One of the responsibilities of the European Medicines Agency (EMA) is granting of marketing authorization to novel therapeutic agents in the European Union (EU). Once approved under the centralized authorization procedure, new medicines can be marketed throughout the EU. However, in many European countries, patient access to novel therapeutic agents is conditional on reimbursement by payers.

Health technology assessment (HTA)—a multidisciplinary process that systematically considers the clinical, social, economic, and ethical issues related to the use of a health technology—informs payer reimbursement decisions in an increasing number of European jurisdictions (1). Unlike EMA, which primarily focuses its assessment on the benefit-risk profile of new drugs, HTA bodies undertake an assessment of clinical effectiveness, such as added therapeutic benefit and real-world relative effectiveness (Reference Chalkidou, Tunis, Lopert, Rochaix, Sawicki and Nasser2), as well as value for money offered by the new technology.

In England, the National Institute for Health and Care Excellence (NICE) is an organization which, as one of its responsibilities, makes recommendations for the payers in the National Health Service (NHS) on whether new technologies should be reimbursed at the national level. NICE Technology Appraisals and Highly Specialized Technologies (for very rare conditions) are the programs focusing on such evaluations (3).

EMA's evidence requirements for marketing authorization have implications for national- and regional-level HTA in Europe. Benefit-risk assessments conducted by the EMA's Committee for Medicinal Products for Human Use require trials exploring the efficacy and safety of an investigational agent. Frequently, these trials are short, based on surrogate end points, and may have a placebo as a comparator or no comparator at all. Such evidence may not be sufficient for an assessment of relative clinical effectiveness. HTA bodies often require additional data for reimbursement decision making (Reference Clement, Harris, Li, Yong, Lee and Manns4). The absence of longer-term comparative data results in significant uncertainty, which can be defined as the lack of conclusive evidence to substantiate the value claims of a product (e.g. due to single-arm trials or immature data) and thus, its clinical and cost-effectiveness.

Currently, EMA has two special approval pathways to facilitate earlier market access to certain products: conditional marketing authorization (CMA) and approval under exceptional circumstances (AEC). EMA grants a CMA when the approval is based on data which, while not yet mature or comprehensive, indicate that the medicine's benefits outweigh its risks. The CMA can only be granted for medicines that satisfy an “unmet medical need” (5). While the CMA decision is based on limited clinical data, successful generation of comprehensive data is statutorily required prior to granting full marketing authorization via postauthorization efficacy studies (6). Medicines aimed at treating rare conditions may also gain an AEC if the sponsor can show that it is unable to provide comprehensive data on the efficacy and safety of the medicine for which authorization is being sought, for example, because of potential ethical issues or limited scientific knowledge in the area. Unlike the CMA, an AEC is not aimed to be converted to full authorization (5).

The lack of robust clinical data at the time of CMA/AEC decisions poses significant risks for patients and the healthcare system and directly impacts HTA decision making. Patients may get access to treatments with unproven benefits and uncertain safety profile. These risks could be addressed through additional data collection once the product is in use in clinical practice. The risk to patients associated with these products can be partially mitigated through restricted and closely monitored use and the risk to the healthcare system can be mitigated through commercial negotiations on the price of the drug. These strategies can be implemented, for example, through various types of managed access agreements (MAA). Companies developing drugs or treatments that are expensive and unlikely to be recommended by NICE for use in the NHS can offer NHS England a patient access scheme (PAS), which commonly consist of confidential discounts (7). The new Cancer Drugs Fund (CDF) offers the opportunity to generate evidence on the effectiveness of new cancer drugs associated with clinical uncertainty while these are being used in the NHS. When a treatment is recommended for use within the CDF, a formal data collection arrangement is drawn up as part of an MAA, outlining the key areas of uncertainty and explaining how these will be addressed through data collection. The other component of the MAA is a commercial access agreement, which determines the level of reimbursement during the data collection period (8). This route is particularly relevant to some cancer medicines which obtain a CMA and are presented for a NICE evaluation with a limited evidence base.

In this paper, we investigate the impact of the uncertainty stemming from less comprehensive data associated with products approved by the EMA under CMA or AEC on NICE's recommendations. Our objective is to explore how NICE advisory committees respond to such uncertainty. Specifically, we investigate if the uncertainty associated with these products leads to negative recommendations and, if not, whether the positive recommendations are subject to further data collection or commercial arrangements. We also analyze if commercial arrangements are more common for products with CMA/AEC than for products with full authorization comparing the odds of implementing commercial arrangements for products with and without CMA/AEC; and whether the conversion to full marketing authorization leads to changes in the NICE recommendations over time. Finally, we draw lessons for the future, as the EMA plans to implement new models aimed at expediting drug development and approval (9). A full list of acronyms used in this manuscript can be found in Table 1.

Table 1.

List of Abbreviations

Results

Between 2002 and 1 December 2016, EMA had granted CMA (n = 28) or AEC (n = 26) to fifty-four products. As of August 2017, three products had their marketing authorizations withdrawn due to (a) lack of efficacy (drotrecogin alfa) (12), (b) inability of the sponsor company to provide the additional data required to fulfil its specific obligations (celecoxib) (13), and (c) commercial reasons (rilonacept) (14). During this period, fourteen CMAs were converted into full authorizations (Figure 1).

Figure 1.

Evolution (2017–2019) of products granted conditional marketing authorization or authorization under exceptional circumstances by the European Medicines Agency up to 1 December 2016 (n = 54).

