Medical Affairs is undergoing an evolution of sorts. This is the first of a three-part series looking at three key areas where external landscape changes are impacting the Medical Affairs function.
1. Greater Consumer Empowerment
Unprecedented access to healthcare information has allowed patients to become more discerning about their health needs, which is influencing pharmaceutical and medical device companies to integrate patient centric strategies that impact across the organisation (1). Empowered consumers leverage knowledge to demand more sophisticated, convenient and personalised therapies (2).Traditionally, companies focused on satisfying the needs of regulators, payers and prescribers throughout the product life cycle, while patient insights were gathered indirectly via healthcare providers (3). However, patients have found their voice and the onus now is on industry to engage with them as key stakeholders and implement solutions that provide more considered support to patients.
Medical Affairs teams can respond to this by taking a ‘360-degree’ approach to engaging with patient communities in designing patient support programs (PSPs) that facilitate holistic disease management. This means the PSP does not simply focus on medication adherence but aims to demonstrate a deep understanding of how the disease and the therapy impact patient outcomes, which informs those services most meaningful to patients for improving their lives (3, 4). For example, PSPs developed for patients with diabetes may need to address the emotional, social and psychological impact of their condition, it’s monitoring and adhering to therapy, while a PSP for an oncology drug may require more focus on managing treatment side effects and how these impact patient lives.
2. Complex regulatory pathways
Innovative therapies, especially biological medicines, are being developed at an accelerated rate, which has created pressure on regulators to implement effective risk management solutions. In Australia, a series of reforms shown below have added to the burden of risk management activities for pharmaceutical and medical device companies (5).
These reforms include the introduction of the Black Triangle Scheme in Australia in 2017 (Figure 1), which has been in effect in the EU since 2013 (6). Black triangle notices will apply for a period of 5 years to biological medicines and therapies that contain a new active substance to indicate the medicine is subject to additional monitoring, as well as highlight the location of safety information along with details of how to report adverse reactions (5-7). These changes reflect the increasing concern of regulators and consumers about the long-term safety risk of some new medications,specifically biologicals that can cause increased risk of adverse events (7). These reforms can only benefit patient outcomes via the increased safety vigilance and risk management, however companies may be challenged by the increased workload and resource implications.
Figure 1. Example of new product labelling under the Black Triangle Scheme.
3. Informing payers about real world data
Healthcare systems globally are evolving from high cost fee-for-service based models towards value-based systems linking payment to performance and, as discussed previously, Australia has been slow to implement these changes (8). There is increasing pressure on pharmaceutical and medical device companies to demonstrate not just clinical effectiveness but the value for money their products provide. This is no longer achieved solely through traditional evidence based medicine in the form of clinical studies to prove the safety and efficacy of a therapy. In fact, companies are now facing unpredictable reimbursement decisions and are challenged to implement strategies to prove long-term, real-world clinical and cost-effectiveness outcomes in securing funding for new therapies (9, 10). Industry as a whole could therefore benefit from coming together as ‘change agents’to face this challenge by working with payers to establish the appropriate mechanism in progressing the collection and use of real world evidence to support therapy funding.
CRC’s mission is to increase our clients’ competitive edge by implementing Medical Affairs solutions to maximize commercial opportunities. Our dedicated Medical Affairs experts are well equipped to find strategic approaches for the current challenges facing industry and implement them with our clients.
National Diabetes Week from July 9th – 15th aims to raise awareness about diabetes, its management and prevention (1). Diabetes presents a huge disease burden with the prevalence of diabetes worldwide estimated at 422 million people, including 1.7 million Australians among whom 500,000 are undiagnosed (2, 3). Each day 280 Australians are diagnosed, which is one person every five minutes (3). The healthcare costs of diabetes in Australia are around $1.7 billion per year, yet when indirect costs such as lost productivity, work absenteeism, and early retirement are also considered, the total cost burden may be as high as $14.6 billion (3, 4).
Insulin is the hormone that regulates blood glucose levels in the body. Type 1 diabetes is an autoimmune disease whereby a person’s immune system destroys the insulin producing cells of the pancreas. In type 2 diabetes, which represents the majority of the disease and cost burden, the body becomes resistant to the normal effects of insulin and/or cannot produce enough insulin. Type 2 diabetes is generally lifestyle related and often associated with obesity/overweight and physical inactivity, yet it is preventable. Increasing the disease burden are a further 2 million Australians with pre-diabetes who are at risk of developing type 2 diabetes (5).
What is the impact of poor glucose control?
Poor control of glucose levels risks the development of micro- and macro-vascular damage, which can result in heart disease, stroke, blindness, kidney failure and lower limb amputation (3, 6). The extent of the burden of these complications is shown in Figure 1 (3). Of particular concern is that only around half of Australians with diabetes achieve the general HbA1c (glycated haemoglobin) glycaemic target of 7% or less (7). HbA1c is the average blood glucose level over 3 months, however it does not provide insights on the extreme high and low glucose levels that people with diabetes may experience on a daily basis. Therefore, even individuals with an acceptable HbA1c result may be at risk of developing diabetes related complications if there is considerable out of range variability in their daily glucose levels (8).
