According to the Center for Disease Control, attentiondeficit hyperactivity disorder (ADHD) affects 3%–7% of children and 2%–4% ofadults. About 2.5 million children and 1.5 million adults currently take ADHDmedication. And since ADHD is only treatable, not curable, people take drugsfor life, equaling a potential boon for pharmaceutical companies. But FDAhearings, concerns over drug safety and abuse, and generic challenges havecombined to create unwanted commotion and speculation about the market’sfuture.
IMS Health data show that US sales of ADHD drugs in 2005 hit$3.04 billion, a 14% increase over 2004, but nothing like the huge year-on-yeargrowth witnessed in previous years. Total prescription growth in 2005 alsoslowed, increasing just 5% to 34.9 million.
All but one of the ADHD treatments fall into two varietiesof stimulants: methylphenidates (Ritalin, Concerta, Metadate CD and Daytrana)and amphetamines (Adderall and Adderall XR).
The market leader is Shire’s Adderall XR, with $974 millionin sales representing 32.1% of total dollar percentage of market share in 2005,according to IMS Health. Adderall XR, introduced in 2001, is a long-actingversion of Adderall, approved in 1996.
Concerta, from Johnson & Johnson’s McNeil Consumer andSpecialty Pharmaceuticals, is second with 27.6% of the market and sales of $838million in 2005. A 12-hour version was approved in 2000.
Eli Lilly’s Strattera, the only nonstimulant, is third with21.8% of the market share, translating to $662 million in 2005. The drug wasapproved in November 2002.
Novartis’ Ritalin, marketed since 1955, is available inshort and long-acting forms, as well as a generic. Novartis also makes FocalinTM, a refined version of Ritalin. Ritalin LA, an eight-hour formulation, placedfourth in total dollar percentage of the ADHD market, with 4.4% in 2005,bringing in $132 million.
Celltech Pharmaceuticals, acquired by UCB in 2004, makesMetadate CD, approved in April 2001. This once-daily formulation had 3% of themarket and $91 million in sales in 2005.
The first-ever ADHD patch—Shire’s Daytrana—was approved inApril for children ages 6–12.
While ADHD medications are highly effective, they carryserious warnings. Side effects range from weight loss, insomnia, aggression anddecreased appetite, to stunted growth, visual hallucinations, suicidalideation, psychotic behavior, hypertension, arrhythmias and possibly death.Furthermore, long-term negative effects, especially on the development of youngchildren’s brains, are not well known. All ADHD stimulants are classified asSchedule II narcotics, a designation for medicines with the highest abusepotential and addiction profile.
These concerns have recently been highlighted. On Feb. 9,2005, Canada’s drug regulatory agency, Health Canada, suspended the sale ofShire’s Adderall XR in that market due to reports of sudden heart-relateddeaths in users. And on Feb. 9, 2006, an FDA safety committee hearing voted 8-7with one abstention to recommend a black-box warning for all ADHD drugs, tohighlight the cardiovascular risk.
“Growth in the market is stalled right now,” says GeoffPenney, category business director for psychiatry at market research firm GfKMarket Measures. “Whether these recurring safety issues will limit futuregrowth is unclear.”
Yet, there are positives. Adderall XR was reinstated inCanada last August, albeit with revised warnings of risk in patients with heartabnormalities. And in March this year, an FDA safety committee of pediatriciansand psychiatrists voted against the black box warning but recommended thatpatients and doctors be made more aware of potential psychosis, aggression andcardiac effects with ADHD medications.
“When you look at the number of prescriptions that have beendispensed for all ADHD medicines, it helps to show how truly safe and effectivethey are,” says Matt Cabry, senior manager, corporate communications, at Shire.“We’ve continued to actually hold, and at certain times grow, our market shareover the past 12 to 18 months.”
Nevertheless, growth of the ADHD market has slowedconsiderably. One explanation could be the limited success ADHD medicationshave found outside the US. “Growth in Europe hasn’t really begun,” Penneystates. “Parents and doctors are averse to prescribing stimulants to kids—it isa cultural issue to some degree. America is the biggest consumer ofprescription drugs in the world; we have a stronger trust in medicines. InEurope, there is more skepticism.”
