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Germany IQWIG Issues Sovaldi Statement
  see below in this report a further explanation about IQWIG
press release from IQWIG, German Institute for Quality and Efficiency in Health Care (IQWiG):
Sofosbuvir: indication of added benefit for specific patients
Better virologic response in genotype 2 chronic hepatitis C / extent of added benefit unclear / no suitable data for other virus types

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.

Gilead's Sovaldi shows "indication of added benefit for specific patients," says IQWiG
In an early benefit assessment under 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 US biotech firm Gilead Sciences' (Nasdaq: GILD) new controversially high-prices hepatitis C drug Sovaldi (sofosbuvir) offers added benefit in comparison with the appropriate comparator therapy.
The dossier submitted by the drug's 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 co-infected with HIV, says the IQWiG.
Sofosbuvir has been available since January 2014 as a treatment for chronic hepatitis C infection. The German government will rely on the recommendation to decide whether to approve the 49,000 euros ($68,000) for a 12-week course that Gilead has put on Sovaldi (sofosbuvir) there. The drug is prices at $84,000 for a 12-week course, in the USA, and has already generated sales of $2.3 billion for Gilead in the first quarter of 2014 (The Pharma Letter April 23).

The German IQWiG - It's Not NICE Benefit Assessment in Germany - New Sense or Nuisance?
Christian Conrad, Novartis Pharma GmbH, Nuremberg, Germany
http://www.ispor.org/news/articles/oct06/german_policy.asp..........The Official News & Technical Journal Of The International Society For Pharmacoeconomics And Outcomes Research
In July 2004, the "Institute for Quality and Economic Efficiency in Health Care" (Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) was officially founded and established in Cologne in the form of a private foundation. Most of the current assessments were assigned in February 2005 (see below).
Some still refer to the IQWiG as the "German NICE", although methods and objectives are fairly different from UK's National Institute for Health and Clinical Excellence (NICE).
The German institute is comparable to HTA bodies in other countries but follows its own self-formulated "methods" (version 1.0 of March 2005, to be found on the institute's website). First of all, cost-benefit assessment of pharmaceuticals is not one of the IQWiG's tasks, although one might come to this conclusion reading the terms "Economic Efficiency" in the IQWiG title. Hence, IQWiG will not consider QALYs (Quality Adjusted Life Years) within its evaluation and there is currently no need for health economic modeling.
Assessment process

Assessments are commissioned by the "Joint Federal Committee" of physicians and health insurance funds ("Gemeinsamer Bundesausschuss", G-BA) or the Ministry of Health. Unlike NICE, dialog, external exchange of information or hearing procedures of the IQWiG, e.g. with manufacturers or patients, are not directly subject to a formalized process.
Timelines are not as closely defined, as it is the case for the technology appraisal process in the UK. Approximately nine months had initially been planned to conduct an IQWiG-assessment, although this has not been achieved with current assessments.
It is worth mentioning that study selection and inclusion criteria follow IQWiG internal standards and may vary substantially from assessment to assessment (e.g. duration of studies included, minimum patient number required). In many cases; these requirements can neither be derived from international recommendations (e.g. guidelines by the European marketing authorization institution EMEA or the international medical expert societies) nor do they meet standards that used to apply during the conceptualization and implementation of studies in these therapeutic indications. As a result, only selected partial quantities of the existing evidence are being viewed.
The evaluation criteria are defined in the corresponding "report schedules" (project descriptions) of the IQWiG, which are issued at the beginning of each assessment process; they are not discussed with concerned manufacturers. There is no such thing as a formal scoping workshop with manufacturers, although the IQWiG is free to consult any external expertise.
During the assessment process, the IQWiG will seek national as well as international scientific advice via external peer reviews to evaluate existing data. At this stage of the assessment, external experts are not made known to the public.

IQWiG will concentrate on head to head trials, it will focus on morbidity and mortality and it is unlikely that IQWiG will consider compliance or most of the commonly accepted surrogate endpoints as relevant factors.

