Perampanel for epilepsy: Still no proof of added benefit

August 19, 2014

The drug perampanel (trade name Fycompa) has been approved since July 2012 as adjunctive ("add-on") therapy for adults and children aged 12 years and older with epileptic fits (seizures). In a new early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether perampanel offers an added benefit over the appropriate comparator therapy. However, such an added benefit cannot be derived from the new dossier either, as the drug manufacturer did not submit any relevant data for this comparison.

Already in the first dossier assessment in December 2012, there was no proof of an added benefit of perampanel because the manufacturer dossier provided no suitable data. The new assessment was conducted upon application of the manufacturer to the Federal Joint Committee (G-BA), which specifies the appropriate comparator therapy.

Appropriate comparator therapy expanded

Fits that affect only a small part of the brain are called "focal" or "partial seizures". In this type of fit, the muscle twitches and spasms remain limited to isolated parts of the body. However, such seizures may spread across the whole body and are then referred to as "secondary generalization". Perampanel is approved as add-on therapy for the treatment of partial seizures with or without secondary generalization in people aged 12 years and older.

The G-BA approved the manufacturer's application for reassessment of the drug according to AMNOG because the appropriate comparator therapy had to be expanded following the change in the AMNOG Regulation for Early Benefit Assessment of New Pharmaceuticals (in §6 (1), Sentence 2, AM-NutzenV): Originally the more economical comparator therapy had to be chosen if several options were available, preferably a treatment with a fixed price. This regulation was dispensed with in 2013. If the G-BA specifies several options as appropriate comparator therapies, the manufacturer is now free to choose a therapy irrespective of the costs.

10 drugs possible as appropriate comparator therapies

The G-BA therefore specified 10 different drugs for the appropriate comparator therapy in form of an individual antiepileptic add-on therapy: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproic acid or zonisamide for all age groups, eslicarbazepine or pregabalin only for adults, or lacosamide only for patients aged 16 years or older. It depends on the basic and prior therapy as well as the reason for treatment switching which of these drugs is used. If a patient is known to have pharmacoresistance, intolerance or another contraindication to the chosen drug, this drug cannot be used.

Manufacturer limits its assessment to subpopulation

In its second dossier, the manufacturer wanted to prove the added benefit of perampanel as add-on therapy only for a certain part of the approval population: for patients with pharmacoresistant and continuing active epilepsy. In its dossier, the manufacturer defined these as patients diagnosed with epilepsy for more than 5 years who, as add-on therapy in basic therapy, already receive at least one antiepileptic drug specified by the G-BA as appropriate comparator therapy.

The manufacturer justified this by claiming that, at first, new antiepileptics are mainly prescribed for resistant patients and in epilepsy centres or specialized practices. From the company's point of view, the manufacturer's proof of added benefit should preferably cover the population that is most likely to benefit from perampanel in the foreseeable future.

Comparisons with placebo instead of drugs

In the three relevant randomized controlled trials (RCTs) used by the manufacturer, each of three different dosages of perampanel is compared with a dummy drug (placebo): The patients either received perampanel as add-on therapy or placebo in addition to their ongoing basic therapy, which consisted of one to no more than three antiepileptics. At least one of the 10 drugs specified by the G-BA was part of the basic treatment.

The dose of antiepileptics of the basic therapy was not allowed to be changed during the treatment phase of 19 weeks. Hence there was no possibility to adapt or change the treatment of patients who continued to have epileptic seizures.

Appropriate comparator therapy not implemented

The manufacturer regarded the treatment in the subpopulation described to already be highly individual so that it could not be further improved by add-on therapy. Hence, from the company's point of view, the added benefit of perampanel as add-on therapy derives from the comparison with placebo.

However, it was not presented in the dossier in a comprehensible way why none of the 10 drugs of the ACT should not be suitable as add-on therapy. The G-BA explicitly allowed the choice for the individual patient. There were also no indications that the study participants were no longer eligible for individual add-on therapy. In contrast, the study data suggest that not all options of drug treatment have been exhausted for these patients.

