Decisions to prioritise the development of one indication for a medicine over another and decisions to launch a medicine in local settings following development are multifaceted. Manufacturers face a wide range of clinical, ethical and economic challenges when preparing a valuation for the new use of a medicine, which can vary significantly across both disease and country settings. From the evidence generated above it is clear that there is no uniform approach towards the development and marketing of multi-indication medicines. Nevertheless, a number of interesting observations can be identified in terms of how manufacturers are prioritising the development and launch of multi-indication medicines and in terms of how medicines become available in a given health care setting.
First, manufacturers show a tendency to prioritise development of niche indications, with high disease severity and unmet need for the first indication of multi-indication medicines. To a considerable degree this strategy seems to resonate with the objectives of health systems prioritising treatments that address significant unmet need and disease severity. Relative to subsequent indications, first indications were more likely to be based on CMA or priority review, indicative of a prioritisation of patient populations with high disease severity and unmet need for the first indication. Further, a higher proportion of first indications received an orphan designation. One limitation of these results is that EMA CMA can only be provided to the first indication of a molecule, which may bias the results in favour of first indications.
Second, the evidence base of subsequent indications tends to be based on more robust study designs. Subsequent indications are more likely to be approved on the basis of phase III head-to-head trial designs, while first indications are more dependent on phase II, single arm trials and include surrogate outcomes as the primary endpoint. These findings are aligned with a higher proportion of CMAs in first indications and a tendency to develop indications with high disease severity and unmet need in the first indication. In theory, development of indications that address unmet need and treat life threatening or chronically debilitating diseases can provide advantages to both patients, through access to a new treatment in the absence of therapeutic alternatives, and manufacturers, through lower requirements for market entry and reduced competition at the time of market entry. A further consideration relates to first-mover advantages, as manufacturers may prioritise sequencing which could result in being first to market, but based on less robust evidence of clinical evidence. However, no significant differences were detected in time from pivotal trial initiation to marketing authorisation across first and subsequent indications. In theory, development time would be shorter for subsequent indications if the safety and toxicity of a medicine has been established in the first indication [2]. However, this may not be reflected in the length of the pivotal trial, particularly if subsequent indications tend to be based on later phase clinical trials. Further research on earlier stages of clinical development could help to clarify this issue.
Third, while HTA coverage recommendation rates are similar across first and subsequent indications submitted for assessment, a number of indications do not launch in local settings. Mapping of MA and HTA coverage recommendation sequence highlighted discordance between the total number of indications launched globally, the total number of indications with MA by the EMA, TGA and Health Canada, and the total number of indications with HTA coverage recommendation. Results suggest that post-development sequencing typically manifests through non-launch of indications, frequently through absence of MA. Only 81%, 73% and 63% of globally launched indications had authorisation in the EMA, TGA and Health Canada, respectively. A number of authorised indications also failed to receive positive HTA coverage recommendations, however, with the exception of Australia, no significant differences were detected in HTA coverage recommendation rates across first and subsequent indications submitted for assessment. HTA coverage recommendation sequence and HTA coverage recommendation rates should be interpreted with caution as variations in the role and scope of HTA are present across settings. As a result, the relationship between HTA and market access differs across settings (See Table 4). In Canada, Australia, Scotland and France, HTA assessment is a pre-requisite for the launch of a medicine. In Germany, launch of a medicine can occur immediately following EMA authorisation and HTA coverage recommendation is determined based on publication of the AMNOG price [15]. HTA is subsequently performed to inform pricing negotiations. Finally, in England, medicines can also be launched following MA. However, as of 2016, all new cancer medicines are subject to NICE evaluations and uptake of drugs prior to NICE evaluation by local commissioning groups and NHS organisations tends to be low [16]. As a result, while HTA coverage recommendation can be used as a proxy for indication launch in Canada, Australia, and Scotland, the absence of an HTA coverage recommendation does not preclude indication launch in England and Germany.
