The Off-Label Conundrum
`
`Off-label use of biologics is increasing as treatment successes,
`patient demand, and new indications grow. While scientific evidence
`and medical opinion still guide usage, high costs, unknown side effects,
`and legal ramifications are primary concerns for payers, physicians,
`and manufacturers.
`BY KATHERINE T. ADAMS, Senior Editor
`
`PHOTOGRAPH BY MICHAEL JUSTICE
`
`bill for a very expensive therapy. It
`remains to be seen if commercial
`third-party payers, who generally
`have been open-minded about off-
`label use of biologics when there is
`literature to support it, will begin
`to sing from Medicare’s hymnal
`about when to bless such usage.
`
`Look also to federal agencies. The
`FDA and the Office of the Inspector
`General have been aggressive in
`going after manufacturers’ practices
`they perceive to be tantamount to
`promoting off-label uses.
`Look to the legal system, though
`this cuts two ways: Patients can sue
`
`When the U.S. Food
`
`and Drug Admin-
`istration issued
`new rules for pre-
`scription drug labeling in January,
`some of the thinking behind it was
`that if their physicians prescribed a
`drug for an unapproved indication,
`patients would be more likely to
`question such use.
`Why would they, though? People
`with cancer — who compose the
`largest subset of patients who use
`biotech therapies — want results at
`all costs, even if for just a few more
`months of life. Other biotech thera-
`pies, particularly anti-inflammatory
`medications, show real promise in
`addressing a variety of previously
`undertreated conditions not now in-
`dicated on their labels.
`To answer “why,” look to Medi-
`care, for starters. With Part D regu-
`lations quite specific about how off-
`label uses are covered, a patient
`could otherwise be stuck with the
`
`“Much off-label use comes
`from physicians and specialists
`talking to each other, working
`with their societies, and attend-
`ing national conferences,” says
`Edmund Pezalla, MD, MPH. “And
`so we tap into their networks.
`That — not the pharmaceutical
`companies — drives use.”
`
`APRIL 2006 · BIOTECHNOLOGY HEALTHCARE 27
`
`
`
`2 of 6
`
`Celltrion, Inc. 1033
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`REGULATORY
`
`SELECTED COMMON OFF-LABEL USES OF BIOLOGICS
`
`Agent
`
`Approved indication
`
`Uses
`
`Adalimumab (Humira)
`
`Rheumatoid arthritis
`
`Psoriasis, ulcerative colitis
`
`Becaplermin (Regranex)
`
`Diabetic foot ulcers, wound care
`
`Bevacizumab (Avastin)
`
`Metastatic colon cancer
`
`Venous leg ulcers, scleroderma, sickle cell
`disease
`
`Wet age-related macular degeneration,
`late-stages breast cancer, lung cancer,
`kidney cancer
`
`Cisplatin (Platinol)
`
`Bladder, testicular, ovarian cancer
`
`Thyroid and lung cancers
`
`Efalizumab (Raptiva)
`
`Psoriasis
`
`Granuloma annulare
`
`Etanercept (Enbrel)
`
`Psoriasis, psoriatic arthritis,
`rheumatoid arthritis, ankylosing
`spondylitis, osteoarthritis
`
`Behcet’s disease, sarcoidosis, wound ulcers,
`vasculitides, pyoderma gangrenosum
`
`Ibritumomab tiuxetan
`(Zevalin)
`
`Infliximab (Remicade)
`
`Non-Hodgkin’s lymphoma
`
`Various cancers
`
`Rheumatoid arthritis, psoriatic
`arthritis, ulcerative colitis, Crohn’s
`disease, ankylosing spondylitis
`
`Kawasaki’s disease, psoriasis, Sjogren’s
`syndrome
`
`Oxaliplatin (Eloxatin)
`
`Metastatic colon cancer,
`pancreatic cancer
`
`Post-surgery drug regimens,
`newly diagnosed colorectal cancer
`
`Rituximab (Rituxan)
`
`Non-Hodgkin’s lymphoma,
`rheumatoid arthritis
`
`Skin malignancies, blood cancers
`
`Sunitinib (Sutent)
`
`Gastrointestinal stromal tumors,
`advanced kidney cancer
`
`Breast, colon, and pancreatic cancers
`(in clinical trials)
`
`Trastuzumab (Herceptin) Metastatic breast cancer
`
`Early-stage breast cancer
`
`SOURCE: BIOTECHNOLOGY HEALTHCARE ANALYSIS
`
`if off-label use results in an injury —
`or they can sue if they are denied
`the best treatment available, a fact
`that is well recognized by physi-
`cians, payers, and the biotechs.
