The Multiple Criteria Qualitative Value‐Based Pricing Framework “MARIE” for Novel Cell and Gene Therapy

Abstract

When setting the price of cell and gene therapies in Japan, the factors considered include the manufacturing and operating costs of the new drug or a comparator, leading to discrepancies between price and values, in particular those specific to cell and gene therapies. Here, we adapted our previously proposed value‐based pricing framework “MARIE” for use in estimating value‐based prices for cell and gene therapies. We adapted “MARIE” for use in pricing cell and gene therapies by adding “curative treatment” and “gene therapy” as value elements. The adapted framework determines prices of cell and gene therapies by multiplying the hypothetical daily price (determined from a drug price conversion table) and the efficacy period (rounded down to the nearest 6 months). We collected information, including on value elements, for new cell and gene therapies approved between 2015 and 2024 (n = 11) and compared estimated prices with actual list prices at the time of initial listing in the National Health Insurance Drug Price Standard. Overall, estimated prices tended to be similar to or higher than the list price. Estimated prices were 91.7% to 546.7% of list prices. We adapted our VBP framework “MARIE” for cell and gene therapies by incorporating elements specific to these therapies and estimated the prices using the information available at listing. Because certain factors, especially treatment duration, are uncertain at the time of initial listing, a system is needed that reevaluates and recalculates prices as additional evidence becomes available.

Study Highlights.

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In the current Japanese drug pricing system, prices do not necessarily reflect the values provided by drugs, especially cell and gene therapies.

WHAT QUESTION DID THIS STUDY ADDRESS?

Adaptation of our previously proposed value‐based pricing framework “MARIE” for use in estimating value‐based prices for cell and gene therapies.

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We adapted “MARIE” for use in pricing cell and gene therapies by adding “curative treatment” and “gene therapy” as value elements and considering the efficacy period.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our proposed approach for drug pricing system enables capturing and reflecting broader values of cell and gene therapies.

Recent therapeutic developments of cell and gene therapies have been met with high expectations such as the promising ability to help solve the issue of diseases that have so far proved resistant to other medical pathways. Yet, these potential solutions come with the problem of costs. Both the pricing and the appropriateness of the expenses incurred by the application of cell and gene therapy to patients have become a topic of discussion, but so far, no consensus has been reached on how to assess the innovative aspect of the therapies and how this reflects in prices. ¹ Different methods need to be used to estimate the price of new conventional drugs and cell and gene therapies, which are referred to as curative treatments because they may be able cure diseases. The Japanese drug pricing system has adopted an approach for conventional drugs that views daily price as reasonable in respect to the provision that their total treatment cost is proportional to their treatment period. Since conventional drugs are often used long‐term, we considered this approach reasonable and designed our MARIE method accordingly. However, since cell therapy and gene therapy often involve single‐dose treatments, we think that it is necessary to consider the price per treatment rather than the per‐day price. In this system, it fails to fully take into account that for single or short‐term therapies (SSTs), including cell and gene therapies, the treatment period is far shorter than the efficacy period. Therefore, the prices of SSTs should reflect their efficacy periods rather than daily prices. However, it is often difficult to determine the price of SSTs with the data available when they are initially approved because few data, especially on long‐term efficacy, are available at that time.

In Japan, new drugs are approved based primarily on evaluations of their efficacy, safety, scientific novelty, and clinical positioning. Subsequently, nearly all drugs are covered by health insurance and are available under the universal healthcare insurance system. Economic considerations are not taken into account at all during the drug approval process. Drug prices in Japan are based on a number of considerations and the manufacturing, distribution, marketing, and research costs of the new drug itself or a comparator weigh heavily on the price. To this, premiums are added in case of additional benefits, such as having high efficacy or safety or a new mechanism of action, improving disease treatment, and being an orphan drug or for a pediatric indication. ² The drug approval category of cell and gene therapies differs from that of conventional drugs, and with the increase in launches of cell and gene therapies in recent years, irrationalities and challenges have become apparent. The manufacturing and distribution cost structures of cell and gene therapies, which require strict manufacturing processes and quality control measures because there are also customized products such as Chimeric antigen receptor‐T (CART) cell therapy, are not the same as those of conventional drugs, so the prices cannot be appropriately calculated by existing methods. In addition, the criteria for determining whether a cell or gene therapy should be considered as a drug or medical device for pricing are not definitive. Thus, challenges exist in pricing cell and gene therapies under the existing drug pricing system.

