CAR-T Therapies Should Impress EU Reimbursement Bodies
Executive Summary
Health authorities in Europe have different approaches to evaluating the cost-effectiveness of new drugs, but in the case of the CAR-T therapies, they are likely to look favorably on factors such as their innovative nature, the small patient populations, and the dearth of effective treatments.
The reimbursement difficulties faced in the UK by the CAR-T therapies Kymriah and Yescarta could be illustrative of the hurdles they will have to leap in other EU countries, which will have similar concerns over cost and the lack of comparator studies that have caused the health technology assessment (HTA) body NICE to issue preliminary guidance rejecting their routine use on the National Health Service.
On the other hand, HTA bodies in Europe are clearly impressed by the products, and if cost-effectiveness can be demonstrated effectively, payers are likely to look favorably on reimbursement requests, particularly if market access deals can be reached.
In fact, according to Novartis AG, Kymriah (tisagenlecleucel) has already secured reimbursement in one of the key EU markets, Germany. And in France, both Kymriah and Gilead Sciences Inc.’s Yescarta (axicabtagene ciloleucel) are being funded under the government’s “temporary use authorization” (ATU) system pending an assessment for general reimbursement.
HTA agencies are also likely to take account of the fact that the CAR-Ts, while expensive (around £280,000 in the UK for example), are orphan drugs for severe life-threatening diseases and will be used in small numbers of patients with conditions that currently have no satisfactory treatments. These considerations may well help to balance concerns by HTA bodies over issues such as the fact that the therapies were approved on the basis of single-arm studies.
In its appraisals, NICE said that that the cost-effectiveness estimates for both therapies were above the range normally considered to be a cost-effective use of NHS resources – i.e., below £50,000 per quality adjusted life year (QALY) gained – and also raised questions around side-effect management and the lack of comparator data. But on the positive side NICE it has recommended interim Cancer Drug Fund coverage for both therapies – the leukemia indication for Kymriah and lymphoma for Yescarta – which suggests that with some further financial wrangling, routine NHS commissioning can be agreed. (Also see "CAR-T Funding: It's (Nearly) All About The Price In The UK" - Pink Sheet, 11 Oct, 2018.)
Novartis and Gilead will therefore be hoping for widespread HTA acceptance of their pioneering therapies across Europe, where Kymriah has been approved for children and young adults with acute lymphocytic leukemia (pALL) and for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and Yescarta for adults with r/r large B-cell lymphoma.
Gilead’s vice-president for medical affairs Europe, Michael Elliott, indicated in July that the company would initially focus its launch efforts for Yescarta in four countries – Austria, France, Germany and the UK – and that it would work with larger countries with slower reimbursement systems to give patients treatment via expanded access programs in advance of reimbursement. (Also see "Interview: Measured Launch, Long Future For Gilead CAR-T In Europe" - Scrip, 9 Jul, 2018.)
Elliott suggested to the Pink Sheet’s sister publication Scrip that he expected the company would be able to find a “good and fairly quick solution” in most if not all European countries. With innovative therapies, he said, “usually the value argument is pretty strong.”
For its part, Novartis says it has submitted reimbursement dossiers to health authorities across Europe and is “actively working” with them to ensure timely access to Kymriah. The company told the Pink Sheet that it had provided the authorities with long-term outcome data in the reimbursement dossier.
“For example, the median follow-up for the three Kymriah trials in pALL ranged from 20-32 months, and from 19-29 months for the two Kymriah trials in DLBCL, and is meaningful for both these aggressive terminal diseases. In addition, Novartis will continue to provide long-term follow up data overtime from both clinical trials and registries.”
Novartis also made much of the therapy’s orphan drug designation, which it pointed out was granted because the treated conditions are chronically debilitating and life threatening and only affect a small number of patients, and the fact that there was no satisfactory treatment for the conditions whereas Kymriah offered a “significant clinical benefit.”
Novartis “believes that these factors – orphan population size, urgent unmet medical need, lack of viable comparators, and substantial magnitude of clinical benefit – support the approach of single arm trial design.”
France
Payers in some countries may well be of a similar view. According to a report by Informa’s Datamonitor Healthcare, France may accept a single-arm study provided there is a “dramatic improvement” such as all patients being complete responders; low or incremental gains could disqualify them from reimbursement.
