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  • An Overview of Methods for Indirect Treatment Comparisons in Healthcare Decision-making

    An Overview of Methods for Indirect Treatment Comparisons in Healthcare Decision-making

    Meta-analyses summarize data from head-to-head trials to evaluate pairs of treatments that have been directly compared.[1] However, in certain circumstances, multiple therapies are of interest, and no data is available on their direct comparison. In such cases, indirect treatment comparison (ITC) is performed for synthesizing evidence surrounding treatments of interest.[2] ITC assumes that the studies are similar and homogenous regarding the administered therapies, patient characteristics, and observed effects, and works best when the inconsistency between indirect and direct evidence is minimal or absent. 

    Various methods of ITC have been developed depending on the availability of individual patient data (IPD) and summary level data (SLD). Some of these methods include naïve ITC, network meta-analysis (NMA), population-adjusted indirect comparisons (PAIC), simulated treatment comparisons (STCs), and matching-adjusted indirect comparisons (MAICs). The choice of these methods depends on the study design, the number of comparators available, and the degree to which the outcomes are measured. In addition, the extent of assumptions employed, methodological limitations, and inherent biases associated with each method also determine the choice of the ITC method.

    Naïve ITC is based on SLD and is used when the treatments cannot be connected by a common comparator. It does not account for heterogeneity and excludes information from the placebo arms when comparing treatments, thereby introducing bias. Hence, this method is mainly avoided to preserve the randomization in trials during the analyses. 

    Network Meta-Analysis (NMA) is perhaps the most popular of the ITC methods. It works with SLD, and compares treatments by combining indirect and direct evidence connected by a network of studies.[3] NMA is considered as the gold standard for ITCs. It offers more an exact estimate of the relative effects of treatments in the network than a single direct or indirect estimate. It also enables for the assessment of intervention ranking and hierarchy. To some extent, this bias can be reduced by using meta-regression, that addresses heterogeneity in treatment effects. It can assess how the effect of treatment changes with a covariate (a patient or methodological attribute). Unfortunately, the usage of meta-regression with NMAs becomes questionable in cases where the number of studies in a network is limited. Furthermore, this approach can only be used when there is a variance study or comparison with only minor variations in impact modifiers.[4,5] Moreover, covariate correction in aggregate-level data may result in ecological bias, which limits the interpretation of estimated results for subgroups. In such cases, Individual Patient Data (IPD) provides adjustments for covariates that cause inconsistencies (e.g., prognostic factors, effect modifiers, etc.). Hence, NMA that leverages IPD can be put to use for conducting analyses that can provide adjustments to reduce such inconsistencies.[6] 

    The application of NMAs and their associated methods are often limited by insufficient evidence networks and heterogeneity across trials. This is resolved to certain extent through population-adjusted indirect comparison (PAIC), which is a targeted approach to enhance ITC.[7] It allows to overcome the challenges faced by NMAs by carrying out a targeted comparison between outcomes for specific treatments and factors. It includes two methods: simulated treatment comparisons (STCs) and matching-adjusted indirect comparisons (MAICs). These methods can help reduce the ambiguity in the comparisons with statistical adjustment. STCs do this by applying predictive equations, whereas MAIC relies on patient reweighting. 

    STCs or MAICs can be used to conduct either “anchored” indirect comparison, in which each trial has a common comparator arm, or “unanchored” indirect comparison, in which the treatment network is disconnected (single-arm investigations). An anchored approach relies on “conditional constancy of relative effects”. In contrast, an unanchored approach works on a stringent assumption of “conditional constancy of absolute effects”. which is more demanding than the former and is not a widely accepted approach [8]  STCs are often appropriate in analyses where numerous comparators are available for a small set of outcomes, whereas MAICs are often suitable in cases with only one comparator but multiple outcomes. The precision of the equations in STC and the effective matching of populations in MAIC determine the dependability of the studies.

    A task force report released in 2011 by the Professional Society for Health Economics and Outcomes Research (ISPOR) defines the fundamentals of conducting ITCs and assessing these studies for informed and efficient decision-making.[4,5] Though the methodological aspects of NMAs have received much attention from researchers, the other ITC methods are yet to be refined to a similar extent. The standardization of these methods is vital to increase their reliability and application.