Out of the fifty-four products that originally had CMA/AEC, thirty were listed on the NICE Web site by August 2017 (Figure 2). Twenty-eight out of the thirty were listed as a NICE evaluation and five products were considered by NICE in clinical guidelines and/or evidence summaries. Three products out of the twenty-eight were evaluated in an indication that differed from the one for which the product received CMA/AEC, or their appraisals were not sought for referral (15;16).

Figure 2.

Data flow of products granted conditional marketing authorization or authorization under exceptional circumstances by the EMA up to 1 December 2016 and availability in the NHS. CMA, conditional marketing authorization; AEC, approval under exceptional circumstances; NICE, National Institute for Health and Care Excellence; BNF, British National formulary; NHS, National Health Service; TA, technology appraisal; HST, highly specialized technologies.

The remaining twenty-five products with CMA/AEC triggered thirty evaluations. Out of these thirty evaluations, six were still ongoing, two were reviews of previous recommendations, seven had been withdrawn (n = 1), terminated (n = 2), discontinued (n = 3), or suspended (n = 1) and therefore did not carry any recommendations, three were not recommended and twelve were recommended (Figure 2). All these twelve products were recommended alongside a commercial arrangement (PAS [n = 8], CDF/MAA [n = 4]).

Two of the twelve recommended appraisals originally received negative recommendations by NICE for the same product and indication: crizotinib and bosutinib. Both products originally received negative recommendations because of high incremental cost-effectiveness ratios and a lack of robust clinical data. The reviews were triggered by the transition from the old CDF, in which cancer products which were not recommended by NICE could be reimbursed by the NHS through this fund (17). NICE recommended crizotinib and bosutinib in their respective reviews following new commercial arrangements (18;19). In the case of crizotinib, the committee concluded that the size of the overall survival estimate with crizotinib was still uncertain.

Although only three products were not recommended (sunitinib, panitumumab, and ofatumumab (20–22), their clinical uncertainty featured amongst the reasons for these negative recommendations. Table 2 contains further details. The conversion to full authorization did not lead to changes in NICE recommendations. The marketing authorizations of sunitinib, panitumumab, and ofatumumab have been converted into full by the EMA but did not trigger a review at NICE. In the case of sunitinib, the conversion from conditional to full authorization was based on an application from the company to extend the indication from the second to the first-line treatment of metastatic renal cell carcinoma based on data available on the first line (23). This triggered a new evaluation at NICE for the same product in the first-line treatment.

Table 2.

Rationale of Negative Recommendations by NICE on Products Granted Conditional Marketing Authorization or Authorization in Exceptional Circumstances

TA, technology appraisals; ICER, incremental cost-effectiveness ratio.

In the case of panitumumab, when its CMA was converted into full authorization, NICE initiated a review proposal but did not go ahead with the review, as the new data were unlikely to have an impact on the recommendations. The company that holds the marketing authorization for panitumumab supported NICE's opinion during consultation (24).

Obligations that the marketing authorization holder for ofatumumab had to fulfil as part of the CMA included conducting a controlled study—ofatumumab versus physician choice in patients with bulky fludarabine refractory chronic lymphocytic leukemia (OMB114242), in addition to the provision of the results from ongoing studies in earlier lines of therapy. The results presented from the study OMB114242 showed that there was no statistically significant difference in progression-free survival, the primary end point (25). As of August 2017, NICE had not carried out a review proposal of ofatumumab's appraisal as it was awaiting trials completion and publication of the final results.

Excluding evaluations which have been withdrawn, terminated, discontinued, or suspended, and thus, analyzing those appraisals for which NICE had issued recommendations, by August 2017, NICE recommended 80 percent (12/15) of the products that were evaluated having received EMA's CMA or AEC up to 1 December 2016 (see Figure 2). All products with CMA/AEC that were recommended by NICE were subject to a commercial arrangement, five of which included data collection requirements. Data requirements outlined as part of the commercial arrangement for products with CMA/AEC are included in Supplementary Table 2. The rest of commercial arrangements were based on PAS and did not require data collection. The odds of carrying a commercial arrangement were significantly higher for products with CMA/AEC than for those with full authorization (OR 9.50; 95 percent CI 2.49–53.12). We conducted a sensitivity analysis restricting the time frame for the analysis from October 2007 onwards, when the first commercial arrangement was granted. We obtained similar results (OR 8.51; 95 percent CI 2.23–47.61). During this period, 70 percent of products with full marketing authorization had a commercial arrangement at the recommendation stage.

Changes up to 2019

As of August 2019, three additional products had their marketing authorizations withdrawn: two due to commercial reasons (antithrombin alfa and ofatumumab) (26;27) and one due to lack of demand for the drug (alipogene tiparvovec) (28). Seven additional products that had CMA or AEC have had their authorization converted into full (Figure 1).

Two of the three products that were not recommended in 2017 remained not recommended (sunitinib and panitumumab) and one (ofatumumab) has had its license and evaluation withdrawn. Out of the six products that had their evaluation ongoing in August 2017, one was still ongoing, two have not been recommended, and three have been recommended with a commercial arrangement (Figure 2).

For example, daratumumab, whose evaluation was ongoing in August 2017, was subsequently recommended for use within the CDF. These recommendations were published before its marketing authorization was converted to full. One of the products that was recommended within the CDF in August 2017 (brentuximab vedotin for CD30-positive Hodgkin lymphoma) exited the CDF and was later recommended for routine commissioning with a commercial arrangement. Its marketing authorization remained conditional. Osimertinib, whose license was converted into full and which was recommended by NICE within the CDF, had its evaluation under review at the end of the data check.

By August 2019, NICE had recommended 78 percent (14/18) of the products that were evaluated having received EMA's CMA/AEC up to 1 December 2016. All products with CMA/AEC that were recommended by NICE were subject to a commercial arrangement.