One cause for concern with the current system of drug pricing in Japan is that prices do not always reflect the values of a drug. This incongruity leads to discrepancies between prices and values, particularly in the case of cell and gene therapies. Currently, no independent pricing rule has been established for gene and cell therapy, and instead, their approval is as an independent category, which is based on their unique nature of providing potential cures for diseases, that is, separately from new drugs and medical devices. Consequently, prices may not reflect the real values of cell and gene therapies as well as they do those of conventional drugs and may be too low or high relative to the therapies' values. Neither patients nor payers are willing to pay more for drugs with less value only because the drugs have high manufacturing costs. Furthermore, determining prices without adequately considering drug values may undermine pharmaceutical companies' willingness to develop and launch new breakthrough drugs in Japan, which may limit patient access to effective drugs. In order to overcome these challenges and maintain a fair and equitable health care system for patients as well as purse holders, prices should be determined on the basis of values to ensure proper allocation of resources. Therefore, a new price calculation method is needed that can adequately reflect the values of innovative breakthrough cell and gene therapies.

One system that has recently received much attention is value‐based pricing (VBP). VBP is based on drug values, which is an appealing rationale to the logic of stakeholders. Moreover, VBP may enable proper allocation of resources. To the best of our knowledge, there are currently no regions where a universally accepted VBP framework has been introduced and is being used for drug pricing. Several research groups have designed VBP methods and estimated prices of products, including cell and gene therapies, ³ , ⁴ , ⁵ , ⁶ , ⁷ but a consensus on the most suitable VBP method is yet to be reached. For example, Jommi et al. defined four operational steps for VBP: identify value domains, measure value, aggregate measures, and convert value into prices. ³ In addition, some groups have attempted to estimate value‐based prices by using a framework of expanded cost‐effectiveness. ⁴ , ⁵ , ⁶ , ⁷ These approaches convert prices by applying quantitative measures such as costs and quality‐adjusted life years; however, not all drug values are easily quantifiable. Therefore, a price estimation method is needed that is based on broad value elements, including qualitative ones, as described by Lakdawalla et al. ⁸ Furthermore, a conventional approach that uses comparator prices is problematic because it considers the medical cost offset caused by replacing expensive comparators and thus overestimates the value of the drug. Also, it is not necessarily required that a new drug be more effective than existing drugs in the new drug approval process; owing to this, methods not based on a comparator are more appropriate. Yet despite the necessity, to date, no versatile pricing framework has been proposed that is not limited to a specific disease area or based on a comparator, that includes broad value elements, and that is applicable to the pricing system in Japan. In light of these issues, we reference our previous article where we proposed the VBP framework “MARIE” (multiple criteria qualitative value‐based pricing framework) as a pricing framework for new drugs applicable to the pricing system in Japan. ⁹ In “MARIE,” drug prices are estimated by qualitatively evaluating broad value elements without requiring comparators.

Despite the fact that “MARIE” was designed for new drugs, it is versatile and can be expanded to consider features of cell and gene therapies, enabling appropriate pricing that reflects their values. Therefore, in the present study, we have adapted “MARIE” for use in estimating value‐based prices for cell and gene therapies and attempted to apply the adapted version to estimate prices of such therapies.

METHODS

We adjusted our previously proposed VBP method “MARIE” ⁹ for use with cell and gene therapies and then used it to estimate prices of cell and gene therapies approved in Japan.

