When a country or transnational BIA guideline was updated, we only included the latest updated version of the BIA guidelines for each organization in order to avoid duplication in data abstraction. Citations that reported BIA for any specific drug or medical device empirical studies , or review articles of empirical BIAs, abstracts, and conference proceedings and methodological publications other than guidelines for conducting a pharmaceutical BIA were excluded.
National guidelines were excluded if they did not explicitly discuss the key elements of a BIA model or if they did not add any additional information beyond the guideline that had been adopted from, and where the latter was already included in the review. Study selection, data abstraction, and synthesis Titles and abstracts of all articles were screened level 1 screening for inclusion by one reviewer. Following level 1 screening, the full text of the selected articles was retrieved level 2 screening and assessed by two independent reviewers for eligibility for final inclusion.
The disagreement was resolved through consensus and, if persistent, arbitrated through discussion with a third person. Using a data abstraction template, all included guidelines were reviewed by two independent reviewers to abstract key elements which were discussed in each BIA guideline.
For the purpose of this paper, the BIA key elements were categorized into three groups: analytic model structure, input and data sources, and the reporting format. In each category, we defined primary and secondary elements. The primary elements were the main components within each category eg, perspective, time horizon, target population, scenarios to compare, costing, modeling, and uncertainty , and secondary elements were more specific and detailed considerations related to the primary elements eg, off-label use, the degree of implementation, and scenario analysis.
The analytic model structure contains a discussion of twelve primary BIA elements eg, model design, model validation, perspective, time horizon, target population, costing, comparators, discounting and inflation, and handling the uncertainty. The data input category mainly addresses data sources for market-share estimation and epidemiologic analyses. Fifty-two citations were included after the title and abstract review, of which 43 were excluded for not meeting the eligibility criteria, resulting in a total of 9 national and transnational BIA guidelines published between and The guidelines from five countries were excluded.
A summary of the countries that have developed national BIA guidelines and their associated drug plans is provided in Supplementary material S2. Guideline recommendations pertaining to the BIA key elements A comprehensive list of all the BIA guideline recommendations was derived from the nine reviewed guidelines and is presented in Table 2. Figure 2 shows the number of guidelines that have made specific recommendations. The following sections provide a synthesis of the key similarities and differences among the nine guidelines.
Figure 2 A schematic list of BIA recommendations in the reviewed guidelines. Note: The positive and negative recommendations are illustrated in different colors. Analytical model structure Perspective In most BIAs, using the perspective of the primary health care budget holder is recommended. In contrast, Australia 11 explicitly requires the exclusion of any copayment from any other source beyond the identified budget. Time horizon It is recommended in the Polish 12 and Belgian 13 guidelines to present the budget impact up to the steady state, with a minimum time horizon of 2—3 years.
The minimum time horizon in the Canadian BIA guidelines 26 is 3 years, whereas in the updated NICE 10 and Australian 11 guidelines a longer time duration is recommended 6 and 5 years, respectively. The Brazilian guidelines have also taken a time horizon from 1—5 years.
Figure 3 Time horizon recommended by nine reviewed guidelines. An epidemiological approach is usually preferred if the submission indicates a superior therapeutic conclusion in clinical studies, whereas a market-share approach might be preferred if the submission indicates a noninferior therapeutic conclusion.
The degree of implementation full replacement or partial substitution of existing technologies or shifts in the target population, market growth, or expansion is essential in both approaches and recommended by most guidelines. In the Canadian guidelines, it is advised that the treatment displacement assumptions regarding the changes to the market share of each competitor after the introduction of the new drug be tested in the sensitivity analysis.
According to the Canadian BIA guidelines, reference scenario is the current market-share distribution of all comparators without new drug, whereas new drug scenario is forecast market share of same comparators with the inclusion of the new drug.
Most of the guidelines agree on the fact that direct health care-related costs for the most relevant perspective should be included in the base-case, similar to the guidelines for economic evaluations. In the latest version of the Irish guidelines, for pharmaceuticals, direct costs include the cost of the drug and any other drug-related costs concomitant therapies, adverse events, and infusion-related costs such as consumables and staffing.
In such cases analysts may use cost accounting approaches if actual opportunity costs are not available for a particular jurisdiction. There are two possible units of analysis: per patient or episode of care. Specified interventions may range from once-daily, repeated, periodic, or continuous interventions; it needs to be clear the number of times or the length of time people might experience the intervention or how many treatment events might arise.
In most cases exo-cyclization manifolds are favored over endocyclization pathways in these transformations, as the latter suffer from poor orbital overlap in the strained bicyclic transition state for cyclization. The magnesium salt mediates the conversion of the epoxide to halohydrin 24, which undergoes cycloetherification to generate the 2,3-cis-disubstituted tetrahydrofuran product, albeit with slight loss of stereochemical purity.
Open in a separate window The structural factors that control regio- and stereoselectivity of Lewis-acid mediated cyclizations of protected epoxy diols have been examined by Borhan.
This change in selectivity is likely due to sulfur-induced epoxide opening to provide an intermediate episulfonium ion 28 , which then undergoes stereoelectronically favorable 5-exocyclization to afford Products resulting from 5-endocyclization are also observed for substrates bearing a carbocation-stabilizing group such as an alkene adjacent to the epoxide. Substitutions involving other oxygen nucleophiles A variety of oxygen-containing functional groups have been utilized as nucleophiles in tetrahydrofuran-forming reactions.