After internal review and publication of an assessment pre-report, there is a timeline of four weeks for the manufacturers and other concerned parties to comment on the report. To structure this input, a form is provided by the IQWiG, restricting the comments to six pages. There are also substantial restrictions concerning the contents of the statement: study design etc. may not be discussed, comments have to address mainly formal issues of the previous assessment, e.g. comments on studies that have been missed by the institute.
The IQWiG may also invite patients or manufacturers and other experts for a hearing. The hearing is not mandatory. The (revised) report will finally be submitted to the G-BA for further processing and implementation.
It also has to be emphasized that none of the IQWiG's assessments and recommendations of the final report will become effective before the G-BA converts the recommendations into binding guidelines (e.g. via so-called "Arzneimittelrichtlinien", drug guidelines). After an IQWiG assessment, the G-BA may or may not evaluate any further aspects (e. g. related to drug costs), based on the IQWiG's recommendations. Therefore, one may consider the IQWiG as the "assessment" body whereas the G-BA comprises the "appraisal" committee.
There is no explicit need for the G-BA to follow the IQWiG's recommendations, although it might be difficult to completely ignore the previous findings. The G-BA may also consider the opinion of additional experts to challenge the results of an assessment and would then have to include additional evidence that had previously been ignored by the IQWiG due to restrictive data selection criteria.
However, even before any authorization and implementation by the G-BA, one may postulate an effect of the IQWiG's publications (e.g. via the internet), as physicians (and their associations) or other organizations (as statutory health insurance companies) are certainly going to recognize, refer to and distribute the preliminary recommendations, e.g. to influence prescription behavior. The relevance and effects of such a premature use of preliminary recommendations are highly debatable.
Main tasks of the IQWiG are (as legally defined):
· Research, representation and assessment of current medical findings on diagnostic and therapeutic procedures for selected diseases;
· Generation of scientific papers, expert reports and statements on questions of quality and economic efficiency of the services rendered under statutory health insurance (SHI);
· Assessment of evidence-based guidelines for the most important diseases from an epidemiological standpoint;
· Issuance of recommendations on disease management programs (DMP);
· Assessment of the benefits of pharmaceuticals; and
· Provision of general information on the quality and efficiency of health care services that is understandable to all citizens
As of February 2006, 53 employees have been hired, including 35 scientists, mainly physicians or life scientists. The Institute's staff will be raised to a head count of approximately 60-70 over the next years. The head of the Institute is Prof. Dr. med. Peter T. Sawicki, a diabetologist who had formerly been heading the department for internal medicine of a hospital in Cologne. Sawicki is also a critical expert for evidence based medicine and has been involved in the conception of guidelines for the DMP Diabetes mellitus.
The IQWIG has six scientifically oriented departments, responsible for data assessment and evaluation:
· Health Economics;
· Department of Biometrics;
· Department of Pharmaceutical Assessment;
· Department for the Assessment of Non-pharmaceutical Therapeutic Procedures, Diagnostic Procedures and Screening Measures;
· Department for Guidelines and Disease Management Programs; and
· Department for the Generation and Methodology of Patient Information.
Two additional departments (communication and quality management; administration) have supportive functions. Furthermore, a "Department for the Coordination of Studies" is planned, but will probably be formed only after the establishment phase of the Institute.
An internationally staffed scientific advisory board (9 members) and a board of trustees (30 members) have consulting functions to support the IQWiG in the process of decision-making. Until now, however, the boards held only one meeting.
In February 2005, the first assessments were assigned to the IQWiG. Concerning pharmaceuticals, a current focus of the IQWiG, the Institute is mainly about to assess the following indications and treatment options:
· Hypertension;
· Asthma and COPD;
· Alzheimer's Dementia (Cholinesterase- Inhibitors, Memantine, Ginkgo);
· Diabetes (mainly insulin analogues and oral antidiabetics); and
· Depression.
In addition, there also is a clear focus on compiling comprehensible information for patients and a new internet platform has recently been issued, addressing patients' needs with respect to a wide variety of diseases and treatment options (http://www.gesundheitsinformation.de/index.html). This also correlates with the Institute's frequently expressed claim to assess "patient relevant outcomes". Distribution of assignments between different IQWiG departments (Feb. 2006):
· Department of Pharmaceutical Assessment: 43 assignments;
· Department for the Assessment of Non-pharmaceutical Therapeutic Procedures, Diagnostic Procedures and Screening Measures: 18 assignments;
· Department for the Generation and Methodology of Patient Information: 7 assignments; · Department of Biometrics: 2 assignments;
· Department for Guidelines and DMP: 2 assignments; and
· Department of Health Economics: 1 assignment.
Looking at the assignment distribution it becomes quite clear that approximately twothirds of the assessments are related to evaluations of pharmaceuticals. The IQWiG's first important assessment result (in addition to a statin-assessment already published in September 2005, which did not have a substantial impact) is a final report for short acting insulin analogues. It was recently published and subsequently submitted to the G-BA. As expected, the criteria and results of this assessment have been very restrictive, considering only seven out of 1017 published studies as relevant. Finally, insulin analogues are not recommended as a therapeutic option owing to "lack of added value".