Overview of the VBP method “MARIE”

“MARIE” estimates prices as daily drug prices via points, which are calculated based on value elements and the maximum number of patients to be treated. ⁹ The value elements are comprised of base and additional elements; the former include four elements, that is, efficacy, safety, scientific novelty, and clinical positioning, and the latter include eight, that is, unmet needs, improvement in quality of life (QoL), improvement in true endpoints, avoidance of productivity loss, improvement in convenience, improvement in diagnosis, pediatric use, and others. These twelve value elements make up the value tree. The “MARIE” base elements have a maximum total score of fifty, that is, twenty for efficacy and ten each for safety, scientific novelty, and clinical positioning. Next is the additional elements, which also have a maximum total score of fifty, that is, ten each for pediatric use and others and five each for unmet needs, improvement in QoL, improvement in true endpoints, avoidance of productivity loss, improvement in convenience, and improvement in diagnosis. Points for each value element are awarded by considering only published information, such as review reports and academic articles.

The base drug prices are estimated by using a conversion table that factors the points for base elements and the maximum number of patients to be treated. Base drug prices in the conversion table were determined in advance from the daily list prices of drugs that had a new active ingredient and were listed in the Japanese National Health Insurance (NHI) Drug Price Standard. Then, the final daily drug price is determined by adding an extra two percent per additional point to the base drug price determined as described above. For example, if a drug has five additional points, 2% × 5 = 10% is added to the base drug price.

Adaptation of the VBP framework “MARIE” for use with cell and gene therapies

Cell and gene therapies are expected to lead to long‐term improvement, despite their short administration period. Therefore, we defined “curative treatment” as another value element for these therapies and added ten points for this element to all cell and gene therapies. Indeed, gene therapy, a highly curative and innovative SST to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use, is expected to achieve complete recovery and allow patients to avoid the burdens associated with a disease and its treatment. For this reason, we included another value element for “gene therapy” under the category others, the twelfth value element in our proposed value tree, ⁹ and added ten points in the category others for all gene therapies. The value tree of the adapted version of “MARIE” used in this study is shown in Figure 1 .

Figure 1.

Value tree of the adapted version of “MARIE” for cell and gene therapies. MARIE—multiple criteria qualitative value‐based pricing framework; QoL—quality of life.

As mentioned above, we have previously proposed “MARIE” as a method for estimating daily drug prices ⁹ that is consistent with the use of daily prices as it is the current system for drug pricing in Japan. Pricing based on daily drug prices is reasonable for conventional drugs because the administration period is nearly identical to the efficacy period and overall drug costs are proportional to the lengths of the administration periods. Despite the logical benefits, this approach is not appropriate for cell and gene therapies as their administration periods are far shorter than their efficacy periods. Therefore, when calculating prices of cell and gene therapies, overall drug costs should be proportional to the length of the efficacy period rather than the administration period. To maintain consistency with “MARIE” for new drugs, we established an approach that uses hypothetical daily prices for calculating prices of cell and gene therapies. Under this approach, the price of each therapy is calculated by multiplying a hypothetical “flat” daily price by the length of the efficacy period. In other words, this approach determines the price per therapy by multiplying the hypothetical daily price, calculated from a conversion table of base drug prices (Table 1 ), by the rounded expected efficacy period of one application of the therapy. We used the same conversion table of drug prices created in the previous study because of the small number of approved cell and gene therapies.

Table 1.

Conversion table of base drug prices according to base points and the maximum number of patients to be treated (data from Takami et al. ⁹ )

Base points	Maximum number of patients
	more than 2,000,000	1,000,000 to 2,000,000	500,000 to 1,000,000	300,000 to 500,000	100,000 to 300,000	50,000 to 100,000	30,000 to 50,000	10,000 to 30,000	5,000 to 10,000	3,000 to 5,000	1,000 to 3,000	500 to 1,000	100 to 500	10 to 100	1 to 10
50	104	208	260	260	403	1209	1430	6500	13,130	14,040	27,560	30,030	56,680	66,560	120,250
45	96	192	240	240	372	1116	1320	6000	12,120	12,960	25,440	27,720	52,320	61,440	111,000
40	88	176	220	220	341	1023	1210	5500	11,110	11,880	23,320	25,410	47,960	56,320	101,750
35	80	160	200	200	310	930	1100	5000	10,100	10,800	21,200	23,100	43,600	51,200	92,500
30	72	144	180	180	279	837	990	4500	9090	9720	19,080	20,790	39,240	46,080	83,250
25	64	128	160	160	248	744	880	4000	8080	8640	16,960	18,480	34,880	40,960	74,000
20	56	112	140	140	217	651	770	3500	7070	7560	14,840	16,170	30,520	35,840	64,750
15	48	96	120	120	186	558	660	3000	6060	6480	12,720	13,860	26,160	30,720	55,500
10	40	80	100	100	155	465	550	2500	5050	5400	10,600	11,550	21,800	25,600	46,250
5	32	64	80	80	124	372	440	2000	4040	4320	8480	9240	17,440	20,480	37,000

Unit of the prices: JPY.