The appropriate comparator therapy was therefore not implemented in any of the studies presented. Hence the company again presented no relevant data for the assessment of the added benefit of perampanel. An added benefit of the is therefore still not proven.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the 's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G‑BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

Explore further: Perampanel for epilepsy: No proof of added benefit

More information: An overview of the results of IQWiG's benefit assessment is given by a German-language executive summary. In addition, the website gesundheitsinformation.de, published by IQWiG, provides easily understandable and brief German-language information on perampanel.

Related Stories

Perampanel for epilepsy: No proof of added benefit

January 30, 2013
The drug perampanel (trade name Fycompa) has been approved since July 2012 as adjunctive ("add-on") therapy for adults and children aged 12 years and older with epileptic fits (seizures). In an early benefit assessment according ...

Dimethyl fumarate for MS: Added benefit is not proven

August 7, 2014
Dimethyl fumarate (trade name: Tecfidera) has been approved since January 2014 for adults with relapsing remitting multiple sclerosis (RRMS). In an early benefit assessment pursuant to the Act on the Reform of the Market ...

Added benefit of the fixed combination of dapagliflozin and metformin is not proven

May 15, 2014
The fixed combination of the drugs dapagliflozin and metformin (trade name: Xigduo) has been approved since January 2014 for adults with type 2 diabetes in whom diet and exercise do not provide adequate glycaemic control. ...

Added benefit of saxagliptin as monotherapy is not proven

December 5, 2013
The drug saxagliptin (trade name: Onglyza) has been approved also as monotherapy in Germany since July 2013 for certain adults with type 2 diabetes mellitus. It is an option when drug treatment is needed, but the drug metformin ...

Rilpivirine combination product in pretreated HIV-1 patients: Added benefit not proven

April 7, 2014
The German Institute for Quality and Efficiency in Health Care (IQWiG) reassessed the antiviral drug combination rilpivirine/emtricitabine/tenofovir. In early 2012, the combination was approved for the treatment of adults ...

Type 2 diabetes mellitus: Added benefit of canagliflozin is not proven

June 17, 2014
Canagliflozin (trade name: Invokana) has been approved since November 2013 as monotherapy and in various combination therapies for adults with type 2 diabetes mellitus when diet and exercise alone do not provide adequate ...

Recommended for you

Study suggests ending opioid epidemic will take years

July 20, 2017
The question of how to stem the nation's opioid epidemic now has a major detailed response. A new study chaired by University of Virginia School of Law Professor Richard Bonnie provides extensive recommendations for curbing ...

Team-based model reduces prescription opioid use among patients with chronic pain by 40 percent

July 17, 2017
A new, team-based, primary care model is decreasing prescription opioid use among patients with chronic pain by 40 percent, according to a new study out of Boston Medical Center's Grayken Center for Addiction Medicine, which ...

Private clinics' peddling of unproven stem cell treatments is unsafe and unethical

July 7, 2017
Stem cell science is an area of medical research that continues to offer great promise. But as this week's paper in Science Translational Medicine highlights, a growing number of clinics around the globe, including in Australia, ...

Popular heartburn drugs linked to higher death risk

July 4, 2017
Popular heartburn drugs called proton pump inhibitors (PPIs) have been linked to a variety of health problems, including serious kidney damage, bone fractures and dementia. Now, a new study from Washington University School ...

Most reproductive-age women using opioids also use another substance

June 30, 2017
The majority of reproductive-age and pregnant women who use opioids for non-medical purposes also use at least one other substance, ranging from nicotine or alcohol to cocaine, according to a University of Pittsburgh Graduate ...

At-risk chronic pain patients taper opioids successfully with psychological tools

June 28, 2017
Psychological support and new coping skills are helping patients at high risk of developing chronic pain and long-term, high-dose opioid use taper their opioids and rebuild their lives with activities that are meaningful ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.