Contents of the dossier for the fixed combination product incomplete: Existing study data not adequately analysed
Since the start of 2012, a new drug called rilpivirine has been available for adult patients infected with the human immunodeficiency virus type 1 (HIV-1). It is marketed by two different pharmaceutical companies, by one as a single agent (trade name Edurant-) and by the other as a fixed combination with other HIV drugs (trade name Eviplera-). In two early benefit assessments pursuant to the "Act on the Reform of the Market for Medicinal Products" (AMNOG), the Institute for Quality and Efficiency in Health Care (IQWiG) has investigated whether the two new drugs have advantages over current standard therapies.
According to IQWiG, there is proof that rilpivirine as a single agent offers a considerable added benefit to men infected with HIV-1. For women, the available studies provide corresponding "indications" of considerable added benefit.
On the other hand, no added benefit can be derived from the manufacturer's dossier for the fixed combination - although precisely the same studies were available to the two pharmaceutical companies. This is because, unlike the manufacturer of the single agent, the company making the fixed combination product did not analyse the study data in a suitable way. Hence the contents of its dossier are incomplete.
G-BA specifies efavirenz as the appropriate comparator therapy
Two pharmaceutical companies introduced the new drug onto the market in Germany at the same time; one as a single agent and one in a fixed combination with emtricitabine and tenofovir. Both products are approved for adults who are beginning a treatment directed at stopping the multiplication of the virus for the first time and in whom not more than 100,000 viral components can be detected per millilitre of blood.
The Federal Joint Committee (G-BA) has in each case specified efavirenz-based therapy in combination with other drugs as the appropriate comparator therapy.
Studies on the single agent also relevant for the fixed combination
Results from a total of 3 studies were available. Since, at the time of the assessment, only analyses after 48 weeks were fully available for the two largest studies, IQWiG's assessment is based on these analyses.
In all 3 studies, rilpivirine was tested as a single agent. Nevertheless, the results are also relevant for the assessment of the combination product, because the dosage of rilpivirine, emtricitabine and tenofovir administered in these studies corresponds exactly to the dosage in the fixed combination.
Viral load is a sufficiently valid surrogate parameter
In its dossier, the manufacturer of the single agent did not submit any data on the patient-relevant outcome "AIDS-defining diseases/death", i.e. on the outbreak of AIDS and on survival. Instead, the manufacturer used results of "viral load" in order to prove the added benefit. The viral load denotes the number of components of a virus present in the blood and it shows how active HIV is.
In principle, IQWiG considers this "surrogate parameter" as valid, i.e. meaningful, because patients in whom the number of viruses can be persistently suppressed below the limit of detection have, according to the current state of knowledge, a lower risk of developing AIDS or of dying. However, it is unclear whether a treatment has just as great an effect on the patient-relevant outcome as on the surrogate parameter.
Effect depends on gender
As regards the reduction in viral load, the 3 studies showed a statistically significant difference in favour of rilpivirine. However, as shown by the data on subgroups presented in this dossier [on the single agent], this only applies to male patients. This means that gender is here an "effect modifier". IQWiG therefore determines that there is proof of an added benefit in HIV-1-infected men, but not in women. Because of the described uncertainty concerning the size of the effect on the patient-relevant outcome, the extent of this added benefit cannot be quantified (is "non-quantifiable").
Fewer neurological side effects
Rilpivirine as a single agent also has advantages in terms of side effects: "neurological events" such as headaches or insomnia occurred less frequently. However, the analysis presented by the manufacturer contains a few uncertainties, which is why IQWiG considers there is no proof here, but only an "indication" of a lesser harm with rilpivirine compared to efavirenz.
Based on the overall results on side effects and viral load, the Institute considers that for male patients, there is proof of a considerable added benefit and for female patients a corresponding "indication".
No proof of added benefit of the fixed combination
In contrast to the single agent, there is no proof of an added benefit for the fixed combination of rilpivirine, emtricitabine and tenofovir. In its dossier the manufacturer did not analyse the available data in a suitable way.
Subgroup analyses (age, gender, severity of disease etc.) are routinely required in every dossier. However in this case the manufacturer did not carry these out, despite the fact that its dossier refers to the same studies reported in the dossier submitted by the manufacturer of the rilpivirine single agent, in which gender had been identified as an effect modifier. It is, however, precisely under these circumstances that such subgroup analyses are essential. The necessary data that the manufacturer should have analysed in an appropriate manner were indeed available. The pharmaceutical company also gives no reasons why the subgroup analyses were not provided.
In addition, the company excluded one study although it contained relevant information. The manufacturer of the single agent product accordingly included this study in its dossier.
In view of these deficiencies, IQWiG considers itself compelled to declare the contents of the dossier as "incomplete".
Dossiers are of a widely differing quality
"What is immediately striking in the assessment of rilpivirine, is the widely differing quality of the two dossiers - although the data on which they are based are practically identical", commented Institute Director J-rgen Windeler. "Whereas one manufacturer has used and suitably processed all the available data, the other has completely excluded one relevant study and has also not properly analysed the two other studies". The motives remain obscure.
G-BA decides on the extent of added benefit
The dossier assessment is part of the overall procedure for early benefit assessment conducted by the G-BA. After publication of the manufacturer's dossier and its assessment by IQWiG, the G-BA initiates a formal commenting procedure which provides further information and can 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.
You can also find easily understandable and brief German-language information about rilpivirine and rilpivirine/emtricitabine/tenofovir on the website gesundheitsinformation.de, published by IQWiG.
The G-BA website contains both general English-language information about the procedure of benefit assessment pursuant to -35a Social Code Book V and specific German-language information on the assessment of rilpivirine and of rilpivirine/emtricitabine/tenofovir.
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