Systematic reviews and meta-analyses can be powerful tools for generating the evidence needed to inform clinical decisions, reimbursement decisions and the development of clinical practice guidelines (1,2). In the hierarchy of evidence based medicine (EBM), where clinical evidence is ranked according to the strength of freedom from bias,meta-analyses are ranked at the highest level for informing healthcare related decisions(3).
Systematic review versus meta-analysis
A systematic review aims to address a specific clinical or scientific question using a comprehensive plan, literature search strategy and explicit selection criteria to identify relevant studies, assess the methodologic quality of these studies, explore differences among study results and qualitatively and/or quantitatively synthesize their findings(4).
Meta-analysis is a statistical method conducted after a systematic review that combines data by drawing on the power of multiple studies to inform and quantify the efficacy, safety and/or utility of a healthcare intervention.Specifically, meta-analysis uses statistical techniques to synthesise and quantitatively summarise the results of individual studies. This increases the overall sample size and thus improves the statistical power of the analysis and precision of the treatment effect estimates (5–7).
The value of a meta-analysis is that where the size and direction of the treatment effect is consistent among studies, it confirms this common effect. Where the treatment effect is quite variable among studies, meta-analysis can help to identify the reason(s)why, which is also informative to clinical decision-making.
Are all meta-analyses the same?
There has been some debate in the literature about the types of studies that should be included in a meta-analysis to ensure they can inform healthcare decisions(8–10).As observed by Pickup (2013), meta-analyses can be classified as one of two distinct types, i.e. those that:
Regarding healthcare decisions, it is important that clearly defined methods are used to identify and examine appropriate patient cohorts with the relevant baseline demographic and disease characteristics to properly represent the target patient population for whom the therapeutic efficacy,safety, cost-effectiveness and optimal use of therapies is being considered by healthcare decision-makers(10).
Literature summary meta-analyses
Meta-analyses that include only randomised controlled trials (RCTs) as the highest level of study evidence in the EBM hierarchy, such as those conducted according to the Cochrane Collaboration Guidelines, have been described as “literature summary meta-analyses” (11,12). RCTs are favoured for having a more valid study design compared with other types of studies, whereby randomisation removes confounding and the double-blind process minimizes biases such as the placebo effect(8).
However, it can also be argued that including only RCTs in a meta-analysis may dilute the results. For example,the dilution may come from including less relevant RCT studies that contain a broader population of individuals who may not all be relevant to the clinical or reimbursement question being asked about the effect of a healthcare intervention on a particular patient segment (8,10).
Furthermore, excluding observational or non-RCT studies can also result in valuable information not being captured such as the duration of treatment effect over a longer patient follow-up period.Therefore, literature summary meta-analyses may be suboptimal for real world decision-making and indeed, even misleading, where decisions about clinical effectiveness and cost-effectiveness require examination of the entire body of evidence for relevance to real world patient populations and use, as opposed to only RCTs as the highest quality of evidence (10).
‘Decision-making meta-analyses’, as described by Pickup 2013,are designed to assess all relevant studies that include the target patient segment for the healthcare intervention of interest(10). These meta-analyses may include patient data focused on a particular level of disease severity or patients with a specific treatment history. There is a growing consensus that the inclusion of observational studies in meta-analyses could be advantageous since they increase the size of the specific patient population of interest, can provide patient data over a longer time period and include other valuable information that cannot (logistically) be examined by RCTs, yet is more reflective of real world clinical practice (8,10,12).
An example of this is the systematic review and meta-analysis conducted by Pickup and Sutton (2008)who showed the benefit of including both RCTs and before/after (observational)studies in their analysis of continuous subcutaneous insulin infusion (CSII) versus multiple daily insulin injections (MDI) for controlling severe hypoglycaemia in patients with Type 1 diabetes(13).Although CSII is recommended by several national healthcare guidelines, previous meta-analyses had reported ambiguous results for the effect of CSII in controlling severe hypoglycaemia. However, Pickup and Sutton (2008) purposely focused on patients at risk of severe hypoglycaemia as the target population of interest who could potentially benefit from CSII by following a targeted study selection process.Consequently, they found the worst controlled subjects on injections had the most improvement on insulin pump therapy. They also reported that patients who attended clinic visits in the before/after studies were more likely to have had problems with glycaemic control than volunteers in RCTs.
