Cost-Effectiveness of Cell-Free DNA-Based Noninvasive Prenatal Testing: Summary of Evidence and Challenges

Scarcity

Scarcity exists because the claims on health care resources outstrip the resources that are available. This provides the rationale for economic appraisal, because without scarcity there would be no need to make difficult resource allocation decisions. For example, the decision about whether or not to implement a cfDNA NIPT testing strategy would not need to depend on the cost of that strategy, but could focus instead purely on the benefits to pregnant women and families.

Opportunity Cost

The existence of scarcity leads directly to an important economics concept, namely, opportunity cost. If scarce resources are used to produce a particular health care program or service, those resources cannot be used to produce other goods or services. Opportunity costs reflect the benefits that are forgone by not producing those other services. The opportunity cost of using resources in a particular way is defined as the benefits that would have resulted from their best alternative use. When economists refer to costs, they usually mean opportunity costs. This is different from the financial costs—the costs of goods and services in terms of money—though very often financial costs are used to measure opportunity costs. As an example, from the perspective of a national committee responsible for all screening programs in a public health system, the opportunity costs of additional investment in cfDNA NIPT could be the potential health benefits of investing instead in new screening programs for cancer.

Incremental Analysis

Economic appraisal involves a comparison between two or more alternatives in terms of their costs and consequences. An economic appraisal ought to be comparative, because a health care program can only be thought to be worth doing or not relative to some alternative—even if that alternative is a do-nothing strategy. An incremental analysis is carried out to express the results of an economic appraisal. This is an assessment of the extra costs and benefits of one option compared with another—the additional costs incurred by one health care program are compared with another, in relation to the additional benefits of that health program compared with the other. Note that if the comparator is a do-nothing strategy it is unlikely to have zero costs and consequences, and these should also be accounted for.

To give an illustration, Torgerson and Spencer showed the importance of incremental analysis by analyzing data on the cost-effectiveness of biochemical screening for Down's syndrome as a replacement for screening by maternal age. An estimate had been published showing that introducing biochemical screening in a population of 20,000 pregnant women would cost £413,500 (including costs of screening, invasive testing, and terminations of pregnancy) and might prevent eleven affected births, giving a cost-effectiveness ratio of £37,591 per case identified. Torgerson and Spencer pointed out that for the same number of women existing antenatal screening procedures based on maternal age already cost £79,000 (including invasive testing and terminations of pregnancy) with four affected births potentially prevented. So, the true cost-effectiveness of biochemical screening when compared to preexisting services was (£413,500 − £79,000)/(11 − 4) = £334,500/7 = £47,786, a higher cost per extra affected case identified than for the estimate based on average cost alone.

Perspective

The perspective of an economic appraisal is important because among other things it determines what constitutes a cost, that is, what costs are included in the appraisal. Perspectives commonly taken in economic appraisals are those of the health service (or individual components within it, e.g., the hospital), the purchaser or payer of health care, and society as a whole. A societal perspective, which is the broadest perspective, might include health services costs, costs borne by patients and families, and costs in other sectors, for example, costs arising due to production losses from time off work. Researchers should be explicit about the viewpoint they adopt so an assessment can be made as to whether the costs included in an economic appraisal are complete and appropriate. The choice of perspective is important for an economic appraisal of cfDNA NIPT, as it affects the costs included. For example, one perspective is that of the prenatal test provider, who might only be interested in the costs of providing standard prenatal screening, cfDNA NIPT, and invasive diagnostic testing. A broader health service perspective might also include health care costs of pregnancy and childbirth, and termination of pregnancy. A societal perspective additionally includes lifetime costs of caring for individuals born with Down's syndrome, such as lost earnings from parents taking time off work.

Cost-Effectiveness Analysis

Cost-effectiveness analysis is one form of economic appraisal; others are cost-benefit analysis, cost-utility analysis, cost-minimization analysis, and cost-consequences analysis. The main form of economic appraisal that is encountered in the context of cfDNA NIPT is cost-effectiveness analysis, so we focus on that here. As with other forms of economic appraisal, cost-effectiveness analysis seeks to evaluate the costs and consequences of different options. One alternative is preferred to another if it provides greater benefit at the same or lower cost, or has lower cost for the same or greater benefit. Once data on the costs and benefits of the options being compared has been calculated, the first decision rule for this kind of appraisal is to reject any intervention dominated by another alternative or combination of alternatives; a dominated alternative has a greater cost with fewer or the same benefits, or lower benefits with the same or greater costs. For example, Garfield et al. calculated that a contingent cfDNA NIPT test strategy incurred a cost of US$59,228,142 in 100,000 pregnant women to detect 170 cases of Down's syndrome. This compared favorably with standard prenatal screening, which costed US$59,748,721 and detected 148 cases of Down's syndrome. Therefore in this case cfDNA NIPT dominated standard prenatal screening, and the latter strategy was therefore rejected.

The choice between nondominated alternatives is more complex because it leaves open the question which of two alternatives is preferred if one provides greater benefit than the other, but at a higher cost. A cost-effectiveness ratio (CER), defined as costs divided by benefits, can be calculated to inform this. The CER most often used in health economics is called an incremental CER, or ICER, which measures the incremental cost of an activity relative to its best alternative divided by its incremental effect.

In cost-effectiveness analysis, costs are regarded as opportunity costs measured in monetary terms, and benefits are measured in units other than money. For example, in the case of cfDNA NIPT, benefits might be measured in terms of the number of cases of Down's syndrome diagnosed or the number of procedure-related miscarriages. Costs and benefits are therefore measured in different units and are not comparable with each other; directly weighing the value of effects against the value of costs is not possible. For decision-making, the ICER is measured against a ceiling ratio or threshold; to be regarded as cost effective any intervention must have an ICER which is on, or below, this threshold. To illustrate, Morris et al. calculated the cost-effectiveness of cfDNA NIPT as a universal testing strategy compared with standard prenatal testing in a population of 10,000 pregnant women. The costs of the cfDNA NIPT universal strategy and standard screening were estimated to be UK£1,825,000 and UK£279,000, respectively. The two strategies were estimated to produce 16.49 and 13.24 diagnoses of Down's syndrome, respectively. Neither option was dominant. The incremental cost and incremental effect of cfDNA NIPT as a universal testing strategy versus standard prenatal testing strategy were UK£1,546,000 and 3.25 cases, respectively, with an associated ICER of UK£475,692 per extra case detected. By using the aforementioned ceiling ratio it is possible to judge whether or not cfDNA NIPT is cost effective in this case. For example, if the ceiling ratio was UK£500,000 per extra case identified, that is, we are prepared to pay up to UK£500,000 to diagnose an additional case of Down's syndrome, then cfDNA NIPT is good value for money because the ICER is below the threshold. Alternatively, if we are only prepared to pay UK£100,000 per extra case identified then cfDNA NIPT would not represent good value for money. A potential problem with cost-effectiveness analysis, which affects its usefulness for decision-making, is that the ceiling ratio may not be known (see later).