**1. Introduction**

Science may be seen as something that is involved in measuring what a thing is not. Science may be about hypotheses where it may be a form of communication, which is in a constant flux, challenging earlier stated definitions. Because the hypothetical does not exist, we set limitations and perform measurements according to systematic methodology, that may then lead to understanding of possibilities. When enough views are examined to concern that what is observed is certain within as set of specifications, then we may have a better understanding of what a thing may be. Techniques that investigate copy number aberrations may be no different, they typically measure that a test sample is not equal to a control reference. Controls to assure quality are also similar, in that they typically aim to measure that a sample it not according to certain

standards. In practice, such standards may lead to empirically defined acceptance criteria, that could for instance be used to determine that the DNA concentration of a sample is not within the expected range. These ranges or acceptance criteria are often initially determined by predefined logic, but they may be adjusted following evaluation of discernable observations that via empirical logic may lead increased accuracy. Laws may be similar in origin as well; in that they typically focus on what should not be done, though they not as often may be adjusted based on empirical logic. Consequently, conscious law may invite its subordinates to examine "*what is too much*," but often fails to provide understanding and transparency about its purpose.

When developing software that may have a medical purpose, we may find ourselves embroiled in the practical application of regulations that are currently being enforced, such as the IVDR. We may also find ourselves in contact with these regulations, for instance via implementations of these standards into company policy. While standardization certainly has positive effects: to the quality of care, the consistency of outcomes and reducing costs, in other areas it may be experienced as impeding endeavor. Research may be such an area where regulations based on predefined logic block innovation. Innovation in science may leads to progressive leaps by discovery via intuitive understanding of discernable observations. Understanding of possibilities may for instance have led to the introduction of Multiplex Ligation-dependent Probe Amplification (MLPA) in 2002 [1]. When developing devices such as software, that may have a medical purpose, we may find ourselves stuck in the morasses of regulations as well. These standards and their implementation in organizations typically tell us what to do, or rather what we should not do, but they do not seem to focus on explaining how we should get things done. One-to-one implementations of regulations often lead to documentation cultures where the intended purpose of implemented regulations may have been lost altogether.

In this section, we like to discuss and consider strategies involved in the development of software that may or may not lead to a product with a medical purpose. We will try to use the new IVDR standard to provide guidance and consider obstacles that may be prevalent in commercial endeavor. Can we develop high quality products and fulfill the requirements of the IVDR harmoniously? By evaluation of the different pieces that make up the IVDR and observation in scientific writing of the effects of its implementation in practice, we will attempt a discussion to see if the IVDR really requires huge piles of documents and rigid structures. Perhaps the IVDR does value research and innovation, but it just takes time to understand the law, by gaining experience applying the law. We may then also learn how such standards are to be implemented in crossover design, where research and diagnostic are very near to each other such as clinical trials. Finally, we will discuss a methodology to quality assurance when developing software, that is designed to react quickly to changes, which tends to be essential in a dynamic field, while also upholding IVDR standards for quality assurance with patient safety as continuous mindset. We will then use this methodology and apply it in a few examples on a software project currently in development, that involves the analysis of digital Multiplex Ligation-dependent Probe Amplification (digitalMLPA) data to establish chromosomal aberrations [2].

#### **2. Barriers to effective implementation of regulations**

Since the release of MLPA, the technique has been become a widely used tool for copy number detection and methylation status analysis on DNA samples in both a

#### *Quality Assurance When Developing Software with a Medical Purpose DOI: http://dx.doi.org/10.5772/intechopen.113389*

research and diagnostic setting [3]. The increased use of MLPA in diagnostics, for instance where detection of copy number variation has prognostics significance [4, 5] has led to increased demands for more diverse products, as well as their certifications for In-Vitro Diagnostic (IVD) usage. MLPA has great properties to be used in routine applications and for screening [6] to detect, treat or prevent many more serious early-onset health conditions, such as when applied for newborn screening for Spinal Muscular Atrophy (SMA) [7]. Conventional MLPA reactions are however limited to about 40 targets, and thus broad-spectrum screening may need many different conventional kits, while some diseases may even need multiple kits for a single diagnosis, such as with Duchenne Muscular Dystrophy (DMD) [8]. Also, investigation of complex tumors, such as Multiple Myeloma (MM) often requires a more detailed mapping of Copy Number Alterations (CNAs). To respond to this demand, MRC Holland (Amsterdam, the Netherlands) developed digitalMLPA, a technique combining MLPA and Next-Generation Sequencing (NGS), to detect disease-related CNAs. This technique combines the advantages of NGS and MLPA and has the potential to include up to 1000 probes in a single reaction [2] requiring only a minimum of 20 ng. digitalMLPA already showed that the method is reliable in different studies and can provide comprehensive profiling of disease-related unbalanced genetic aberrations as well as to detect specific point mutations. Due to the ability to focus on a specific range of targets, relative low cost, and short turn-around time [9], digitalMLPA could represent a valuable addition to diagnostics and screening tests.