By including a specific “at risk” patient group, the authors appropriately captured an important patient segment in need who could benefit the most from CSII, which was shown to be superior to MDI in reducing severe hypoglycaemia from both RCTs and the before/after observational studies(13). Importantly, the RCTs and before/after studies showed consistent results regarding severe hypoglycaemia reduction, although the magnitude of the difference favouring CSII over MDI was higher for the before/after studies.
Examples such as this show that when a meta-analysisis purposely designed to address a specific clinical or reimbursement question, it can fully inform the true value of a healthcare intervention – whether it be a drug, device or other intervention -for a specific patient population in need that is relevant to the real world clinical setting.
At CRC,our medical affairs capability is well equipped to conduct high quality systematic reviews and meta-analyses for a broad range of client situations relevant to clinical, regulatory,reimbursement, market access and other healthcare decision making.
Australia’s healthcare system is complex with both Federal and State Governments sharing the responsibilities of funding and delivering healthcare services, which are further split between public and private sectors (1). In making healthcare purchasing decisions, the Australian Government develops policies grounded on an evidence based medicine (EBM) approach (1, 2, 4). EBM harnesses data ranked according to its quality to inform decisions relating to health care policies and the approval of products for reimbursement (5). The preparation of high-quality data, such as systematic reviews and meta-analyses requires a high level of expertise and critical appraisal, therefore these resources provide a higher level of confidence and are therefore ranked at the top of the pyramid, as shown in Figure 1.
A recent health policy report by the Organisation for Economic Co-operation and Developments has flagged that Australia has the 5th most obese population among all OECD country’s (1). Additionally, the aging population is increasing (1 in 4 Australians will be over 65 by 2060) and this population has a higher need for health services (7, 8). Health service experts are concerned with the cost burden being placed on the healthcare system due to increasing levels of chronic illness and aging populations.
Value based healthcare (VBHC) combines the use of robust clinical data with cost-benefit analysis of real world data and a patient-centric approach, as shown in Figure 2. This system would see reimbursement based on quality of care and patient outcomes in the real world rather than the volume of procedures and patient visits (10). This approach aims to encourage the use of real world data via ‘pay for performance’ programs to extract greater value from the healthcare services provided (11).
In 2012, the Boston Consulting Group published a report analysing progress in developing infrastructure (patient registries and programs to capture quality data) to enable a VBHC system (12). Each country’s progress was examined using four categories; clinician engagement, national infrastructure, data quality and data use. Australia scored low in relation to readiness to implement a VBHC system, particularly in terms of data use and infrastructure. In 2016, 25 countries were examined for indicators of alignment with VBHC parameters (11). This assessment again described Australia’s overall alignment as moderate and noted that Government and major payers have not yet implemented plans for systematic change. While Australia has made some progress in terms of setting up disease registries, there is to date a lack of data sharing which reduces the usefulness of these registries (13).
Ultimately, it needs to be determined whether the upfront cost of putting in place new policies, infrastructure, disease registries and data analysis resources will ultimately result in long-term cost reduction and benefits to the Australian community.
Pay for performance solutions based on real world health outcomes aim to maximise value in the healthcare system for all stakeholders and countries are increasingly moving towards VBHC to more efficiently and effectively manage rising healthcare costs. Implementing VBHC solutions in Australia would require the collaborative efforts of these various stakeholders. CRC is well positioned to work with them in progressing potential VBHC solutions for clients by drawing on our extensive range of medical affairs and market access capabilities.