When applying the efficacy period to estimate the price, we considered the maximum duration of maintained efficacy measured in long‐term treatment studies and rounded it down to the nearest six months. For example, 5.1 years of reported duration was rounded down to 5 years, and 21.1 months to 18 months. For therapies that may require multiple dosing, we divided the calculated value by the maximum number of doses to obtain the price per dose.

Estimated prices of cell and gene therapies

We estimated prices for all eleven therapies approved as new regenerative medical products (cell and gene therapies) in fiscal year (FY; April to March of the following year) 2015 to 2024, that is, TEMCELL (Human (allogeneic) bone marrow‐derived mesenchymal stem cells), KYMRIAH (Tisagenlecleucel), ZOLGENSMA (Onasemnogene abeparvovec), NEPIC (Human (autologous) corneal limbus‐derived corneal epithelial cell sheet), YESCARTA (Axicabtagene ciloleucel), BREYANZI (Lisocabtagen maraleucel), OCURAL (Human (autologous) oral mucosa‐derived epithelial cell sheet), SAKRACY (Human (autologous) oral mucosa‐derived epithelial cell sheet using human amniotic membrane substrate), ABECMA (Idecabtagene vicleucel), VYZNOVA (Neltependocel), and LUXTURNA (Voretigene neparvovec) (indications or performance, non‐proprietary name, and brand name of the therapies are shown in Table S1 ). ¹⁰ We excluded regenerative medical products by conditional and time‐limited approval and ALOFISEL. ALOFISEL failed to achieve the primary endpoint of combined remission rate at twenty‐four weeks in the Phase 3 placebo‐controlled double‐blind parallel trial, ADMIRE‐CDII. ¹¹ Consequently, the European Commission withdrew its approval in December 2024. ¹²

To calculate scores and estimate prices for these therapies, we collected information on their value elements and other necessary information. In the same way as in the previous study, ⁹ we obtained information only from the following publications: review reports created by the Pharmaceuticals and Medical Devices Agency and package inserts (used for information on efficacy, safety, scientific novelty, clinical positioning, improvement in true endpoints, pediatric use, curative treatment, gene therapy, and the duration period), Central Social Insurance Medical Council materials (used for information on the maximum number of patients and the price of therapy at the time of listing in the NHI Drug Price Standard), Common Technical Document (used for information on the improvement of QoL), and academic articles (used for information on the avoidance of productivity loss). The criteria used for scoring are shown in Table 2. The information sources for each therapy were as follows: TEMCELL, ¹³ , ¹⁴ , ¹⁵ , ¹⁶ KYMRIAH, ¹⁵ , ¹⁶ , ¹⁷ ZOLGENSMA, ¹⁸ , ¹⁹ NEPIC, ²⁰ YESCARTA, ²¹ , ²² BREYANZI, ²² , ²³ OCURAL, ²⁴ SAKRACY, ²⁵ ABECMA, ²⁶ , ²⁷ VYZNOVA, ²⁸ and LUXTURNA. ²⁹ , ³⁰ As described above, we added ten points to all the therapies because they are “curative treatments” and an additional 10 points for “gene therapies.”

Table 2.

Value elements used for the price estimation and their scoring criteria

Category	Value elements	Points	Criteria
Base elements	Efficacy	20	Superiority over active comparator
		15	Non‐inferiority over active comparator, superiority over placebo, and superiority as add‐on therapy over standard of care alone
		10	Evaluated in a single‐armed trial
	Safety	10	Acceptable, but with the description that information should be continuously gathered in post‐marketing surveillance
		5	Acceptable, but with the discussions of issues for warnings or contraindications in the review process for the approval
	Scientific novelty	10	Efficacy shown or expected to be shown + novel mechanism of action
		5	Efficacy shown or expected to be shown
	Clinical positioning	10	New or first treatment option
		5	One of several treatment options
Additional elements	Unmet needs	5	Treatment satisfaction is less than 50%, and drug contribution is less than 50%
		3	Treatment satisfaction is less than 50%, and drug contribution is more than 50%
			Treatment satisfaction is more than 50%, and drug contribution is less than 50%
		1	Treatment satisfaction is more than 50%, and drug contribution is more than 50%
	Improvement in QoL	5	Improvement from baseline or against placebo or an active comparator observed
		0	Improvement not observed or data not available
	Improvement in true endpoints	5	Improvement observed
		0	Improvement not observed or data not available
	Avoidance of productivity loss	5	Reports available on the productivity loss for the disease for which the drug was indicated
		0	No reports available on the productivity loss for the disease for which the drug was indicated
	Curative treatment	10	Curative treatment (cell and gene therapies)
		0	None of above
	Pediatric use	10	Approved for use in children
		0	Not approved for use in children
	Others	10	Gene therapy
		0	None of above

Abbreviation: QoL, quality of life.

We compared estimated prices with the actual prices of the therapies at the time of listing.

RESULTS

Estimated prices

The comparison of the estimated prices of the eleven therapies included in this study with the list prices calculated under the current pricing system at the time of listing in the NHI Drug Price Standard is shown in Figure 2 .

Figure 2.

Scoring results and comparison of estimated and actual list prices (a) Scoring of each cell and gene therapy according to value elements (stacked bar graph) and the price as a percentage of the actual list price (*). (b) Comparison between estimated prices and actual list prices.

The median score for the base elements was forty (range, 25 to 45); the score for these elements was highest for LUXTURNA and lowest for TEMCELL. The median score for additional elements was twenty‐five (range, 15 to 40); the score was highest for LUXTURNA and lowest for NEPIC, OCURAL, SAKRACY, and VYZNOVA (Figure 2 a ).

Next, we calculated the difference in estimated prices as a percentage of the list price of the therapy at the time of listing in the NHI Drug Price Standard. For two therapies, the estimated price was lower than the list price: BREYANZI (−5.6%) and SAKRACY (−8.3%). For the other therapies, the estimated price was higher than the list price: It was less than fifty percent higher for KYMRIAH (+20.9%), ZOLGENSMA (+10.7%), YESCARTA (+17.6%), and VYZNOVA (+10.7%); less than one hundred percent higher for TEMCELL (+94.9%) and ABECMA (+94.7%); and 100% higher or more for NEPIC (+446.7%), OCURAL (+446.7%), and LUXTURNA (+341.1%). Thus, the difference was highest for NEPIC and OCURAL (+446.7%) (Figure 2 a ). Overall, the estimated price tended to be similar to or higher than the price of therapy at the time of listing (Figure 2 b ).

DISCUSSION

Significance and novelty of the research

Conventional drugs and cell and gene therapies are in different approval categories in Japan, so in this study, we focused on cell and gene therapies and adapted the proposed VBP framework “MARIE” ⁹ to establish a VBP method for cell and gene therapies that reflects their value elements and special characteristics. “MARIE” calculates daily drug prices by assuming that drugs will be administered continuously over a certain period of time, thus making it unsuitable for use with cell and gene therapies because of their long efficacy period. ⁹ In the present study, we created an adjusted version of “MARIE” for use as a VBP framework for cell and gene therapies by incorporating the concept of the efficacy period as Step 5 (Figure 3 ). Existing Japanese drug price calculation methods calculate drug prices by considering mainly manufacturing costs and do not fully consider the values of cell and gene therapies, whereas the method proposed here estimates value‐based prices.

Figure 3.

Steps in the value‐based pricing framework “MARIE” for cell and gene therapies. MARIE—multiple criteria qualitative value‐based pricing framework.

The conventional evaluation of cell and gene therapies is based on a comparator and, consequently, is affected by the comparator's price or efficacy. In contrast, the method proposed in the present study enables pricing to be based on the values of cell and gene therapies themselves and not on comparator‐based assumptions.

Currently, the ICER (Incremental cost‐effectiveness ratio) is the most commonly used metric in CEA (cost‐effectiveness analysis). However, just because the ICER is used as a general benchmark in CEA does not necessarily mean that it is used as a benchmark for “value.” This is because ICER has several limitations. In fact, evaluations by HTA authorities take various other aspects into account. The value of a pharmaceutical product cannot necessarily be summarized by ICER alone. Consequently, there is a growing trend toward considering various value factors. Second, while an ICER‐based approach relies on the price of a comparator drug, general drug pricing systems require a framework in which the value of each drug is assessed independently based on its own values. Finally, in Japan, prices for all drugs are determined within 60 to 90 days after approval, so speed is essential. Consequently, an ICER‐based approach, which requires long‐term evaluation, is not practical. For these reasons, the framework we propose is a more feasible method for the pricing system than an ICER‐based approach. Therefore, due to differences in approach, we have not compared the prices we have estimated with those deemed reasonable by other organizations such as ICER (Institute for Clinical and Economic Review) and NICE (National Institute for Health and Care Excellence).

Considerations related to estimated prices

The difference between the estimated prices of therapies is associated with the differences in the efficacy period. Cell and gene therapies cure diseases after a very short administration period, so the efficacy period is of greater value for pricing than the administration period. Prices for cell and gene therapies are actually low when presented without evidence showing the length of the efficacy period from long‐term studies. For example, SAKRACY has a similar number of points and patients as NEPIC and OCURAL, which have a similar mechanism, but SAKRACY has an approximately four‐fold lower price (SAKRACY, 12,300,288 JPY; NEPIC and OCURAL, 53,301,248 JPY). The drug approval system in Japan places a higher value on the results of interventional studies than on those of observational ones. We applied such an approach in the present investigation and attempted to determine the efficacy period by referring to results of long‐term interventional studies. The efficacy period results on SAKRACY were available only from observational studies, so a short efficacy period was assumed when estimating the cost, resulting in a lower estimated price than list price (−8.3%).

The method proposed here estimates prices by considering various elements that reflect the values of cell and gene therapies. Accordingly substantial differences were observed between the estimated prices and the actual list prices for some therapies, indicating that current list prices do not necessarily reflect the values of the therapies. For example, our cost estimates showed that the percentage difference between the estimated price and the price at the time of listing was +446.7% for NEPIC and OCURAL, both of which are listed as medical devices, suggesting that the price at the time of listing was much too low.

This study evaluated a VBP method as a means of pricing cell and gene therapies. Besides the appropriateness of the method, affordability must be considered. In the future, higher prices may be proposed for products with newer mechanisms of action, but the proposed prices may be in excess of what is affordable for patients and payers. One way to strike a balance between price and affordability may be to modify or limit the magnitude of lifetime cost savings with cell and gene therapies. The Institute for Clinical and Economic Review proposed a model where only fifty percent of the cost offset for a new technology was allocated in the shared‐saving scenario (a scenario in which the cost offset of new treatment is shared with society) and a model where an upper limit was determined for the cost reduction resulting from the new technology. ³¹ A system that sets some type of upper limit would be useful if pricing systems are expected to have a financial impact above a certain level. However, due to the fact that the severity of a disease and the importance of a drug depend on the indication, setting a uniform upper limit across indications may discourage the development of valuable drugs. Consequently, an appropriate upper limit must be set for each. Another approach is for a discount to be applied when calculating lifetime cost savings. For instance, when estimating the value of vascular endothelial growth factor gene therapy for neovascular age‐related macular degeneration, Berkowitz et al. applied a discount to compensate for the costs of lifelong treatment. ³² It is common to give a discount if the treatment period is long, and a discount should be given also when estimating prices of cell and gene therapies if the long‐term cost reduction is considered to be a value, as described above.

Our VBP approach estimates prices of cell and gene therapies by using the information available at the time of approval. Therefore, long‐term efficacy is not reflected in the price if data from long‐term studies are lacking at the time of approval, even if long‐term efficacy is expected in practice and a long‐term study is ongoing. Similarly, clinical trials may show effects, but real‐world data may suggest that the assumed effects do not persist. In such cases, prices may be over‐ or underestimated, and so they should be updated as evidence becomes available, for example, from long‐term clinical data. Such as, if the value of a drug is underestimated, a price increase may be considered and if the value of a drug is overestimated, a price decrease may result. We added this process as Step 6 in the framework “MARIE” for cell and gene therapies (Figure 3 ). Another approach for dealing with this issue is to incorporate patient‐level uncertainties. For example, the Institute for Clinical and Economic Review has suggested cure proportion modeling, which mixes the survival curves of some cured patients and the remaining uncured patients in cost‐effectiveness analyses, and scenario analysis, which evaluates the uncertainty of the benefit. ³¹ , ³³ Currently, such methodology is not established for estimating prices, but these ideas may be useful in the future.

Limitations

Our study does have some limitations. While some of our assumptions are arbitrary, this arbitrariness was intentionally designed to ensure that “MARIE” can be applied to any country. We believe that the framework and criteria adopted in our analysis are optimal for the purposes of this study. Furthermore, because our framework is highly versatile, its concepts can be adapted for use in other countries. The limitations of the individual assumptions are as follows. The first is the appropriateness of the conversion table of base drug prices. This table was created in our previous study by using the data for three hundred and sixty‐four drugs approved in the past ten years. ⁹ Because values in the conversion table of base drug prices may depend on the time period or included therapies, the most suitable conversion table is still a matter of discussion. However, because the main aim of the present study was to propose VBP methodology for new therapies, changes in the conversion table values of base drug prices are unlikely to have a major effect on the framework of the methodology and can be expected to have at the most a minor impact on the usefulness and applicability of our proposed method.

The second limitation is the small number of included therapies. This is in respect to the fact that only eleven cell and gene therapies have been approved in Japan since 2014. As a result, we could include only eleven products despite having assessed all products approved in the system. In consequence to this limitation, our proposed VBP method will require further verification as additional cell and gene therapies are approved.

The third limitation is the precision of the efficacy period. Basing the efficacy period on the results of clinical studies would provide an incentive for using longer observation periods (because they would increase drug prices), which may result in delayed access to cell and gene therapies. Therefore, in the present study, the maximum duration with maintained efficacy in long‐term treatment studies was rounded down to the nearest six months. Although such a definition may underestimate the efficacy period in some cases, it prevents prices from reflecting a possible clinically insignificant prolongation of the observation period.

The last limitation is the difficulty in interpreting the results. Discrepancies between the estimated prices and the actual list prices imply that current list prices may not fully reflect the values of therapies, but a similarity between the estimated and actual price does not mean that the list price reflects the values. Therefore, the appropriateness of prices needs to be considered carefully.

CONCLUSIONS

We adapted our VBP framework “MARIE” for use with cell and gene therapies by incorporating values specific to these therapies and their efficacy period. First, we estimated prices by multiplying the hypothetical daily prices determined by the original version of “MARIE” and the efficacy periods. Then, we attempted to use “MARIE” to calculate prices of cell and gene therapies and found that overall, estimated prices were similar to or higher than the price of the therapy at the time of listing in the NHI Drug Price Standard. Because some factors, in particular the efficacy period, are uncertain at the time of listing, we suggest that a system is needed for reevaluating and repricing cell and gene therapies as further evidence becomes available.

CONFLICTS OF INTEREST

Akina Takami and Ataru Igarashi are members of the Department of Health Policy and Public Health; Ataru Igarashi reports receiving remuneration from AstraZeneca K.K., Eisai Co., Ltd.; Daiichi Sankyo Co., Ltd.; and Mitsubishi Tanabe Pharma, Co.

FUNDING

No funding was received for this work.

AUTHOR CONTRIBUTIONS

A.T designed the research, performed the research, and analyzed the data. A.T and A.I. wrote the manuscript.

Supporting information

Table S1. Cell and gene therapies for which prices were estimated.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.