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    References

    [1] Ahn E, Kang H. Introduction to systematic review and meta-analysis. Korean J Anesthesiol. 2018 Apr;71(2):103-112. doi: 10.4097/kjae.2018.71.2.103.  [2] Veroniki AA, Straus SE, Soobiah C, et al. A scoping review of indirect comparison methods and applications using individual patient data. BMC Med Res Methodol. 2016 Apr 27;16:47. doi: 10.1186/s12874-016-0146-y.  [3] Tonin FS, Rotta I, Mendes AM, Pontarolo R. Network meta-analysis: a technique to gather evidence from direct and indirect comparisons. Pharm Pract (Granada). 2017 Jan-Mar;15(1):943. doi: 10.18549/PharmPract.2017.01.943 [4] Jansen JP, Fleurence R, Devine B, et al. Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. Value Health. 2011 Jun;14(4):417-28. doi: 10.1016/j.jval.2011.04.002.  [5] Hoaglin DC, Hawkins N, Jansen JP, et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. Value Health. 2011 Jun;14(4):429-37. doi: 10.1016/j.jval.2011.01.011.  [6] Riley RD, Dias S, Donegan S, et al. Using individual participant data to improve network meta-analysis projects. BMJ Evid Based Med. 2022 Aug 10:bmjebm-2022-111931. doi: 10.1136/bmjebm-2022-111931. Epub ahead of print.  [7] Phillippo DM, Dias S, Elsada A, et al. Population Adjustment Methods for Indirect Comparisons: A Review of National Institute for Health and Care Excellence Technology Appraisals. Int J Technol Assess Health Care. 2019 Jan;35(3):221-228. doi: 10.1017/S0266462319000333. Epub 2019 Jun 13.  [8] Jiang Y, Ni W. Performance of unanchored matching-adjusted indirect comparison (MAIC) for the evidence synthesis of single-arm trials with time-to-event outcomes. BMC Med Res Methodol. 2020 Sep 29;20(1):241. doi: 10.1186/s12874-020-01124-6.

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  • Cost Effectivity or Affordability: What Should be Prioritized in India?

    Cost Effectivity or Affordability: What Should be Prioritized in India?

    Rapidly rising cost in healthcare is an increasing cause of concern across the world. Indian healthcare is also experiencing a change, with increasing focus on better quality of medical care services.

    As per the available information, the healthcare spending per capita per annum in India has been observed to be about $109, with total healthcare spending in the range of 4.9% of the country’s GDP. Most of the spending occurs from the private sector with public sector contributing to a mere $ 19 per capita per annum. Concurrently, the average spending per capita per annum in the United States during the same time frame has been found to be approximately $4271 whilst for the United Kingdom, the spending is $ 1675. These figures clearly indicate that healthcare in India is fairly cheaper, a strong reason for a growing medical tourism market in the country. However, when compared with paying power parity and affordability, the cost of medical care is escalating. It is worthwhile to note that as per World Bank estimates, more than 44% of Indian population earns less than one dollar a day.

    In India, a silent crisis in access to essential medicines confronts most patients who seek treatment of acute and chronic diseases. Close to 40% of Indians live on less than US $1 per day and most of them pay Out-Of-Pocket (OOP) for using healthcare. OOP spending in India is over four times higher than public spending on healthcare. Unexpected illness can have a catastrophic effect on the family of the ill person: direct out-of pocket payments could push 2.2%% of all healthcare users and one-fourth of all hospitalized patients, into poverty in a year.

    In addition, most Indians pay for medicines – a key factor that can contribute to the impoverishing effect of OOP payments for healthcare. According to the World Health Organization (WHO), an estimated 649 million people in India do not have regular access to essential medicines. Public provision of these medicines is poor; the median availability of 30 essential medicines in six states in India varied between 0% and 30%. Patients are forced to buy medicines from the private market, a compulsion that often spells calamity for those who can ill afford the twin burdens of sickness and healthcare costs.

    Drug regulatory agencies all over the world approve medicines for use in their countries on the basis of an evidence-based process which evaluates the data on their efficacy (obtained through randomized controlled trials) and safety. In India, in light of the public health problems that we face, the widespread poverty and high OOP expenditure incurred by patients, the drug regulatory authorities have an additional responsibility: to ensure that the medicines being approved for manufacture serve the public health needs of the country and are cost-effective. Moreover, patients value quality, safety and cost-effectiveness of a medicine; it matters little to them whether the medicine is branded or unbranded and whether it is promoted through the retailer or the doctor.

    India and its pharmaceutical industry have acquitted themselves very creditably on the global platform. Indian generics account for about 40% of the anti-retroviral medicines provided globally. Worldwide, these low-cost high-quality medicines are a lifeline to millions of people. There are an estimated 10,563 manufacturers in India, and more than 65,000 formulations. These numbers look impressive but the paradox is that, at home, large portions of the population lack access to even the most essential drugs. The limited funds available are frequently spent on ineffective or unnecessary medications. The money spent on overpriced medicines is very often also a waste of precious resources. Since these medicines outnumber those which are cost-effective, they directly impact the availability of and access to essential medicines.