The increase in demand to product variation and product accreditation may be seen with more products in the biochemical arena and urges companies that are involved in manufacturing to upscale. The departments that are involved in production, support, testing, sales, and shipping for instance will all need to expand. Next to that, the demand for Conformité Européenne (CE) marked products requires accreditation, which often requires further expansion of departments that are involved in quality assurance, quality control and regulatory affairs, though we may find an overhead for nearly all departments, including software development. Today, patient safety is an increased priority to both patients, providers, payers, and policy makers alike [10]. This shift requires also changes to production systems that demand higher quality standards, as well as continuity in performance and delivery. For European countries the European Union rules enforces such standards by stating that medical devices or equipment intended for a medical purpose must undergo a conformity assessment to demonstrate they meet legal requirements to ensure they are safe and perform as intended. "Software is a medical device as well if the manufacturer has made the software for medical use…," states the website of the Dutch Government. For medical devices the Medical Devices Act (MDA) becomes applicable, and it is then important to determine in which class a device falls if one wants to continue in that direction. Depending on the class, certain requirements will apply for accreditation. This may for instance determine if the manufacturer may obtain a CE marking directly or whether an external audit need to be performed by a competent authority. Under the new Medical Device Regulation (MDR) the rules will be even stricter with regards to classification of a medical device and software has a high chance of being classified as a class IIa or higher. Though the European Union enforces such standards, there are no EU-harmonized rules governing the pricing and reimbursement of medical devices, member states are therefore responsible for establishing national social security schemes, including healthcare policies to promote the financial stability of their healthcare insurance systems [11]. One way of promoting social security systems is by expanding public health insurance aiming to reduce the risk of expenditures and

improving health outcomes [12]. As a result, some healthcare providers in certain member states may only reimburse medical expenses in case the used products are CE marked. But in a commercial environment there may not always be interest to invest great amounts of time and money to obtain such markings, if a product is not economically viable to generate profit, for instance in the case of product intended to diagnose rare diseases. Even if a product for a rare disease is successfully developed, obtaining reimbursement from healthcare systems can be challenging. Pricing and reimbursement decisions often consider the cost-effectiveness of treatments, and with a limited patient population, it can be difficult to demonstrate cost-effectiveness compared to more prevalent conditions.

As regulations grow in scope and impact, understanding their precise role, effects, and limitations will become increasingly important for companies that make products and the hospitals using them. Especially for health providers there is a growing demand for transparency with the patient and the public in terms of how treatment decisions are made and when and why errors and unexpected outcomes occur [12]. So, while regulation may potentially provide a variety of benefits for instance in terms of maintaining safety and quality in patient care. At the same time, we may recognize that due to the extent, variability, and fragmentation of the regulatory system it is hard for regulations to act effectively, and it places a massive burden on provider organizations [13]. Design and production of biotechnological products and its related software may be an industry that is best understood by those who deliver it. It may thus be questionable whether there are competent authorities that have the expertise to provide dedicated investigations into quality systems that target specific areas where professionals are scarce to be found. Next to that with the new regulation being far more comprehensive than IVDD and it will require an estimated 80–90% of IVDs on the EU market to undergo a conformity assessment by a Notified Body (NB) [14]. Will there even be enough NBs to handle the increasing demands from the industry? When competent authorities cannot provide a dedicated system evaluation that provides insight into the effectiveness of such a system, then what will be their focus? Is it enough to merely evaluate that all generic protocols are in place and that version numbers on protocols and check forms match, or will they allow the profession to set the appropriate standards because it is best positioned to determined what is needed to improve safety.

Even if the profession itself may determine its protocol, then still the question arises if fast growing industries are equipped to effectively apply fast changing regulations internally while also expanding its internal machinery, especially when governments quickly apply new rules but do not have a framework yet in place to provide support and understanding on those legislations. The drive for companies to comply certainly exist, since care providers that use their products often may only reimburse their spendings in case the products used are CE marked. The drive to comply may therefore become a goal on its own and often is resolved within companies by expanding procedures and regulations. Clinical research may be an area that is being subjected by increasing regulation, research ethics committees and research and development offices are responding to social and political pressures that may lead to compromising clinical care [15].

