PARIS, Dec 9 (APM) - The first two cost-effectiveness opinions of France’s economic and public health evaluation commission (CEESP) - for Roche’s breast cancer drug Kadcyla (trastuzumab emtansine) and ViiV’s HIV drug Tivicay (dolutegravir) - have been published showing the use of ICER and QALY calculations long-used in the UK by NICE.

Posted online at the end of last week, the secret workings in the relatively-new role for CEESP show it is taking a slightly wider angle lens than NICE by including the broader societal impact of a drug and assessing it over a 10-year life cycle.

However, given this slightly different approach, CEESP noted the wildly high cost per quality adjusted life year (QALY) calculation for Kadcyla in advanced breast cancer - just as NICE did without the additional parameters in the calculation. (APMMA 39351)

The opinions of CEESP will have been used by the French economic committee for health products (CEPS), together with the opinions of the Transparency commission (CT), in negotiating the prices of the drugs.

Up until now, the work of CEESP in carrying out medico-economic evaluations - something it began doing from last year - has been kept secret, at the request of industry, to protect sensitive market and pricing information. CEESP opinions can only be published once drug prices have been agreed.

Only drugs considered by the manufacturers to have a relative value in their therapeutic field judged as ‘major’, ‘important’ or ‘moderate’ (ASMR 1-3) plus forecast sales in the second year of at least 20 million euros, are assessed by CEESP.

In the case of Tivicay, the opinion mentions the fact that ViiV Healthcare claimed ‘important’ therapeutic value (SMR) and a ‘moderate’ clinical benefit ranking (ASMR III) in terms of efficacy and resistance in comparison with Merck & Co’s Isentress (raltegravir) in pre-treated HIV-positive adult and adolescent patients. The Transparency Commission (CT) finally granted Tivicay important therapeutic value and a ‘minor’ clinical benefit ranking (ASMR IV). The turnover targeted in the second year of marketing is blacked out in the document.

CEESP said the company submitted an economic evaluation in an indication that is more restricted than that featured in the marketing authorisation - adult HIV-positive patients, pre-treated with antiretrovirals and in virological failure, and naïve to integrase inhibitors.

It said ViiV’s methodological approach is “acceptable in view of the HAS recommendations, although it has substantial reservations concerning the choice of comparator,” that is considered to be justified in comparison with the available data but not representative of the available therapeutic alternatives in real life in the treatment of HIV infection.

No analysis of the budgetary impact was submitted by ViiV Healthcare; but this is not compulsory.

Concerning its cost-effectiveness, on the basis of the price claimed by ViiV, “according to a societal perspective and a lifetime horizon, the incremental cost-effectiveness ratio (ICER) of dolutegravir versus raltegravir is estimated at 16,526 euros per QALY (quality-adjusted life year) gained and at 15,341 euros per year of life gained,” CEESP says.

Uncertainty concerning the ICER is mainly explained by the cost of second line and salvage treatments, CEESP says. “Considering the highest possible cost of treatment combination in the various lines, the ICER varies between 16,526 euros and 48,197 euros per QALY,” the commission says.

Although the opinion is aimed at the French economic committee for health products (CEPS), CEESP says the “price claimed by the pharma company also has a strong influence on the model results: the dolutegravir treatment strategy is dominant in comparison with the raltegravir treatment strategy with a 20% fall in price and the ICER is 36,261 euros per QALY if the price increases by 20%”.

Tivicay finally obtained a face value price identical to that of Isentress.

Finally, CEESP says it expects to receive real-life data “to confirm the results of the ICER by integrating all relevant comparators. Further, the population of patients in the restricted indication to which dolutegravir is effectively prescribed shall be specified”.

Concerning Kadcyla, for which Roche requested and obtained an ‘important’ clinical benefit ranking (ASMR II), the methodology of the medico-economic study was also judged “acceptable” with “minor reservations” and the pharma company did not submit a budgetary impact study.

For its cost-effectiveness model, with a lifetime horizon (10 years), gain in year(s) of life (0.72) and in QALY (0.45) and the cost differential (85,759 euros) between the two strategies leads to a differential ratio for trastuzumab emtansine in comparison with GlaxoSmithKline’s Tyverb (lapatinib)+capecitabine of 191,661 euros/QALY.

“Probabilistic sensitivity analyses performed by the pharma company show that at the price claimed, ICERs of around 212,000 euros/QALY and 235,000 euros/QALY are associated with confidence levels (namely, probability that the ICER shall be below these values) of 50% and 80% respectively,” CEESP notes.

The parameters that most modify ICER are the “utility (values) of the various states of health, method and duration of extrapolation of overall survival data, cost of the disease in the ‘progression’ state of disease and taking into account trastuzumab emtansine wastage (residual loss),” it adds.

By halving the price requested, the ICER nevertheless reached 92,127 euros/QALY.

France does not apply a threshold for incremental cost per QALY beyond which a drug is not accepted for reimbursement but the threshold generally considered acceptable in the U.S. medical literature has long stood at $50,000 (40,500 euros) before recently being raised to $100,000 (81,000 euros) per QALY.

In the UK, NICE uses a maximum QALY threshold of 20,000 pounds (25,300 euros) for most treatments, but is known to stretch to 50,000 pounds (63,100 euros), and on occasion even more, for certain end-of-life therapies. However, many cancer drugs still fail to fall within this threshold and are therefore rejected for public funding by NICE. In this case, the emergency Cancer Drugs Fund considers paying for patients’ treatment on a case by case basis.

In future, CEESP says it expects utility data in metastatic breast cancer from future clinical trials based on a definitive analysis of overall survival taking into account residual losses of the drug.

The annual cost of Kadcyla treatment with the price finally obtained is below the 50,000 euro threshold adopted by CEPS, as Roche pointed out last week on the occasion of the product launch press conference (APMMA 40731).

The social security funding law (LFSS) for 2012 entrusted HAS with the task of performing or validating the medico-economic studies required for the evaluation of health products and technologies. An order published in October 2012 set out a framework for the conditions of this evaluation and the first files were submitted a year later.

CEESP has completed the examination of several files although until now none had been made public, HAS having reached an agreement with the French pharmaceutical industry body (LEEM) not to publish the opinions until the price of the product has been determined.

The reimbursement approval for Tivicay came through on November 7 (APMMA 40376) and the reference price for Kadcyla was published on November 14 (APMMA 40448).

Several other drugs that have been evaluated by CEESP have also obtained their price these last few weeks, including Gilead’s HCV drug Sovaldi (sofosbuvir), but publication of the opinions requires discussion between CEESP and the relevant pharma company so that the two parties agree on the information to be masked in the name of trade secrets. In particular, the price the pharma company initially claimed does not feature in the CEESP opinion.

In September, the chairman of the HAS board, Jean-Luc Harousseau, expressed the desire that the CEESP opinions should be published more promptly so as not to be issued much later than those issued by the other European health product medico-economic evaluation agencies (APMMA 39910).

The first two efficiency opinions, whose posting online was announced by HAS on Friday in the form of tweets, are thick documents, (42 pages for Kadcyla and 38 pages for Tivicay). Dated March 11 and May 27 respectively, they comprise the actual opinion (not more than two pages in either case) followed by four appendices (context of the request; detailed critical analysis of the efficiency model; summary of the critical analysis; exchange(s) with the relevant pharma company).

The opinion itself is divided into a summary of the objective and context of the study, an assessment of the compliance of the economic evaluation with HAS methodological recommendations, the CEESP conclusion and any supplementary data to be provided at some later date.

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