Figure 1. Poorly controlled diabetes leads to complications
It’s not only about glucose levels
Diabetes is a complex chronic and progressive condition affecting people not only physically, but often also their cognitive, psychological, emotional and social well-being (9-11). Poorly controlled glucose levels can negatively impact cognitive function and daily activities (9), while the burden of managing diabetes may lead to emotional distress for affected individuals and their family/carers (11). People with diabetes are also twice as likely to suffer from depression compared to those without diabetes (10). Remaining motivated to manage their diabetes without ever having a break becomes a relentless challenge that can leave affected people frustrated and overwhelmed (10, 11). This may result in “diabetes burnout”, which manifests as self-destructive behaviours such as eating unhealthy food and administering estimated insulin doses without prior glucose testing in an attempt to ‘free’ themselves from the confines of their condition (12).
How do available self-glucose monitoring methods measure up?
A key aim of glucose monitoring is to keep glucose levels within a specified target range and so avoid the extreme highs and lows that can lead to acute and long-term complications (7, 8). Glucose monitoring also shows those with diabetes the effects of food intake, exercise, medications and other factors (e.g. illness) on their glucose levels. However, available self-monitoring methods may not be fulfilling their needs. Indeed, one may argue that these methods, which are invasive, serve as a constant reminder to people about their diabetes.
The most widely used glucose monitoring method is self-monitoring blood glucose (SMBG) or “finger stick” testing. However, many individuals are not performing SMBG as recommended, typically because it is invasive, painful, inconvenient, time consuming and tends to undermine their daily activities (12, 13). Indeed, a comprehensive review identified that people with type 2 diabetes not prescribed insulin fail to regularly monitor their blood glucose levels (15). Alternative systems such as flash glucose monitoring (FGM) and continuous glucose monitoring (CGM), while providing individuals with a more complete picture of their glucose levels, are still invasive. These technologies are also not readily accessible to many people with diabetes due to their lack of suitability (e.g. requires technical competence) and high cost, while calibration with finger sticks is still needed.
Is non-invasive glucose monitoring the answer?
Maintaining good control of glucose levels is essential for people with diabetes to stay healthy and prevent or reduce the risk of complications. Moreover, these individuals want to be in control of their diabetes rather than the condition controlling them. This presents a real opportunity for a glucose self-monitoring system that is non-invasive, accurate, painless, convenient and discrete with the ability to transmit data to their family/carers and healthcare providers (16). Such a system also has the potential to considerably improve adherence to self-monitoring which, in turn, would help to reduce the diabetes burden and associated healthcare system costs (16).
To this end, a key emerging technology is saliva based glucose detection, which presents an attractive and potentially more accurate, sensitive and low-cost alternative to available methods for measuring glucose levels. This is because saliva based technology offers non-invasive, painless and convenient sample collection with the ability to detect glucose concentrations 100 times lower than identified in blood (17,18). Glucose detection in saliva is a simple, discreet process involving a small disposable test strip impregnated with glucose oxidase, which is placed in the mouth. The glucose oxidase reacts with the glucose in saliva to ultimately produce an electrochemical signal that is subsequently processed by a handheld reader or smart device to produce a glucose level reading.
To have a non-invasive, painless, convenient and discreet method for monitoring glucose levels, ideally with data connectivity to inform family members, carers and healthcare providers, would be the ‘Holy Grail’ in diabetes management and prevention.
Fortunately, an innovative, first in class, saliva-based technology for monitoring glucose levels, which has all these attributes and is likely to be low cost, is on the horizon. Called the glucose biosensor system, it is expected this technology will go a long way in helping address the growing diabetes burden across the globe. For further details see Glucose Biosensor.
Figure 2. Image of salivary glucose biosensor
Can more be done beyond available glucose monitoring methods to manage and even prevent diabetes? To help affected individuals gain control over their diabetes? Absolutely.
Diabetes is a therapeutic area about which CRC is passionate. Based on our team’s solid medical affairs and market access expertise in this and many other therapeutic areas, we welcome the opportunity to plan and implement a wide range of initiatives in contributing to the commercial success of our pharma, biotech, device and other healthcare industry clients.
In an ideal world, healthcare professional (HCP) education about pharmaceutical and medical device therapies is always distinguishable from promotion. Yet the reality is that medical education and promotion can sometimes cross paths such that their distinction becomes blurred. Indeed, one could argue that medical education conducted by pharmaceutical and device companies is a form of promotion as the reality is that there is ultimately a product to sell. On the other hand, since the pharmaceutical/medical device company researched and/or developed the product, it can also be argued that the company is amongst those best placed to educate HCPs about that product.
