Companies Get 19 EU Paediatric Extensions in 2016, But Many Firms Miss Trial Completion Deadlines

A report from the European Medicines Agency shows that in 2016, 19 products were awarded a six-month extension of their supplementary protection certificate for conducting pediatric trials, while the amount of scientific advice offered for pediatric medicines continued to rise.

A total of 19 active substances gained a pediatric extension to their supplementary protection certificates (SPCs) in 2016, compared with 28 substances in 2015 and 13 in 2014, while two products secured a two-year extension of their orphan market exclusivity, compared with one in 2015.

2016 also saw a continuing increase in the number of items of scientific advice offered to companies developing medicines for use in children, according to European Medicines Agency’s 2016 report to the European Commission, which looks at both the rewards and incentives available under the EU Paediatric Regulation and at the statistics on companies that failed to meet their obligations in terms of completing pediatric investigation plans (PIPs).

One of the rewards offered by the regulation is a six-month SPC extension when the results of studies conducted in compliance with an agreed PIP are included in a marketing authorization application.

The following 19 active substances benefited from such an extension in at least one EU member state in 2016:

Table 1: Six-month SPC pediatric extensions

Company	Product	Countries where extension granted
AbbVie	Humira (adalimumab)	Greece, Romania, Slovakia
Actelion	Tracleer (bosentan)	Austria, Cyprus, Germany, Greece, Slovakia
Alcon	Travatan (travoprost)	Austria, Greece, Ireland, Italy, Luxembourg, Spain
Astellas	Vesicare (solifenacin)	Italy
AstraZeneca	Crestor (rosuvastatin)	Cyprus, Belgium, Greece, Spain
Bristol-Myers Squibb	Orencia (abatacept)	Cyprus
Bristol-Myers Squibb	Baraclude (entecavir)	Cyprus
Genzyme	Cholestagel (colesevelam)	Denmark, Germany, Ireland, Italy, Spain, Sweden
GlaxoSmithKline	Menveo (meninogoccal conjugate vaccine)	Cyprus, Denmark, France, Ireland, Italy, Luxembourg, Netherlands, Spain, Sweden
Merck Sharp & Dohme	Ezetrol (ezetimibe)	Czech Republic, Finland, Germany, Greece, Ireland, Spain
Merck Sharp & Dohme	Emend (aprepitant)	Cyprus, Belgium, Denmark, Ireland, Slovenia, Sweden
Novartis	Certican/Afinitor (everolimus)	Cyprus, Denmark, Finland, Germany, Italy, Sweden
Novo Nordisk	Levemir (insulin detemir)	Belgium, Finland, Greece, Ireland, Lithuania, Luxembourg, Netherlands, Romania, Spain
Pfizer/Wyeth	Tygacil (tigecycline)	Belgium, Czech Republic, Germany, Greece, Luxembourg, Slovakia, Spain
Roche	Valcyte (valganciclovir)	Belgium, Czech Republic, Germany, Hungary
Sanofi Pasteur	Gardasil (human papillomavirus vaccine)	Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Netherlands, Sweden
Servier	Corlentor/Procoralan (ivrabadine)	Belgium, Germany, Greece, Ireland, Luxembourg, Netherlands, Spain
Uriach	Rupafin (rupatadine)	Czech Republic, Germany, Greece, Ireland, Luxembourg, Slovakia
Wyeth Europa	Enbrel (etanercept)	Cyprus

Orphan Extensions

Other rewards that can be obtained under the regulation are a two-year extension of orphan market exclusivity when the product has complied with an agreed PIP, and a pediatric-use marketing authorization (PUMA) for a new pediatric use of an off-patent drug.

In 2016, two orphan drugs secured two-year exclusivity extensions: GlaxoSmithKline’s Strimvelis (CD34+cells) for patients with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID), for whom no suitable human leukocyte antigen-matched related stem cell donor is available; and Vpriv (velaglucerase alfa) from Shire Pharmaceuticals for long-term enzyme replacement therapy (ERT) in patients with type 1 Gaucher disease.

Just one PUMA was granted in 2016: for Proveca’s Sialanar (glycopyrronium bromide) for the symptomatic treatment of severe sialorrhea in children and adolescents aged three years and older with chronic neurological disorders.

As well as incentives and rewards, the regulation also provides for the EMA to highlight delays in submitting applications for PIPs or waivers from the PIP requirement. Applications are supposed to be submitted no later than the end of healthy subject or patient pharmacokinetic studies, which can coincide with the initial tolerability studies, or the initiation of the adult Phase II studies (proof-of-concept studies).

“In cases where a phase II study in adults is already completed by the time of the PIP submission, the submission is in principle considered delayed unless justified,” the report notes. Late submissions of PIPs/waivers have been recorded since 2010 for those that have a delay of more than six months and where such delays are not justified, it adds.

In 2016, 21 PIPs (or 23% of the total) saw submission time lags of six months or more, while the figure for waiver submissions was 14 (27% of the total), according to the report. This represented a substantial increase over 2015, when just seven PIPs (10%) and four waivers (8%) were late, and was particularly noteworthy given that the numbers of delayed submissions had been steadily decreasing since 2010.

Laggardly Completion Of PIPs

Companies can also be hauled over the coals for failing to comply with the expected completion date for PIPs. In 2016, the EMA analyzed the figures for PIPs with an expected completion date of up to June 30, 2016 – this cut-off date was chosen because applicants are supposed to submit completed study reports within six months of their completion, and because studies (and PIPs) completed after June 2016 may not have been subjected to a compliance check.

In total, 210 PIPs should have been completed by June 30, 2016, but only 124 (59%) were completed on time. “Of the remaining 86 that have not been completed, 32 (15%) have not provided a justification,” the report comments.

Scientific Advice

The report also examines progress with scientific advice (SA) offered to drug developers by both the EMA and the national competent authorities.

It says that the number of SA procedures offered by the EMA, including those relating pediatric medicines, has been growing steadily since the Paediatric Regulation was implemented. In 2016, 24% of requests for SA or protocol assistance were related to pediatric drugs, compared with 21% in 2015 and 20% in 2014.

In the same year, the national competent authorities offered a total of 56 items of advice. Germany led the field with 19, the UK was second with 15, and Spain came third with seven.

From the editors of Scrip Regulatory Affairs.