    To address the anarchy of drug prices which is impoverishing people, we need a comprehensive cost-based system, and not the market-based system of price regulation. The drug approval system in India needs to be overhauled on the lines suggested by the recent parliamentary committee which looked into the functioning of the CDSCO. The process of drug approval needs to be rigorous, evidence-based, transparent, and in line with the interests of public health in India. The present predicament, of poverty of access to medicines amidst a plenty of overpriced, non-essential medicines which worsen poverty, should not be allowed to continue to imperil the lives and health of Indians.

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  • Vaccine Use – Costs and Concerns – Indian Perspective

    Vaccine Use – Costs and Concerns – Indian Perspective

    Vaccines are important preventive medicines for primary health care, and a critical component in a nation’s health security. Although international agencies such as the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) promote global immunization drives and policies, the success of an immunization program in any country depends more upon local realities and national policies.

    The market for vaccines in India shows immense potential. The country has not only been self-sufficient in meeting its domestic requirements but has also emerged as a leading global exporter of vaccines across the world. The Indian vaccine industry began as a network of state owned manufacturers supplying basic childhood vaccines to the national immunization program. India’s vaccine production sector is likely to expand dramatically to an estimated size of $871 million by this year which was estimated to be $350 million in 2011, says a report by GBI research.

    India articulated its first official policy for childhood vaccination, a policy that was in alignment with the WHO’s policy of “Health for All by 2000” (famously announced in 1978 at Alma Atta, Kazakhstan) and introduced six childhood vaccines (Bacillus Calmette-Guerin, TT, DPT, DT, polio, and typhoid) in its immunization program. Measles vaccine was added much later, in 1985, when the Indian government launched the Universal Immunization Program (UIP) and a mission to achieve immunization coverage of all children and pregnant women by the 1990s. The last few years have brought many achievements for the Indian vaccine industry. A new bivalent oral cholera vaccine, meningitis-A vaccine, and an indigenous Japanese encephalitis (JE) vaccine were developed by Indian manufacturers in collaboration with international partners and are now licensed in India. In March 2014, India received its polio-free certification from WHO, in line with the disease being eradicated from the country. Recently, Bharat Biotech, an Indian vaccines manufacturer, has announced a breakthrough in developing the world’s first Zika vaccine. The company is now looking to seek regulatory approvals to expedite further clearances.

    Vaccine pricing strategies usually consist of a set of process that include but not limited to- carrying out the target population analysis; constructing a vaccine target product profile (TPP) and comparing it to projected or actual TPPs of competing vaccines; determining vaccine positioning in the marketplace; estimating the vaccine price-demand curve; calculating actually vaccine costs (manufacturing, distribution, and research and development); accounting for various legal, regulatory, third party and competitor factors; overall product portfolio; pricing objectives; and pricing structure. The routinely administered vaccines in India which are usually administered by infants and children (BCG, Hep-B, Measles, chicken pox, Rota virus, pneumonia vaccines, etc) are priced between Rs 150 to 4,000. However, prices may vary due to change in brands and/or different vaccine administration charge and consulting fees of the doctor.

    In recent decades, however, a number of privately owned firms have emerged, which have completely transformed the industry landscape. Their biggest success factor is similar to the approach that has been followed by Indian generic pharmaceutical manufacturers. This model involves concerted efforts to develop vaccines for not only tropical neglected diseases, but also cheaper alternatives of vaccines that are already available in the West. Despite its recent growth, however, the Indian vaccine industry still has a number of challenges to address. Even though the market is growing continuously, India is lagging behind its global peers in terms of vaccine coverage with a significant number of lives lost due to vaccine preventable deaths.

    According to UNICEF, vaccination coverage varies considerably from state to state, with the lowest rates in India’s large central states. Differences in uptake are geographical, regional, rural-urban, poor-rich and gender-related. On average, girls receive fewer immunizations than boys and higher birth order infants have lower vaccination coverage. UNICEF works closely with the Indian government on its Universal Immunization Programme (UIP). Introduced in 1985, the UIP has made great progress in expanding Routine Immunization (RI) coverage across the country, and today, it is one of the largest programmes of its kind in the world. The UIP supports national and state governments to boost routine immunization (RI) and supplementary immunization, including for polio, measles, and Japanese encephalitis. It also supports the introduction of new vaccines such as Pentavalent, Hepatitis B and rubella.

    Despite such a bright picture, vaccinations for babies are proving to be excellent money-spinners for doctors, especially the newer ones that have not been recommended by the government and are not even a part of the National Immunization Programme. The profit margins are much higher for the non-mandatory vaccines and doctors are made to prescribe those in order to position these unnecessary products.  Costs of vaccines and vaccination coverage have been big issues in India in recent years, as the country’s healthcare system has expanded and demand for treatments increased, with very little vaccination coverage. Despite price caps and some discounting on the part of big pharma, some therapies remain too expensive for Indian patients to afford. If irrational vaccines with high costs enter the market without being a part of the national immunization programs; the patients are likely to face the challenges of spending huge amount of money.

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