1. Organisation for Economic Co-operation and Developments. OECD Health policy in Australia. 2015.
2. Australian Department of Health. Evidence-based medicine and POCT. http://www.health.gov.au/internet/publications/publishing.nsf/Content/qupp-review~qupp-evidence-based-medicine-poct. 2013
3. Australian Department of Health. Evidence Based Practice. http://www.health.gov.au/internet/publications/publishing.nsf/Content/natsihp-companion-toc~invest-enablers~evidence
4. Australian Commission on Safety and Quality in Health Care. Australian Safety and Quality Framework for Health Care: Putting the Framework into Action: Getting started. 2016.
5. Sackett DL, Rosenberg WM, Gray J, Haynes RB, Richardson WS. Evidence Based Medicine: What it is and what it isn’t. British Medical Journal. 1996; 312
6. Glover J, Izzo D, Odato K, Wang L. Darthmouth College.
7. University CM. Evidence based medicine pyramid. http://libguides.cmich.edu/cmed/ebm/pyramid
8. Braithwaite J. Robust, evidence-based treatment will boost ailing medical system. The Australian. 2016.
9. Amalberti R, Nicklin W, Braithwaite J. Preparing national health systems to cope with the impending tsunami of ageing and its associated complexities: Towards more sustainable health care. Int J Qual Heal Care. 2016; 28(3):412–4.
10. Porter ME. A Strategy for Health Care Reform – Toward a Value-based System.
N Engl J Med. 2010; 363 (1): 1-3
11. The Economist Intelligence Unit. Value-based healthcare?: A global assessment. 2016.
12. The Boston Consulting Group. Progress Toward Value-Based Health Care. 2012.
13. The Economist Intelligence Unit. Value-based healthcare: A global assessment. Country Snapshot: Australia. 2016.
The popularity of consumer health and fitness wearable technologies (“wearables”) such as the Fitbit and Apple Watch is growing. As individuals are becoming better informed and thus, more empowered to play an active role in managing their health, it is unsurprising that the wearable market is expected to flourish. Health wearables, by definition, are autonomous, non-invasive technologies worn by individuals that are capable of measuring, tracking and storing data on physiological responses.1
While there is still uncertainty as to whether wearables directly contribute to positive behaviour change with regards to lifestyle habits and treatment adherence, they still have the potential to impact healthcare (Figure 2).2 2 By providing a platform that facilitates telemedicine and allows remote and ambulatory monitoring, wearables can significantly improve the provision of healthcare.1,2 1,2
As healthcare systems are becoming more focused on preventative actions, wearables will play an increasing role in patient care. Healthcare professionals (HCPs) and patients are able to access real-time longitudinal health data instantly, therefore, allowing wearables to assist in the management of chronic conditions such as diabetes.1-3 1-3
Wearables can be broadly classified as consumer general wellness device (e.g., health and fitness trackers like the Fitbit and Apple Watch) or regulated medical grade devices.4 4
The U.S. FDA has released a guideline to provide medical and wellness device manufacturers with clarity on the differences between general wellness and regulated medical devices.
In this guideline, general wellness products are categorised as products that are low risk and have an intended use that either:4 4
Wearables that fall into the above categories will not be required to comply with pre-market review and post-market regulatory requirements. Health wearables that are medical grade and pose a higher risk would be regulated by the U.S. FDA.
In Australia, medical devices are regulated by the Therapeutic Goods Administration (TGA) as per the Australian regulatory guidelines for medical devices (ARGMD) — which are currently under review — or the In Vitro Diagnostics (IVD) guidance.5,6 5,6 Health wearables, whether as a stand-alone product and for the software contained within, would fall under the definition of a medical device and would be classified according to the risk they pose (Table 1).
Given the technological advancements and innovation, an independent review of medicines and medical device regulation in Australia was conducted and published in March 2015.7 7 With regards to medical device regulation, the panel recommended that:7 7
At CRC, we understand what it takes to bring innovative new technologies to market. Health wearables will undoubtedly play a key role in healthcare, allowing patient and HCPs to work together to improve the diagnosis and management of conditions and diseases. Our expert team are ready to work with you to bring your innovations to those who need them the most.