`Labeling changes or no, off-label
`prescribing is an important part of
`the practice of medicine and the
`evolution of care, which means that
`the FDA cannot rule on the appro-
`priateness of treatment. “Our cur-
`rent dilemmas are about the need
`for healthcare to incorporate un-
`certainty as well as a bias toward
`medical evidence,” says Edmund
`
`Pezalla, MD, MPH, vice president
`and medical director of Prescrip-
`tion Solutions. “There needs to be
`an emphasis on good evidence
`when making coverage decisions,
`but plans also need to leave enough
`room for decision making in special
`cases.”
`With the biotech pipeline flush,
`the subject of off-label use is likely
`to become more important — and
`more touchy — not just because of
`their cost but also because, for now,
`few biotech drugs can show long-
`term safety data. “I would think that
`
`this would be of more concern be-
`cause of the expense that the plan
`and members are incurring, and be-
`cause there may be severe conse-
`quences that are not fully fleshed
`out,” notes Sean Brandle, vice pres-
`ident at the Segal Co., a New York-
`based employer consultant. “That’s
`what I would be telling our clients.”
`
`COST AND CONSEQUENCES
`Last November, Skin & Aging, a
`journal for dermatologists, published
`an article that explored the off-label
`uses of 14 biologic agents for treat-
`
`28 BIOTECHNOLOGY HEALTHCARE · APRIL 2006
`
`
`
`3 of 6
`
`Celltrion, Inc. 1033
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`REGULATORY
`
`ment of dermatologic conditions.
`Tumor necrosis factor inhibitors
`adalimumab (Humira) and etaner-
`cept (Enbrel), and monoclonal anti-
`bodies infliximab (Remicade) and rit-
`uximab (Rituxan), were listed as
`effective in treating various skin can-
`cer and inflammatory conditions, de-
`spite lacking indications for them.1
`“Residents get exposed to off-
`label usage,” says Francisco A.
`Kerdel, MBBS, BSc, chief of derma-
`tology at Miami’s Cedars Medical
`Center, and a coauthor of the article.
`This is particularly true, he says, in
`dermatology, “where we have rare
`conditions for which no effective
`therapy has been available. The new
`biologics can treat these conditions
`in a very effective manner.”
`Effective as though these drugs
`may be, trial data about off-label
`uses are generally limited. For ex-
`ample, women taking trastuzumab
`(Herceptin) have been followed for
`an average of only 2.5 years. Yet,
`their success is a magnet for more
`experimentation. Trastuzumab is
`known to be prescribed off-label for
`nonmetastatic breast cancer, a de-
`velopment that has generated at
`least as much hype as scientific evi-
`dence of its effectiveness.
`“We follow clinical trial data
`rather than the label, so there are
`cases where a drug will have some
`pretty good evidence” to support off-
`label use, says John Watkins, RPh,
`MPH, director of pharmacy formu-
`lary development at Premera Blue
`Cross, in Mountlake Terrace, Wash.
`In an interview with BIOTECH-
`NOLOGY HEALTHCARE in February,
`Watkins singled out the use of rit-
`
`1 Available online at:
`«http://www.hmpcommunications.com
`/SA/displayArticle.cfm?ArticleID=
`article4869».
`
`Three forms of off-label use
`With biologics, off-label can mean three things: varying the dosage
`or dosing schedule, using the product for a condition for which it
`has no FDA indication whatsoever, or using it to address another
`aspect of a disease the drug is approved to treat.
`Edmund Pezalla, MD, MPH, vice president and medical director
`of Prescription Solutions, gives an example of the latter. “We see
`a lot of interferon requests for suppressive therapy in hepatitis C,
`even though the initial therapy wasn’t successful in eradicating the
`disease, in order to keep the infection in check.”