Medical education and promotion are quite different activities:
However, when does the line between these two distinct activities become blurred? The following three cases, adjudicated by the Medicines Australia Code of Conduct Committee (“Committee”), help to shed some light.
Case 1. Selective data as medical education
Scientific or technical information provided to HCPs should be fair, accurate and balanced, particularly comparative information between therapies, to support clinical decision-making. Yet what if a pharmaceutical company’s Medical Liaison team was to distribute an email to HCPs containing selective excerpts of efficacy and safety data from a regulatory agency assessment report to favourably compare its therapy with a competitor product? This was the case where the selective extraction of data in an email was consequently considered by the Committee to be unfair, unbalanced and misleading to HCPs.(1) Being extracted data, it was without relevant context and omitted key report information about the competitor therapy, The selective email information thus did not accurately reflect the equivalent report content and would likely have the effect of discouraging use of the competitor therapy, while encouraging use of the company’s product. Although the full report was provided in the email, the Committee concluded the email content was promotional information and not medical education as it provided selective data to discredit the competitor therapy.(1)
Case 2. Off-label information as medical education
Companies are responsible for ensuring therapy content at medical educational meetings aligns with the approved Product Information and to brief HCP speakers accordingly when presenting at these events. However, at one meeting (one of a series of educational meetings sponsored by a pharmaceutical company) the international HCP speaker presented study data on the long-term use of a drug for up to 12 years, although its approved treatment duration was 12 weeks.(2) Moreover, the data presented was for a different compound of the drug moiety to that approved in Australia, which was indicated for a maximum of 12 weeks’ use. The Committee concluded the educational content focused on a product not available in Australia, although containing the same drug moiety, and would encourage off-label prescribing for long term use which, in turn, had potential safety implications for patients. In this case, educating on the long-term use of an unapproved compound of the same drug moiety was tantamount to off-label promotion of the long-term use and associated safety of the approved product in Australia.(2)
Case 3. Manufacturing tour as medical education
The primary objective of HCP attendance at company sponsored medical education events is to enhance medical knowledge and the quality use of medicines. Companies must be able to justify the event’s educational content and its relevance to HCP attendees’ area of expertise. However, would an overseas manufacturing facility tour organised (and sponsored) by a pharmaceutical or medical device company qualify as necessary HCP education? On the surface, one of two extremes could be argued – either it is education overkill or an example of promotion disguised as medical education.
Yet it was neither of these extremes in a case adjudicated by both the Medicines Australia Code of Conduct Committee and Appeals Committee where a pharmaceutical company had organised for a group of HCPs to visit its biotechnology manufacturing facility following their attendance at a nearby third party scientific meeting.(2) The tour aimed to provide HCPs experiential understanding of the manufacturing process – its complexities, challenges and quality standards – for a specific biological therapy by seeing it first-hand. This would help to build their confidence of the process, as well as knowledge of potential patient reactions to the therapy’s complex protein molecules. The HCPs would also benefit from interacting with the R&D and manufacturing process personnel, which in turn could benefit patients. The Appeals Committee accepted the appropriateness and relevance of the tour for these reasons and so overturned the Code of Conduct Committee’s view that the purpose was to promote the company’s biological product, encouraging HCPs to continue prescribing and recommending. Of relevance is that there was no biological substitute for the company’s product, while other companies had held similar manufacturing plant tours for HCPs in educating on the complexities of biological therapies.(2)
Erasing the blur
The above mentioned cases show that the line between medical education and promotion is not always clear. Rigorous scrutiny in the planning of medical educational activities and content – ideally via a quality control process involving various stakeholders who can provide multiple perspectives – is therefore important to minimise the risk, intentional or unintentional, that the education becomes, or is perceived to be, promotion.
These cases also illustrate the importance of context. In Case 1, the selective use of data emailed to HCPs, which was non-contextualised, showed how incomplete information can easily morph from education to promotion, whereby the data becomes distorted, biasing one therapy over another. In Case 2, where an educational meeting focused on the long-term treatment duration of an unapproved compound with the same drug moiety as the approved product indicated for short-term use, HCPs will likely be encouraged to prescribe the latter for long-term use. Whether this effect was inadvertent or not, the meeting’s educational value was consequently outweighed by the promotional goal. Case 3 shows that even when an educational activity is consistent with industry standards and benchmarks and there is a broader relevant context to justify it – in this example the need to provide HCPs experiential learning about a complex biologicals manufacturing process that could not realistically be provided another way – the (mis)perception of promotion disguised as education may still arise.
Medical education and promotion are both key activities conducted by pharmaceutical and medical device companies. Our dedicated Medical Affairs team at CRC is well equipped to help plan and implement a wide range of impactful, yet compliant educational and promotional review activities for healthcare industry clients, ensuring the line between medical education and promotion is clear.
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.
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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