Scientific acceptance and credibility of the IQWiG now strongly depend on contents, quality and implementation of the next assessment results, e.g. those for Cholinesterase- Inhibitors & Antihypertensives.

Only head to head trials of the short acting insulin analogues against the traditional insulins have been included. Indirect comparisons are not considered relevant. Furthermore only published studies and only comparisons against products, which are registered in Germany, have been included.
Currently, the G-BA is about to implement binding drug guidelines. This could lead to restricting the use of insulin analogues to a certain patient population.
In general, the G-BA's implementation of IQWiG assessments is crucial and does not necessarily have to be congruent with all of the IQWiG recommendations. However, in the case of insulin analogues, the G-BA is going to follow the IQWiG's recommendation to restrict SHI-reimbursement of this drug class.
In its evaluation of clinical effects, IQWiG focuses on complications and mortality based on data of RCTs. The first examples of IQWiG assessments lead to the following conclusions: IQWiG will concentrate on head to head trials, it will focus on morbidity and mortality and it is unlikely that IQWiG will consider compliance or most of the commonly accepted surrogate endpoints as relevant factors.
The core points one might criticize regarding IQWiG procedures are a lack of specification regarding assessment criteria; and that essential parts of the IQWiG paper on methods have not been put in more specific terms. Currently, the method paper is being re-evaluated by the IQWiG. The new version should therefore also include the development of a scientifically substantiated benefit concept, as this has not been defined in the method paper that is now being used for benefit assessment.
The transparency and participation principle needs to be further implemented. During the process of benefit assessment, the IQWiG must not shut itself off from structured professional dialog with the manufacturers concerned. The process that has been established with drug regulatory bodies and authorities (e. g. EMEA or the German BfArM) may very well serve as an example of such a structured and transparent dialog. To allow this valuable discussion and exchange of information, the IQWiG may not rely on separation but should intensify communication, also with corporate experts, e.g. for scoping issues. The IQWiG primarily evaluates the published results of controlled clinical endpoint studies (randomized controlled clinical trials, RCTs). As a result, benefit assessment is abbreviated to a secondary test of the efficacy of pharmaceuticals based on the clinical studies submitted during the marketing authorization process. An evaluation like that could also be achieved by a mere Cochrane review.
The effect of pharmaceuticals under everyday conditions is largely ignored, although the benefit of drugs shows itself in practical application compared to specifically available therapeutic alternatives.
It is therefore also important to select an adequate point in time for the assessment and to apply a broad methodical assessment approach. Benefit assessments, especially those of innovative pharmaceuticals, should not be made directly after and certainly not before marketing authorization. Recently, there have been two assignments by the G-BA to conduct assessments for new drugs (for the treatment of diabetes) even before the official marketing authorization was granted for the German market. At this point, the practical benefit of a pharmaceutical under everyday conditions cannot be proven. Broad application experience will only be available a few years after marketing authorization. Depending on the therapeutic indication, a time window of at least three to five years between marketing authorization notification and assessment commission would seem appropriate.
Scientific acceptance and credibility of the IQWiG now strongly depend on content, quality and implementation of the next assessment results, e.g. those for Cholinesterase-Inhibitors and Antihypertensives. The restrictive evaluation of insulin analogues does confirm some of the initial criticism that has been associated with the IQWiG.
As mentioned before, G-BA and BMG (Bundesministerium fuer Gesundheit, MoH) also play a crucial role, as the G-BA is responsible for the final appraisal and implementation of the Institute's recommendations and the BMG takes responsibility for the legal supervision. It remains to be seen to which extent certain political objectives or even public pressure will influence this final step of the appraisal process, especially in the light of the on-going process of the German health care reform and cost-containment measures.
In the end, similar to NICE changing its appraisal process and participation policy over the years, it will be exciting to see how long it takes until first relevant changes of the IQWiG's assessment process will be implemented. Further details and publications concerning the IQWiG may be found on the internet on the institute's homepage: http://www.iqwig.de/.
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