`Dosage variations come in different flavors. What Pezalla sees
`with rheumatoid arthritis or psoriasis treatments is that higher doses
`sometimes are used at induction of the drug, but that some patients
`are unable to come off the higher dose. “They go on the mainte-
`nance dose and then relapse. Then they go back to the induction
`dose and get better again. So, we have to work with the physician
`on what’s actually happening with that particular individual.”
`The drug label, Pezalla explains, is based on the averages from
`clinical trials. “You’ll see things written like ‘A dose of 50 mg is no
`better than a dose of 25 mg.’ Well, yes, on average. But there are
`probably a few people out there for whom the higher dose is the
`only way to go.”
`With infusibles, costs rise and fall with dosage changes, some-
`times because the dosage is more creative. “We see unsupported
`off-label use with dosing parameters that are exorbitant. You will
`get someone who tries to justify a low dosage of something that is
`not supported in the literature — but often, you see a higher
`dosage,” says Dave Willcutts, CEO of Minneapolis-based
`Ancillary Care Management. “The interesting thing is that once
`you start tightening the parameters, you don’t see the doses come
`down. [The physicians] stop prescribing the drug altogether.”
`Off-label usage related to nonapproved indications is common in
`pediatric practice where an adult medication or dose may be pre-
`scribed for a child. In most such cases, although a particular drug
`may not have been shown to be effective in children or for a par-
`ticular age group, there may be no other options, says Pezalla.
`
`uximab to treat rheumatoid arthri-
`tis (which at the time was still an
`unapproved indication; since then,
`the FDA has granted Genentech an
`RA indication for rituximab). “We
`know the data are there,” he said at
`the time, “so we will approve its use
`based on those data.”
`In fact, Pezalla, at Prescription So-
`lutions, estimates that at least half
`the pharmacy benefit manager’s
`
`total reimbursement load is for off-
`label usage. Prescription Solutions,
`like many formulary administra-
`tors, requires prior authorization
`for all specialty drugs. It also issues
`updated guidelines for off-label use
`on the basis of scientific evidence
`and accepted medical opinion.
`“Our clients — employers and
`health plans who are paying for
`these medications — want the right
`
`30 BIOTECHNOLOGY HEALTHCARE · APRIL 2006
`
`
`
`4 of 6
`
`Celltrion, Inc. 1033
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`tracks infusible use by three cate-
`gories: FDA indication, off-label use
`supported by the literature, and off-
`label use not supported. How a cen-
`ter ratchets up its off-label use, says
`Willcutts, determines where they
`fit into the grid.
`“If you look at something like IV
`gamma globulin [IVIG], where off-
`label use is significant, the number
`of conditions not supported by the
`literature that [nonetheless] drive a
`physician to prescribe the therapy is
`very high. If it’s not controlled, it
`can represent a significant portion
`of someone’s IVIG spend.”
`
`It remains to be seen if
`commercial third-party
`payers, who generally are
`open-minded about off-
`label biologics’ use if the
`literature supports it,
`begin singing from
`Medicare’s hymnal about
`when to bless such usage.
`
`people to get the medications, but
`they also want to make sure that
`they don’t overspend in one area
`because they need to deliver health
`care to the whole group,” says Peza-
`lla. Some clients, Pezalla notes, try
`to limit their exposure this way by
`refusing to cover off-label uses of
`any kind.
`At Regence Blue Shield of Idaho,
`Terry Killilea, PharmD, vice presi-
`dent of pharmacy, says “We rely on
`that overused term evidence-based.”
`When determining whether an off-
`label use qualifies as a covered ben-
`efit, Killilea says, the questions to
`be asked are: Is it a good trial?
`Can we perform the classic evi-
`dence-based analysis?
`“If they’ve done only two tri-
`als and have not shown benefit
`through the appropriate statis-
`tical strategy, then they have
`not documented benefit in pa-
`tients,” says Killilea. “If there
`are no data confirming value,
`you can’t just assume value.”
`Still, Regence doesn’t com-
`pletely discount limited trial in-
`formation. If there are only
`small trials, then you enter a
`subjective world where cohort stud-
`ies and published case reports have
`to be evaluated to determine poten-
`tial benefit. “It’s difficult, because if
`you’re going to stick to evidence-
`based data, you need evidence of
`benefit,” says Killilea.
`Dave Willcutts, CEO of Min-
`neapolis-based Ancillary Care Man-
`agement, which manages infusion
`services for payers, sees off-label use
`of infusibles as a growing area for
`concern. “The longer these prod-
`ucts are out, the more they will be
`used off label,” Willcutts says. To
`control costs, Ancillary Care Man-
`agement has a grid system that
`
`REGULATORY
`
`knit oncology community. The Na-
`tional Comprehensive Cancer Net-
`work estimates that as much as 75
`percent of biologics prescribing in
`cancer care is off label, and more
`than 100 trials for all kinds of can-
`cers and off-label treatments are in
`progress. Chemotherapy itself came
`about as an off-label use of mustard
`gas derivatives in the 1940s.
`“Oncology moves much faster
`than its literature,” says Pezalla.
`“Most members who request cov-
`erage already have gone through the
`first, second, and sometimes third-
`line therapies, whether they are
`standard chemo, surgery, or
`radiation therapies. So, we
`have developed our guidelines
`to be as flexible as possible and
`to allow reasonable use.
`“At the same time, our
`clients don’t want us to ap-
`prove the use of drugs that
`have no evidence in the litera-
`ture, have been shown to be
`ineffective, or basically are ex-
`perimental.”
`Surging costs and short-
`term benefit continue to top
`his clients’ lists of concerns. Al-
`though the number of deaths per
`100,000 cancer patients has fallen
`by about 9 percent since 1993, the
`cost of treatment is up 75 percent
`since then, with 60 percent of can-
`cer drugs being used off-label. The
`annual price of trastuzumab ther-
`apy is about $48,000; colon cancer
`treatment involving several biologic
`and conventional drugs can cost
`$250,000 annually.
`You might expect that federal
`policy regarding Medicare Part D
`coverage of off-label uses of biologic
`therapies would trouble oncologists
`— and you would be right. Under
`the Part D benefit, Medicare will pay
`
`With time, what is and isn’t ac-
`ceptable changes, Willcutts adds.
`“You saw that with Enbrel being
`used off-label for Crohn’s, until the
`literature came out and said ‘Nope,
`it actually doesn’t work for that,’
`and now [that use] has fallen off.”
`
`THE CANCER ARENA
`Perhaps because many cancer pa-
`tients have few viable treatment op-
`tions, oncology is like no other field
`of medicine in terms of therapeutic
`experimentation — and the result-
`ing knowledge of what appears to
`work and what doesn’t tends to cir-
`culate quickly through the tightly
`
`APRIL 2006 · BIOTECHNOLOGY HEALTHCARE 31
`
`
`
`5 of 6
`
`Celltrion, Inc. 1033
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`REGULATORY
`
`for off-label usage only if it is cited
`in 1 of the 4 FDA-approved drug
`compendia. Drug plans do not have
`the authority to cover any use not
`specifically listed in the compendia.
`Mark Ratain, MD, professor of
`medicine and director of the Ad-
`vanced Solid Tumor Clinic at Uni-
`versity of Chicago Hospitals, thinks
`unit cost and reimbursement aren’t
`as important as cost-effectiveness.
`He suggests using a metric, like
`comparing a specific off-label pro-
`cedure with a year of dialysis, to de-
`termine how cost-effective a use is.
`“Though clinical trials of off-label
`usage have been limited, the data
`that are available are still valuable,”
`says Ratain, “and most oncology
`drugs have survival metrics associ-
`ated with them.”
`
`SAFETY ISSUES
`As cost is a prime consideration,
`so too are safety and unwanted side
`effects. Killilea, at Regence, says sig-
`nificant side effects always must be
`taken into account. “When you
`look at an evidence-based review,
`you have to look beyond the num-
`ber needed to treat, or NNT, which
`represents how many people you
`need to treat to show a benefit —
`say, 1 out of 20. You also look at the
`number needed to harm, or NNH,
`which is how many patients you
`treat before you see side effects. It’s
`not a cost equation. I would say po-
`tential side effects are as important
`as, if not equal to, cost aspects.”2
`Kerdel, at Cedars Medical Center,
`agrees that experimentation should
`not be without regard for patient
`safety. “If you use a drug off-label,
`you shouldn’t expect more serious
`side effects than have been pub-
`lished for that given drug in the FDA-
`indicated manner,” says Kerdel.
`
`LEGAL EGGSHELLS
`Legal issues surrounding off-
`label use are complex and involve
`more than the FDA. “There’s the po-
`tential for a lawsuit under the False
`Claims Act, which might be an issue
`for a U.S. Attorney or the OIG,” says
`Allen G. Minsk, JD, partner and
`chair of the Food & Drug Practice
`Team in the Atlanta-based law firm
`Arnall Golden Gregory. A False
`Claims Act case can arise when a
`physician or a pharmacist may fill a
`prescription for an unauthorized
`use, submit a form for reimburse-
`ment, and then be reimbursed for
`the unapproved use. A manufac-
`turer that promotes off-label infor-
`mation for a reimbursable product
`could be found to have caused a
`false claim to be made.
`Then there are product-liability
`considerations. “Let’s assume that
`the biologics company promotes
`off-label use, the physician uses it,
`and the patient gets injured,” says
`Minsk. “The patient is likely to sue
`everybody in the claim in an effort
`to obtain some settlement, such as
`recouping medical expenses.”
`The promotional practices of
`biotech and pharmaceutical manu-
`facturers are under intense federal
`and state scrutiny now, and any-
`thing that smells like off-label pro-
`motion could land the manufac-
`turer in a world of trouble. “Partly,
`it’s a matter of Medicare and Medic-
`aid expenses,” he explains. The gov-
`ernment wants to ensure that pa-
`
`2 Recombinant factor 7a (NovoSeven), an
`clotting drug approved for congenital he-
`mophilia, has shown promise in treating
`cerebral hemorrhages, but has been linked
`to deaths, strokes, heart attacks, and other
`complications, as reported recently in
`JAMA. The package insert has been
`changed to include a warning about side
`effects in patients without hemophilia.
`
`tients receive products for approved
`indications, “not those promoted
`off-label, which may not have gone
`through the regulatory process.”
`Whistleblowers know this, and
`these kinds of lawsuits are becom-
`ing more common. Last year,
`Genentech and Biogen Idec faced a
`whistleblower suit claiming that
`rituximab, which at the time had
`indications for non-Hodgkin’s lym-
`phoma, was being promoted as a
`treatment for arthritis (a use not ap-
`proved until this year). Employees
`often file such suits, says Minsk. “It
`wouldn’t surprise me to see more
`whistleblower cases.”
`Minsk cautions that the line be-
`tween promoting off-label use and
`educating physicians about the uses
`of a drug often blurs. “When I pro-
`mote a product,” Minsk explains,
`“I’m giving a certain perspective
`with the hope that I may sell some-
`thing. If I’m educating, I’m presum-
`ably giving as much information as
`I can so that the recipient can be as
`educated as possible. It’s the differ-
`ence between providing the high-
`lights of a story versus describing it
`in its entirety.”
`The advice Minsk gives to his
`clients is that if there is legitimate
`benefit to an off-label use, then pro-
`ceed through the regulatory chan-
`nel to obtain FDA approval for that
`ise. If the regulatory approach is not
`taken and if no alternative therapy
`exists, then provide the physician
`and the patient with as much ob-
`jective information as they need to
`make an educated decision.
`The legality of off-label use will
`not disappear — not as long as the
`practice continues to lead to break-
`throughs in medical care. It just faces
`a lot more scrutiny now that biotech
`BH
`makes the stakes bigger.
`
`34 BIOTECHNOLOGY HEALTHCARE · APRIL 2006
`
`
`
`6 of 6
`
`Celltrion, Inc. 1033
`Celltrion v. Genentech
`IPR2017-01122
`
`