Navigation Links
Sofosbuvir: Indication of added benefit for specific patients
Date:5/2/2014

The drug sofosbuvir has been available since January 2014 as a treatment for chronic hepatitis C infection. In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined whether the new drug offers added benefit in comparison with the appropriate comparator therapy.

The dossier submitted by the drug manufacturer provides indications of added benefit for non-pretreated patients infected with the virus of genotype 2. However, the extent cannot be quantified. There were no suitable data in the dossier for patients who are infected with other virus types (genotype 1 and 3 to 6) or who are coinfected with HIV.

An addition to previous standard drug therapy

Hepatitis C viruses attack the liver and can trigger inflammation there. If this becomes chronic, cirrhosis can develop and liver function progressively deteriorates. Moreover, the risk of liver cancer increases. Sofosbuvir inhibits the reproduction of hepatitis C viruses and is administered in addition to the drugs peginterferon alfa and ribavirin, which are already on the market; in certain cases it is administered in addition to ribavirin alone. According to the approval, treatment duration differs for the individual patient groups.

The dual combination of peginterferon alfa and ribavirin is the current treatment standard; in genotype 1, this also applies to a triple combination with boceprevir or telaprevir (triple therapy) in most patients.

The Federal Joint Committee (G-BA) therefore specified peginterferon alfa and ribavirin as appropriate comparator therapy, and, in genotype 1, triple therapy as additional option.

No adequate analyses for most virus types

The manufacturer presented no adequate analyses for infection with type 1 and type 3 to 6 viruses and for HIV coinfection. It analysed results from studies in which the respective comparator therapy was tested in at least one study arm and compared these in a "historical" comparison.

It included both randomized controlled trials (RCTs) and one-arm studies on the sofosbuvir side, but only RCTs on the comparator side. It justified this by claiming that it wanted to reduce the number of hits of its literature search. However, the database for the comparison was different because of this and the comparison itself was therefore unsuitable. A first literature search by IQWiG showed that a number of studies were not considered in the dossier.

One direct comparative study on genotype 2

The situation was different for genotype 2: Here, the manufacturer cited an open-label RCT (FISSION), in which treatment-naive (i.e. non-pretreated) adults with genotype 2 and 3 hepatitis C infection were investigated. In the intervention arm, they received 12 weeks of sofosbuvir plus ribavirin, and in the control arm, they received 24 weeks of peginterferon alfa plus ribavirin.

Hence sofosbuvir was administered in compliance with the approval only for the therapeutic indication genotype 2; and, as a result, only these data were evaluable for the benefit assessment. For genotype 3, the Summary of Product Characteristics (SPC) specifies a treatment duration of 24 weeks. The manufacturer itself did not consider the FISSION study in its dossier for patients with genotype 3.

High risk of biased results

Overall, IQWiG assessed the risk of bias of the FISSION study as high. The main reason was that the manufacturer only included those participants in the analysis who had received at least one dose of the medication they were randomized to. However, particularly in the control arm, where not the new drug, but conventional drugs were administered, some patients refused to have their planned treatment.

This is a general problem of open-label studies, where it is known who receives which treatment. This poses the risk that patients discontinue the study prematurely depending on which treatment they were randomized to. This compromises the aim of randomization: the comparability of the treatment groups. This is exactly what happened in the FISSION study, which may lead to (highly) biased results.

Mortality and quality of life: added benefit not proven

As no deaths occurred in the FISSION study in the therapeutic indication genotype 2, there could be no differences between the treatment groups, and therefore no proof of added benefit, in the outcome "mortality". This also applies to health-related quality of life, but in this case because the dossier contained no evaluable data for this outcome.

Advantage in sustained virologic response

Instead of the patient-relevant outcome "development of hepatocellular carcinoma (HCC)", the manufacturer used sustained virologic response (SVR). It could show that there was a statistically significant group difference in favour of sofosbuvir. IQWiG conducted its own sensitivity analyses because of the high risk of bias. It tested how the effects changed when missing values were imputed with different strategies. The researchers found out that the result in favour of sofosbuvir was robust.

Valid surrogate for incidence of liver cancer

SVR is not itself a patient-relevant outcome and cannot be equated with "cure", and there are no studies in which SVR is validated as a surrogate outcome in accordance with the usual criteria employed by IQWiG. Nevertheless, the Institute accepts SVR here as a surrogate for the reduced incidence of liver cancer. This is because it is currently accepted that patients with no detectable hepatitis C virus in the blood are at lower risk of liver cancer. However, it is unclear how many cases of liver cancer can in fact be prevented by sofosbuvir.