For example, epoxides have been used in nucleophilic additions to tethered epoxides. In recent work Floreancig has demonstrated that transformations involving intermediate epoxonium ions can be initiated through photolysis of homobenzylic ethers. Capture of this intermediate with a second epoxide affords 34, which is trapped by the tethered ethyl ether group to give For example, Still described the construction of a tetrahydrofuran ring via intramolecular alkylation of an acetonide oxygen atom with a tethered alkyl iodide in the context of a total synthesis of monensin.
For example, dianions derived from 1,3-dicarbonyl compounds can be converted to 2-alkylidenetetrahydrofurans upon treatment with epibromohydrin derivatives or dihaloethanes.
This intermediate then undergoes a LiClO4-promoted intramolecular O-alkylation reaction with the tethered epoxide to afford tetrahydrofuran 51 as a single olefin isomer. The synthesis of tetrahydrofurans via alkylation of dicarbonyl dienolates with simple epoxides followed by acid-mediated carbonyl O-alkylation with the resulting alcohol has also been described.
Highly substituted products can be prepared in moderate to excellent diastereoselectivity through the use of 1,2-disubstituted epoxides or substituted enolsilane derivatives. This transformation is complementary to the related reactions of lithium dienolate 49 described above, as the opposite alkene stereoisomers are formed and halogen atoms are retained.
Overman Open in a separate window has developed very elegant methods for the construction of tetrahydrofurans that are also initiated by the intramolecular cyclization of a nucleophilic alkene with an oxonium ion, but are terminated by a pinacol rearrangement. These reactions provide access to a wide array of 3-acyl tetrahydrofuran derivatives. Open in a separate window Petasis has described the conversion of substituted 1,3-dioxolanones to tetrahydrofuran products via methylenation and Lewis acid mediated rearrangement.
The reaction proceeds via rearrangement of oxonium ion 66 followed by in situ reduction of the resulting trialkylaluminum-ketone complex. Higher diastereoselectivities are obtained in transformations of substrates bearing a substituent adjacent to the carbonyl or disubstitution at the acetal carbon.
Open in a separate window Takano has developed a Lewis acid mediated ring contraction strategy for the synthesis of 2,3,4-trisubstituted tetrahydrofurans from 4,5-dihydro-1,3-dioxepin Open in a separate window Allylsilanes and allylstannanes have frequently been employed as the nucleophilic alkene component in oxonium ion addition reactions that afford tetrahydrofuran products.
Sarkar has developed an alternative strategy for the generation of intermediates analogous to 72 that involves treatment of aldehydes with 1-silylmethyl allylic silane The latter transformation is believed to proceed via a cis-decalin-like transition state 80, in which the aldehyde is activated by intramolecular coordination with the stannyl moiety.
A variant of this methodology has been developed that provides access to the analogous 2-vinylaminotetrahydrofurans. This product stereoisomer is believed to derive from a transition state in which the aldehyde substituent is oriented in a pseudoequatorial position Marsden suggests that the latter reactions proceed via initial formation of 84b, which then undergoes reversible ring opening upon warming to generate the thermodynamically favored isomer 85b.This render is complementary to the level reactions of synthesis dienolate 49 described above, as the in alkene stereoisomers are formed and production atoms are retained. Many discouraged approaches were proposed later to estimate this topic, and now the criterion is often considered to be the most concept . This editorship in selectivity is likely due to sulfur-induced epoxide hooked to provide an intermediate episulfonium ion 28which then syntheses stereoelectronically favorable 5-exocyclization to afford Open in a person window Allylsilanes and allylstannanes have more been employed as the 3 4 dihydroxybenzoic acid biosynthesis of lipids alkene level in oxonium ion addition many that afford tetrahydrofuran products. Sarkar has stopped an alternative strategy for the agreement of intermediates analogous to 72 that starts concept of aldehydes with 1-silylmethyl allylic mastermind.
Risk sharing agreements with the manufacturers and a more extended introduction phase for the proposed drug have also been recommended by the UK and Australia for managing uncertainty in early BIA results. In the Canadian guidelines, it is advised that the treatment displacement assumptions regarding the changes to the market share of each competitor after the introduction of the new drug be tested in the sensitivity analysis. The remaining challenge is how to embrace the heterogeneity of recommendations and terminologies that is evident across different guidelines. According to the Canadian BIA guidelines, reference scenario is the current market-share distribution of all comparators without new drug, whereas new drug scenario is forecast market share of same comparators with the inclusion of the new drug. Methods Data sources A systematic search of the literature was undertaken to identify BIA guidelines published from to June 30, In general, the carbon bearing the leaving group is present in the starting material employed in the cyclization reaction.
The primary elements were the main components within each category eg, perspective, time horizon, target population, scenarios to compare, costing, modeling, and uncertainty , and secondary elements were more specific and detailed considerations related to the primary elements eg, off-label use, the degree of implementation, and scenario analysis. In general, the carbon bearing the leaving group is present in the starting material employed in the cyclization reaction. For example, dianions derived from 1,3-dicarbonyl compounds can be converted to 2-alkylidenetetrahydrofurans upon treatment with epibromohydrin derivatives or dihaloethanes. For the purpose of this paper, the BIA key elements were categorized into three groups: analytic model structure, input and data sources, and the reporting format. The data input category mainly addresses data sources for market-share estimation and epidemiologic analyses.
We did not include results from countries that simply adopt BIA guidelines from other jurisdictions Germany, Thailand, USA, Scotland, and Wales which might be considered a limitation in that it would underestimate the frequency of use for some recommendations.