Growth could be further impeded by the final FDA decision onblack boxes, which if approved could deter physicians and patients from drugtreatment. A black-box warning for cardiovascular risk would add to the blackbox already present on Strattera, warning of potential suicidal thinking inadolescents, and Adderall and Adderall XR, concerning amphetamines’ abusepotential. Daytrana, whose approval closely followed the FDA advisory committeehearings, is the first methylphenidate product with a warning about suddendeath and use in patients with structural cardiac abnormalities.
Anathea Waitekus, a senior analyst at market research firmDecision Resources, believes there will “eventually be some sort of revision ofthe labeling, but probably not a black box.”
Waitekus believes market growth will continue, driven by anincrease in the diagnosed and drug-treated adult populations, which she sayscould gain a market share of $1.8 billion by 2014. A recent statisticallysignificant analysis of ADHD medication use by Medco Health Solutions showedthat the number of adults aged 20 to 44 using ADHD medicines increased morethan 139% from 2000 to 2005, outpacing increases in children 19 and younger by82%. Yet the study notes that cardiovascular risks associated with ADHD drugsare greater in adults than children; therefore, those safety issues should betaken into account when prescribing.
Females are also increasing their market presence. Medcoshowed that among women aged 20–44, use increased 164% from 2000 to 2005.During the same period, use in girls ages 10–19 increased 90%, outpacing boysby 45%. Waitekus says, “Physicians are realizing that children don’t have to behyper to have attention deficit, and that has been leading toward diagnosis anddrug treatment of the inattentive subtype, which females tend to show more of.”
Promising new drug formulations will also help marketgrowth. These include Shire’sAdderall XR2, a 15-hour extra-extended release version intended for adults; andNRP-104, a new amphetamine formulation that guards against abuse. NRP-104results from Shire’s collaboration with New River Pharmaceuticals, a companyspecializing in less easily abused formulations of scheduled drugs. A new drugapplication (NDA) was submitted in December 2005.
NRP-104’s safety profile is especially appealing because ofstimulant misuse. The recent study “Non-medical use of prescription stimulantsin the US,” conducted by researchers at RTI International and published in theFebruary 2006 online edition of Drug and Alcohol Dependence, was based on asecondary analysis of data collected during 2002 for the National Survey onDrug Use and Health. It found that 7.3 million Americans have misused ADHDstimulants, representing 35% of the total population reporting prescriptionstimulant misuse, and concluded that about 1 million teenagers and young adultshad misused prescription stimulants during a 12-month period, with 75,000showing signs of addiction. Larry Kroutil, the study’s lead author, believesthe findings confirmed what people have long suspected: “The misuse ofprescription stimulants in general, but particularly those that are prescribedfor treatment of ADHD, is a significant problem in the US.” However, he addsthat while care in diagnosing and monitoring patients is necessary, the studydoesn’t advise against medication. “Clearly, there are demonstrated benefits touse of these drugs.”
In addition to abuse, drug treatment in young children isalso controversial. Waitekus says children are increasingly diagnosed atyounger ages because of structured environments, such as day care, wherehyperactivity is more noticeable. “Some doctors are treating these kids,3-year-olds, with anti-psychotics and ADHD off-label because they don’t knowwhat the children have,” she states. Penney agrees, but adds, “There is anatural tendency to limit the use of drugs at that age. It is difficult to tellif you are diagnosing ADHD or if the child is just a normal energetic6-year-old.” No treatment currently on the market is approved for use inchildren under the age of 6.
Generic threats also loom. Generics companies Barr, Teva andImpax have challenged Shire’s Adderall XR, while Andrx Pharmaceuticals hascreated difficulty for J&J’s Concerta. Shire settled with Impax: Shire hasfive years to switch patients from Adderall XR, Impax can sell an Adderall XRgeneric from 2010, and Impax will pay a royalty on generic sales. Shire is alsoin settlement talks with Barr. Though the pediatric exclusivity period forConcerta was due to expire on March 17, 2004, McNeil Consumer & SpecialtyPharmaceuticals has successfully delayed Abbreviated NDA approvals for genericversions.