Table 4
– ROLE OF HTA AND REQUIREMENTS FOR LAUNCH OF NEW INDICATIONS ACROSS GERMANY, FRANCE, ENGLAND, SCOTLAND, CANADA, AND AUSTRALIA
Country
|
HTA agency
|
Type of assessment
|
Role of HTA
|
Requirements for launch
|
Germany
|
Federal Joint Committee (G-BA)
|
Relative clinical benefit assessment
|
Informs pricing negotiations with the National Association of Statutory Health Insurance Funds
|
EMA authorisation
|
France
|
Transparency Committee - Haute Autorité de Santé (HAS)
|
Relative clinical benefit assessment
|
Informs pricing (ASMR) and reimbursement rate (SMR)
|
EMA authorisation and SMR rating above insufficient
|
England
|
National Institute of Health and Care Excellence (NICE)
|
Clinical and cost-effectiveness
|
Issues binding reimbursement recommendations. Indirectly influences pricing through cost-effectiveness thresholds
|
EMA authorisation and NICE approval*
|
Scotland
|
Scottish Medicines Consortium (SMC)
|
Clinical and cost-effectiveness
|
Informs pricing and reimbursement decisions by NHS boards. NHS boards not required to follow recommendation, but must wait for an SMC assessment to be issued.
|
EMA authorisation and SMC assessment
|
Canada
|
Canadian Agency for Drugs and Technologies in Health (CADTH) and pan-Canadian Oncology Drug Review (pCODR)
|
Clinical and cost-effectiveness
|
Informs provincial pricing and reimbursement. Provinces are not required to follow recommendation and negotiate either jointly or individually with manufacturers.
|
Health Canada authorisation and CADTH/PCODR assessment**
|
Australia
|
Pharmaceutical Benefits Advisory Committee (PBAC)
|
Clinical and cost-effectiveness
|
Informs pricing and reimbursement in Pharmaceutical Benefit Scheme (PBS). Minister of Health makes final decision following positive PBAC recommendation
|
TGA authorisation and PBAC approval
|
Source: The authors from [15–20] |
Abbreviations: ASMR – Amélioration du Service Médical Rendu (France), EMA – European Medicines Agency, HTA – Health Technology Assessment, NHS – National Health Service, SMR – Service Médical Rendu (France), TGA – Therapeutic Goods Administration (Australia) |
* NHS organisations are able to start using a new drug prior to NICE guidance but uptake is low and commissioning groups typically wait for NICE guidance to be issued. Since 2016, NICE aims to evaluate all new cancer drugs. |
** Provinces are able to fund drugs without CADTH/PCODR assessments but uptake is low and CADTH/PCODR recommendations typically inform negotiations |
Finally, HTA coverage recommendation timelines tend to be faster for subsequent indications. Interestingly, subsequent indications had a tendency to have faster HTA coverage recommendation timelines, in England, Germany and Canada. This could partly be explained by higher quality pivotal clinical trial designs and increased proportion of standard approvals seen in the subsequent indication group. Another possibility is that first indications face higher barriers to entry. HTA agencies may receive efficiency gains from prior evaluations of a medicine in previous indications.
Our analysis is not without limitations. First, the present analysis is limited to indications launched globally, and thus no conclusions can be drawn about decisions not to develop indications pre-development; future research may explore this. Second, our sample is limited to 25 multi-indication medicines. In an ever-expanding universe of multi-indication products, further research on a larger sample may help strengthen signals and improve external validity of results. Third, the results presented here predominantly reflect oncology medicines with multiple indications; further research is needed to establish whether our findings apply to multi-indication medicines in other therapeutic areas. Fourth, the impact of secondary patents and market exclusivity extensions was not explored in the analysis. The current patent regime enables drug innovators to pursue secondary patents for new uses of existing pharmaceuticals, while regulatory agencies may grant extensions in market exclusivity. These benefits may impact the timing of decisions to launch a product locally and could contribute to differences seen across settings in the timing and availability of indication extensions. Finally, reforms to HTA systems during the study period may influence results. For instance, the AMNOG process in Germany was not introduced until 2011, meaning no HTA reports were available prior to that [15]; further, NICE introduced reforms to their HTA timelines in 2016 as part of their change to the Cancer Drugs Fund (CDF), committing to processing all HTA submissions in 90 days after regulatory approval [16]. This could contribute to the decrease in HTA coverage recommendation time seen for subsequent indications in England, but moreover, could influence launch decisions based on integration of the CDF into NICE recommendations [17].