1. Glaros, C. & Fotiadis, D.I. Wearable devices in healthcare. Intelligent paradigms for healthcare enterprises. Systems thinking. (eds B.G. Silverman, A. Jain, A. Ichalkaranje, & Jain, L.C.) 237-264 (Springer, New York, 2005).
2. Piwek, L., Ellis, D.A., Andrews, S. Joinson, A. The rise of consumer health wearables: Promises and barriers. PLOS Medicine 13, e1001953, doi:10.1371/journal.pmed.1001953 (2016).
3. Georga, E.I., Protopappas, V.C., Bellos, C.V. & Fotiadis, D.I. Wearable systems and mobile applications for diabetes disease management. Health and Technology 4, 101-112 (2014).
4. United States Food and Drug Administration. General wellness: Policy for low-risk devices. Guidance for industry and food and drug administration staff. (Silver Spring, 2016).
5. Therapeutic Goods Administration. Overview of the new regulatory framework for in vitro diagnostic medical devices (IVDs). (Canberra, 2011).
6. Therapeutic Goods Administration. Australian regulatory guidelines for medical devices. (Canberra, 2011).
Better access to healthcare information has raised patients’ expectations leading to them independently garnering an understanding of their condition and managing their own healthcare (Figure 1).1 Healthcare professionals (HCPs), therefore, are now no longer the sole decision-maker when it comes to healthcare choices.1,2 In response to the changing customer base, the biopharmaceutical industry is moving away from product-centric approaches to ones that are patient-centric.
A number of industry trends and patient factors are contributing to this shift from product-centricity to patient-centricity (Figure 1).
Decreased productivity and over-investment in R&D, saturation of large disease states and an increased focus on niche indications where it is difficult to get return on investment are all limiting the impact of product-centric approaches.3
Furthermore, patients are becoming more value-minded due to the rise in out-of-pocket expenses from new but costly health innovations and a growing range of lower-cost generic medicines following a rising number of patent expirations.3,4
Patients are increasingly key to approval and reimbursement decisions as regulatory bodies not only require real-world patient data but are also considering patient preferences and actively seeking patients’ input.1
Figure 1. Drivers shifting the decision-making from HCPs to patients.1,4
The biopharmaceutical industry, therefore, is under increasing pressure to create value to the patient while demonstrating commercial productivity and growth.
It is important to understand what it means to be patient-centric. Patient-centricity can be defined as acknowledgement that the needs of a patient or a distinct patient population — including their physiological, psychological and social needs — are at the core of decision-making.1,5
Increasingly, the industry is integrating patient-centric approaches across all stages of drug development from clinical trials to marketing (Figure 2). In doing so, companies will be able to create more value for patients through solutions that give patients the best possible health outcomes.4
Figure 2. Patient-centricity across all business functions.
Keeping patients at the core of key business functions can give biopharmaceutical companies a competitive edge for strong commercial growth as they develop and deliver meaningful health technologies (Figure 3).
Patient-centricity can inform clinical trial design and assist with patient recruitment and retention thereby driving the development and delivery of new, high-value health innovations.6,7 Furthermore, companies will be able to gain clarity on where their core activities and competencies are and how they align with patients’ needs thus, informing their strategy, decision-making and resource allocation.6
Figure 3. Patient-centric business functions can help drive commercial growth.6,8
Engaging and collaborating with patients and other stakeholders is a key step to acquiring important data on patients’ needs, behaviours, utilisation patterns and health outcomes.4 The amalgamation of this data can provide valuable insight and inform strategies for improving medicine use, increasing uptake and driving commercial growth (Figure 4).
Figure 4. Steps to becoming patient-centric.
When it comes to increasing revenue, productivity and growth there are three broad categories of patients to keep at the core of commercial strategies, those: 8
A white paper published by Kinapse Consulting suggested that significant culture shift would be required for companies to be successful in patient-centricity. This involves shifting their focus from disease to patient segments and providing integrated healthcare spanning the full spectrum of a patient’s needs, however this could prove challenging.4
A more achievable option encompasses multi-faceted strategies (Figure 5) to increase productivity, growth and demonstrate value should be targeted and optimised to HCPs and patients and aim to: 4,8
Figure 5. Patient-centric strategies for increasing product uptake.
At CRC we strive for quality and excellence as our expert team collaborate with our clients to develop innovative, patient-centric medical affairs solutions that will boost commercial productivity and growth. Our competitive advantage coupled with our extensive expertise in medical affairs and strong ties to the biopharmaceutical industry will allow us to reinvigorate your product portfolio, expand access and increase product uptake. We will achieve this through effective and innovative stakeholder engagement and management, medical communication and health education, brand planning and pre-launch and launch strategies.
Interactions between biopharmaceutical companies and healthcare professionals (HCPs) are under increasing scrutiny. New regulations and calls for transparency are making it more difficult for sales representatives to access HCPs.1 1
As the biopharmaceutical industry becomes increasingly patient-centric in their activities, the role of medical affairs is expanding. This has led to a rise in the number of projects initiated and led by medical affairs thus creating a need for field-based medical affairs people who are therapeutic area experts such as medical science liaisons (MSLs). It has been reported that, on average, biopharmaceutical sales representatives spend approximately 2 minutes with HCPs whereas the length of engagement between MSLs and HCPs is around 1 hour.2 2
HCPs benefit from interactions with MSLs
Biopharmaceutical products are becoming more complex due to the development of new technologies such as genomic sequencing. As a result there is an increasing amount of complicated scientific and medical information available.2 2 HCPs, therefore, are demanding more detailed information and educational materials that will help them navigate their way through these new technologies and products.2 2 This is where MSLs are able to provide the most value to HCPs.
As therapy experts, MSLs are able to translate this complex and specialised scientific and medical information into practical insights to improve decision-making, thus delivering value to HCPs and patients. 2 2 Furthermore, MSLs can engage HCPs in high-level discussions that do not simply involve the translation of science but also include the exploration of health outcomes and real-world data.2 2
The dissemination of information and insights through the provision of high-quality educational materials is another way MSLs are able to be of value to KOLs, HCPs, and other stakeholders. 3 3
The value of MSL teams
The role of MSLs extends beyond that of key opinion leader (KOL) relationship management and facilitating the exchange of unbiased scientific information (Figure 1).1,3 1,3 MSLs play a key role in executing medical affairs plans that are in line with the company’s brand plan.
MSLs are able to obtain and share valuable medical insights into patients’ needs and intelligence on competitor products from KOL interactions, scientific conferences and meetings.2,3 2,3 These KOL insights can inform and drive commercial activities and product lifecycle plans. Furthermore, they can be used to help plan and design clinical trials and real world studies, which are increasingly required for demonstrating product value for approvals, reimbursements and access.1,3 1,3
CRC offers a flexible MSL headcount
Our strong expertise in medical affairs across the entire drug development lifecycle allows us to support your product launch by offering flexible and cost-effective MSL resourcing on a per project basis. This allows you to redeploy your resources to where they are needed most. We can leverage off our existing and extensive KOL and stakeholder networks, engage and nurture these relationships, create advocacy and garner valuable insights to help shape and maximise your commercial opportunities. In addition, we can provide innovative medical liaison strategies and assist you with your stakeholder management planning.
Evers, M. et al. Pharma medical affairs 2020 and beyond. (2012)
Groebel, R. Exploring the changing role of modern medical science liaisons. (2015). https://www.veeva.com/wp-content/uploads/2015/09/AR-Changing-Role-of-Medical-FINAL-8.10.15.pdf
Gupta, S. & Nayak, R. An insight into the emerging role of regional medical advisor in the pharmaceutical industry. Perspectives in Clinical Research 4, 186-190 (2013).
CRC provides Medical Affairs solutions to the Pharmaceutical industry throughout the Drug Development Life Cycle. Our objective is to maximise the value of therapeutic compounds from pre-launch through to commercialisation and beyond.
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