series.

Improving the Process

The compendia-based model for coverage decisions was developed during a time when fewer drugs were available for patients, the cost of oncologic agents was lower, and there was less appreciation of the potential long-term harms of treatments. Given the changes that have taken place in the overall landscape of cancer treatment and costs, this model should now be reassessed, Dr Basch and colleagues argue.

To reach that goal, the authors offer four steps that could be taken to improve the review process.

These include developing methodologic standards for evaluating evidence used to back off-label drug recommendations; combining the findings into one "single, rigorously developed resource," as opposed to several inconsistent guides; evaluating whether the researchers who are reviewing and determining these policies have any potential financial conflicts of interest; and making this information free to the public (compendia listings are currently available only to subscribers).

"As far as who is in the best position to drive this area moving forward, the new FDA Oncology Center of Excellence would likely be able to take on this role," said Dr Basch, "although they would require support and infrastructure to do so."

Alternatively, it could be accomplished by a new partnership of public and private payers, but with enforced policies to limit relationships with industry.

Dr Basch and coauthors have disclosed no relevant financial relationships.

JAMA. Published online August 25, 2016. Full text

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