Since progress must continue and patient care comes first, we may see in the industry that care providers find ways around the jungle of regulations to provide dedicated care for their patients. At the same time, we may see that in certain countries, individuals working in the industry completely shy away from care positions altogether where following regulations have overtaken the main priority above patient care. Shortages in dedicated trained staff are currently seen in all health care branches [16],

#### *Quality Assurance When Developing Software with a Medical Purpose DOI: http://dx.doi.org/10.5772/intechopen.113389*

subjecting patients to insufficient care, delays, and medical errors. Adequate staffing is essential for the delivery of quality care and safe nurse working conditions, which in turn are associated with better patient outcomes [17], A similar trend may be felt in research where overregulation is counterproductive, as it tends to discourage researchers. In other areas of endeavor such as software development or areas of technical production, companies may even outsource the required piles of papers needed to be sent to competent authorities. Outsourcing may have a negative effect, as it increases the gap between different entities involved in quality assurance, blocking harmonization of processes and feedback into design and production.

Next to that standards are often implemented by individuals that do not have an active role in the processes to which they apply. If we need to comply, then we may want to comply to patient safety and we would need to understand on an individual level how these standards may be implemented to further that goal. Enforcement to comply to regulation for its own sake may lead to atrophy of consciousness [18], as well as being a hinderance in intuitive progression via discovery. Why would this be any different when working in the medical sector where we are dealing with the health and lives of individuals? Caution comes from wisdom, not from fear (of noncompliance). Prudence requires awareness of the pitfalls to be avoided. Controls that are a threat to awareness, are a threat to patient safety and public health and therefore must be investigated on their effectiveness and improved or removed. Governments and managers ought to aid developers in providing the tools they need to properly perform the task at hand and to be established with minimal risks to patient safety. They may want to attempt to oversee and provide recommendations or key bits of information that leads to harmonization of different areas of endeavor rather than to disperse and divide. Consciousness itself may need to be our highest priority in establishing patient safety when developing products that are used as medical devices. Consciousness itself is self-regulating [19] and self-correcting which may often not be the case for ever-expanding systems that may become mostly self-serving. How can we then navigate through the morasses of regulations as developers while focusing on progress and prioritizing patient safety?

As an individual it seems irresponsible to attempt to vanquish the negative of regulation as it may lead to reductionism ignoring the social values which clearly may also play an important role in science [20]. Instead, we may apply the positive norm opportunely which practically exists only as spirit of the determining lawmaker, spirit which gives formal seriousness to some requirements which she/he considers rightful according to asset of values which contains the requirements and the interests historically determined [21]. As a scientist it may be easy to ignore the intangible and through creativity and logic deduction, dualistically reason that our intentions are good, thus as such we may avoid in clear consciousness, attempting to get deeply acquainted with new regulations. We may however also attempt to resolve the issue as a scientist and stimulate awareness and aim to create procedures that attends toward self-correction and allowing natural evolution of these procedures while considering both the product or goal and the human factor.

We could even draw this concern further and wonder why authorities themselves do not focus more on investigating legal consciousness, which is an area that can be defined as the attempt to make sense of the decisions of applicants. If even in areas of welfare, it may be clear that applicants 'know the law' and (ab-)use it [22], such may also be expected in other areas. In the end, when considering standards and regulations, as well as most integer companies, we may consider that they both aim for the same, with respect to patient safety. The new IVDR for instance, increases

its focus on measuring effectiveness, accurate description and strengthening post marked research, all of which have been introduced for the benefit of the patient. We may also see that agencies are set in place to measure the real-world pertinence and relative clinical effectiveness of the IVDR [23]. We may further see that the IVDR as a key point aims to preserve innovation, safeguards quality, safety, and accessibility of innovative diagnostics.

When we want to design and develop medical software in a time of fast changing technologies and regulations, where demand often exceeds availability, whether related to development of products, or being knowledgeable about the exact meaning of new regulations, we may often just want to move forward and gain experience along the way if we keep our intentions always to act to the benefit of the patient. Manufacturers must strive to do the best as is possible with the information available at that time and evolve along the way as more information becomes available. Prudence, or acting in accord with what is real, is crucial when developing anything that is used in diagnosis, but we must also strive to have patience and understanding when working in teams. Stress, due to high workloads and unrealistic deadlines, rarely is an indicator that results in improvement of patient care [24] and productivity on the work floor. The virtues that we extent to patients, to some extend must as such also be applied to staff, disposing both parties to act well in relation to the end of medicine. Next to this, we may state that virtues of different people involved in medicine may be correlated with the goals of purposes of the medical encounter [25]. However, without a common agreement about goals and values, virtue theory cannot survive in health care [26]. In practice we may be more willing to get into a position of agreement, when the path ahead becomes clearer, and focus may be placed on well-defined shared objectives.