For the outcome "secondary diseases", IQWiG therefore recognizes an indication of a benefit for sofosbuvir.

No quantitative conclusion on harm possible

The data on side effects contained in the dossier could only be assessed to a limited extent. The manufacturer presented these data on the basis of the proportions of patients with at least one event. However, this type of analysis is only suitable to a limited extent because the observation period of the patients was different in the two study arms.

Severe adverse events only occurred once in each of the two study arms. A statistically significant difference in the outcome "treatment discontinuation due to adverse events" in favour of sofosbuvir was not robust in the sensitivity analyses performed by IQWiG. With regard to side effects, IQWiG therefore considers the added benefit as not proven.

Overall positive effect remains

For treatment-naive patients with genotype 2 chronic hepatitis C, an overall positive effect of sofosbuvir in comparison with the appropriate comparator therapy remains with regard to serious secondary diseases. The extent of this added benefit which was determined with the surrogate "SVR" is non-quantifiable, however, because it is unclear how often the development of liver cancer can in fact be prevented. With regard to side effects, an assessment was only possible to a limited extent. Greater harm from sofosbuvir is unlikely, however, so that it would not be justified to downgrade the added benefit.

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 manufacturer'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.


'/>"/>

Contact: Dr. Anna-Sabine Ernst
presse@iqwig.de
49-022-135-6850
Institute for Quality and Efficiency in Health Care
Source:Eurekalert

Related medicine news :

1. Finnish research to revolutionise indications for knee surgery
2. Southwest Skin and Cancer Institute Employs Botox for New Indications
3. Global Vaccine Market Trends and Disease Indications Analysis with 2022 Forecasts in New Research Report at RnRMarketResearch.com
4. Apixaban in atrial fibrillation: Indications of considerable added benefit
5. Aflibercept in colorectal cancer: Indication of minor added benefit
6. Global Critical Care Market Will Reach $3.2 Billion in 2019 - Growth from Factor Concentrates, New Indications and Increasing Demand for Albumin in Asia-Pacific
7. Indication of considerable added benefit of vemurafenib in advanced melanoma
8. Antibody-coated stents: Indication of disadvantages
9. Abiraterone: Indication of considerable added benefit in certain patients
10. Turoctocog alfa in patients with hemophilia A: Added benefit not proven
11. Geriatric health professionals experience added burden when caring for own family members
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/21/2017)... ... 2017 , ... Chicago plastic surgeon, Dr. Anil R. Shah, MD , ... benign bony lump located on the forehead usually attributed to a facial fracture. Their ... pain. Dr. Shah has discovered an approach that is minimally invasive. He is an ...
(Date:4/21/2017)... ... 2017 , ... Young Asset Protection, an insurance provider and ... greater Pittsburgh metropolitan region, is joining forces with the local chapter of the ... , Variety the Children’s Charity is a national organization dedicated to empowering, enabling, ...
(Date:4/21/2017)... ... April 21, 2017 , ... The Patient Advocacy Community of The Beryl Institute ... 2017 Ruth Ravich Patient Advocacy Award in recognition of her extraordinary contributions to ... the award at The Beryl Institute’s annual Patient Experience Conference on March ...
(Date:4/21/2017)... ... April 21, 2017 , ... Crossover Symmetry ... O2X , an active lifestyle company that provides Human Performance Training and education ... police offers, first responders, military officers and others in service through the development ...
(Date:4/21/2017)... ... April 21, 2017 , ... Airway ... new partnership with the highly regarded and well renowned Asian distributor, Discovery Sleep. ... & myTAP PAP Nasal Pillow Mask, and will stabilize and strengthen Airway’s presence ...
Breaking Medicine News(10 mins):
(Date:4/19/2017)... 2017 The Mobile X-Ray product segment is the ... during the forecast period Mobile X-Ray segment is ... mobile X-Ray devices market, which is estimated to be valued ... a CAGR of 7% over the forecast period. Mobile X-Ray ... than US$ 100 Mn in 2017 over 2016. The segment,s ...
(Date:4/19/2017)... NEW YORK , April 19, 2017 /PRNewswire/ ... This report on the prostate cancer ... of the global market. Increasing prevalence of prostate ... as innovation in the development of new drugs ... hormone-refractory prostate cancer drug due to lesser side ...
(Date:4/19/2017)... , April 19, 2017  Sorrento Therapeutics, ... antibody-centric, clinical-stage biopharmaceutical company developing new treatments for ... the closing of its previously announced underwritten public ... at a public offering price of $2.00 per ... estimated offering expenses payable by Sorrento.  The net ...
Breaking Medicine Technology: