1. New products in development (and further assumptions)
The market for ADHD treatment has attracted pharmaceutical companies to invest heavily in new product development. Results of literature searches and the database analysis [49] are summarized in Table 3.
Table 3  New products in development for treatment of ADHD in children and adolescents: overview of compounds not yet available in England and Germany  Only projects in phase III of clinical development or products already marketed in the United States. DaytranaR was formerly known as "MethypatchR", SparlonR as "AttenaceR". Data source: InnoVal-HC, 2006 [49].  A number of further pharmaceutical preparations and variants of methylphenidate are in phase III of clinical development in Europe, some of which have already received marketing authorization in the United States. These include a transdermal system (TDS, approved as DaytranaR in the United States, April 2006) of methylphenidate with duration of action of 12 hours (wear time, 9 hours). At present, in the absence of head-to-head trials against established oral formulations, the main advantage of this product seems to be convenience-related [49-51]. For modeling, it has therefore been assumed that it would capture no more than 10% of methylphenidate prescriptions. This implies the expectation that there will be no significant problems associated with skin sensitization.
Dexmethylphenidate, the chirally pure active isomer of methylphenidate, has been licensed as FocalinR (Novartis) in the US in May 2005, also as an extended-release formulation [49,52]. As there is currently no evidence of superiority in terms of efficacy or tolerability [49,53], it has been assumed that FocalinR will become available in Europe without a price premium over branded immediate-release (RitalinR, also Novartis) or modified-release methylphenidate (ConcertaR, Janssen-Cilag), respectively. Given its investment in FocalinR, it has been considered unlikely that Novartis would launch RitalinR LA (a long-acting preparation of methylphenidate available in the United States and some other markets) in England and Germany.
At the time of writing, few scientific data were in the public domain about lisdexamphetamine mesylate (NRP104), a new chemical entity that is an inactive prodrug of amphetamine believed to have a reduced potential for abuse and overdose compared to other ADHD drugs. The reason is that the amphetamine is conjugated to a specific amino acid and is activated only when metabolized in the gastrointestinal tract. Shire filed the product with the Food and Drug Administration (FDA) in December 2005 for the treatment of ADHD in children aged 6 to 12. Phase III study results presented at the Annual Meeting of the American Psychiatric Association in Toronto, May 2006, indicated similar efficacy and tolerability compared to mixed amphetamine salts (AdderallR) and duration of action of 12 hours [49]. A preliminary review of NRP104 by the U.S. Drug Enforcement Administration indicated that the compound would not be subject to controlled-substance scheduling [54], although this initial judgment has been revised since. The compound was launched by Shire in the United States end of July 2007 under the trade name "VyvanseR". For modeling it was assumed that the product will be introduced to the English and German markets in 2008 and (except for the "Extremely Low Case" scenario) overtake modified-release methylphenidate products in terms of prescriptions by 2012. Obviously, this rests on the assumption that clinical advantages of NRP104 (regarding abuse potential, possibly tolerability profile, as well as label and summary of product characteristics) will be confirmed.
Modafinil has been licensed as "ProvigilR" as a wake-promoting agent for patients with narcolepsy and shift work sleep disorder in the United States and England. Its manufacturer, Cephalon, has reformulated modafinil for children as once-daily 85 mg film-coated tablets, which it claims to be smaller and easier to swallow. Of note, this change of formulation should protect the new indication from generic competition [49]. While its mechanism of action is not fully understood, modafinil is classified as nonstimulant [55-57]. Similar to atomoxetine [58], a selective norepinephrine reuptake inhibitor, improvement of core symptoms had an effect size on core symptoms (school version of ADHD-RS) of 0.69 [59] to 0.76 [60]. This compares to effect sizes around 1.0 typically achieved with stimulants [58]. In August 2006, Cephalon announced discontinuation of modafinil development for ADHD due to safety concerns raised by the FDA, and the company intends to replace modafinil by its successor compound in development, armodafinil [61]. It has been assumed for modeling that armodafinil (like atomoxetine [62,63]) would become a second line treatment option after stimulants.
Finally, mixed amphetamine salts are marketed successfully in the U.S. (AdderallR, AdderallR XR, by Shire) but have been licensed neither in England nor in Germany. It is believed that these products will not become available in Europe. Further compounds in phase II clinical development for ADHD include selective GABA-B receptor antagonists (SGS742, by Saegis, a privately held company with Novartis among its investors) and ampakine molecules (by Cortex). These projects have been excluded from the present study in light of their inherent uncertainty; statistically, attrition rates of compounds in clinical phase II are as high as 62% [64].