One French payer said that the Transparency Committee, which carries out benefit assessments for the government’s HTA body, the Haute Autorité de Santé, would pay most attention to whether or not remission was achieved, and whether "that remission is translated into a cure,” the DMHC report said.
France is in fact already gathering valuable information on the use of Kymriah and Yescarta. Both were granted ATUs in July this year, after the therapies received the green light from the European Medicines Agency but before full marketing authorization by the European Commission in August.
An ATU allows patients to be prescribed an unapproved medicine under certain conditions – it must be for a serious or rare disease, there must be no appropriate treatment available on the market, efficacy and safety must be “strongly presumed” in the light of clinical trials conducted for the marketing authorization application (MAA), the is drug expected to provide a real clinical benefit, and treatment cannot be delayed. ATUs are valid for a year and can be renewed two months before expiry.
Under the Kymriah ATU, Novartis had to submit a report to ANSM every two months, with all data collected on, for example, the characteristics of the patients treated, the actual conditions of use, and data on efficacy and pharmacovigilance, as well as any other safety-related information. Similar requirements applied to Yescarta.
During the ATU period, medicines are fully funded by the health insurance system, and are provided by the company free of charge or at cost determined by the company. Once the product obtains a marketing authorization (MA), the regulatory agency ANSM sets a date for the end of the ATU, taking into account factors like the date of notification of the MA and the time needed to bring the product labeling into line with the MA and (where relevant) to put a risk management and risk minimization plan in place. However, it does not take into account activities needed to complete pricing and reimbursement discussions. The time from the MA to the end of the ATU is at least one month and at most three months.
Following the MA, the company can submit an application for the drug to be paid for under the normal health insurance system, and until that application is approved, a “post-ATU” system comes into play to pay for the product.
Germany
Novartis said Kymriah is already available to patients in German hospitals. Noting that the costs of new inpatient therapies are included in the hospitals' diagnosis-related group (DRG) system ono or three years, the company said that, as part of a NUB (new diagnosis and treatment method), individual clinics will be able to negotiate hospital-specific charges for the costs of Kymriah with the health insurance companies from spring 2019.
"Until the agreement on the NUB payment, individual patients or the treating hospitals will generally reach out to the health insurances prior to treatment onset to receive confirmation that reimbursement for the therapy will be granted," it explained.
Meanwhile, a benefit assessment of Kymriah is being conducted by the German Joint Federal Committee (G-BA), the decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds. The G-BA, which carries out health technology assessments, said the benefit assessment procedure began on Sept. 15 this year and the assessment would be published on Dec. 17. Written comments will then be invited until Jan. 7, 2019, and completion of the procedure is expected at the beginning of March.
One German payer interviewed by DMHC said it believed a single-arm trial would be acceptable to the HTA body where “there is no comparator and just best supportive care is available, such as for the first treatment ever in a certain disease.”
Moreover, for orphan drugs in Germany, additional therapeutic benefit is assumed by virtue of the marketing authorization, without reference to an appropriate comparator, provided annual health insurance expenditure for the entire population treated with the drug remains below €50m. Once this threshold is exceeded, manufacturers are required to submit data on additional therapeutic benefit and orphan drugs are evaluated and prices renegotiated in the same manner as for all other drugs.
No information on Yescarta has yet been published on the G-BA website.
Spain
According to the DMHC report, one Spanish payer said that single-arm studies, or those with very small numbers of patients, had to be accepted for such drugs because there were no other options. The payer suggested that in return for awarding reimbursement, payments for the therapies could be staggered depending on how successful they proved to be.
Another said a broader perspective was needed when evaluating these kinds of therapies, looking beyond the direct medical cost offset and taking account of informal care elements. Patient-reported outcomes would “probably be the most important outcome to evaluate."
One payer stated that longer-term results were preferred, and that for the amount of money spent on a gene therapy, it was important to understand the outcomes one year or more after administration.
Alternative payment models are needed “because we do not have any other options,” said another Spanish payer. “It is important that you can pay in phased doses because you do not know what will happen in the future…the public health system probably will start to pay in one year for patients who are still alive, or pay per month but not starting at the beginning, starting with a three-month delay or something like that.”
Only six or seven hospitals in Spain are expected to be in a position to administer CAR-T therapies by the end of 2018, according to another payer, which said that “probably in two years it will expand to 20 in Spain, and in 3-4 years, almost all third-level hospitals will have this kind of treatment.”
From the editors of Scrip Regulatory Affairs.