Between J&J and Shire, Penney thinks Shire will come outahead. “Generics will likely come,” Penney says, “but the challenge to thegeneric manufacturers is not reproducing the chemical compound, but thedelivery system technology. Concerta will likely be the first to go generic,with Adderall XR to follow some years later.” A spokesperson for J&Jdeclined to comment on how the company plans to maintain Concerta’s marketshare.
Shire’s Cabry says, “We have been reasonably successful indefending our intellectual property, so much so that there is no chance that ageneric would come on market this year.” Penney agrees, saying Adderall XR’sgeneric challenge “is a non-issue. Adderall XR is king.”
If Adderall XR is king, Shire is its kingdom. Waitekusprojects by 2014, Shire will own about 50% of the ADHD market due to a strongpipeline, marketing experience and promising new products. On top of itsamphetamine franchise, Shire recently expanded into methylphenidates withDaytrana, allowing more direct competition with Concerta.
As the first ADHD patch, the jury is still out on Daytrana.While advantageous for its ease of application, lack of negative foodinteractions and visual verification of compliance, Daytrana also contains awarning regarding contact sensitization—which in its most serious manifestationcould render patients incapable of responding to methylphenidate in anyform—and its ease in removal raises unique abuse concerns about patch sharing.
Waitekus has mixed views. “I never really thought that thepatch would
do that well,” she states. “Patches in general just don’tseem to do that well.” However, Penney says, “the patch represents a uniquedelivery with some advantages. When you can differentiate yourself, you cangain a market share.” And Waitekus admits that “if anything, it just givesShire another reason to demonstrate its expertise … now it is just one-stopshopping with Shire.”
Shire’s pipeline includes Adderall XR2, predicted to bepopular with adults who want treatment to last through the workday. But themost promising successor to Adderall XR’s throne is NRP-104. Waitekus predictsNRP-104 will become the first ADHD drug to achieve blockbuster status. “IfShire and New River can take this amphetamine formulation and develop a drugthat is truly not scheduled or at risk of being abused, and is as effective asamphetamine, they are just going to corner the market. Even if it is scheduled,it will still have an advantage, because it has that aura of not having thepotential to be abused.” NRP-104’s favorable safety profile also increases thelikelihood that it will be successful in markets outside the US.
Challenges exist for Eli Lilly. Strattera, the market’s onlynon-stimulant, is losing share. A label update in December 2004 concerning therisks of liver damage, and a black box warning about suicidal tendencies inadolescents, probably didn’t help. Yet Waitekus thinks the true reason for thedecline is Strattera’s efficacy. “It is hard to compete with methylphenidateand amphetamine,” she says, “those drugs work really well, so Strattera is justnot that effective.”
Problems also exist for Cephalon, whose Sparlon—a strongerdosage of sleep disorder drug Provigil—was submitted for treatment of ADHD inchildren aged 6–17. In March, the FDA’s Psychopharmacologic Drugs Advisorycommittee rejected Sparlon by a vote of 12-1 because of safety concerns relatedto Stevens-Johnson syndrome, a potentially fatal skin rash. Waitekus thinks ifSparlon receives a black box, “it just won’t be able to compete with theamphetamines and methylphenidates.” She also notes that Provigil has been usedoff-label for ADHD and is not considered very effective. “Psychiatrists usedrugs off-label all the time, and they are just not impressed [with Sparlon].If it was so great, they would already be using it.”
To succeed, any new formulation will have to beat themethylphenidates and amphetamines. “To have a drug that is any better thanmethylphenidate or amphetamine in efficacy would just be extraordinary,” saysWaitekus. She predicts formulations that last longer and have less potentialfor abuse.
From the June 01, 2006 Issue of MM+M - Medical Marketing and Media
