Biomedical Market Leaders Learning to thrive

THREE FORMS OF KNOWLEDGE

Knowledge is more than information. It is the actionable understanding of a situation. Three kinds of knowledge enable action: Declarative knowledge, who or what something is. For example, we may or may not know the market shares in a therapy area or the organisational structure of a healthcare system Causal knowledge, what gives rise to a situation. For example, we may or may not know what causes the adoption of a new product to vary between accounts Procedural knowledge, how something happens. For example, we may or may not know how market access is achieved in a given situation.

than other companies? My research has studied this for many years and, in the following paragraphs, I distil it down to a few, actionable lessons.

First, admit ignorance

The journey to knowledge begins with agreeing what the firm does not know but needs to. That knowledge comes in three forms (see box 1) and learning begins with defining what kind of knowledge needs to be created. Is it declarative (e.g., What are the primary issues facing a clinical speciality?) or causal (e.g., Why do some patients not adhere to treatment?) or procedural (e.g. How do professionals choose between treatment options?). In practice, many firms collect information habitually but not reflectively, without thinking about what they are trying to learn. But, in my research, the ability to identify and admit to critical knowledge gaps is characteristic of learning organisations. To do so requires two component capabilities, first an analytical facility to spot the gap and second the cultural knack to avoid blaming. Firms in which admitting ignorance is a culturally unacceptable, blameworthy fault are very unlikely to learn or endure in a changing market.

Choose your weapon

The task of creating knowledge has been usefully compared to cooking. There are many ways to cook a meal and the method you adopt depends on what ingredients you have and what it is you want to prepare. When organisations learn, their “recipe” is shaped by the kind of knowledge they want create and the data and information “ingredients” they have available. That said, there are three main ways — deduction, induction, and abduction — of turning those ingredients into either declarative, causal or procedural knowledge. Although different functions and professions tend to prefer one way of “cooking” information over the other, it is simplistic to judge them as better or worse approaches. Organisational learning is pragmatic, meaning the best approach is the one that works in a given situation.

Deductive learning

When market change is clear and measurable, and the goal is to understand that change, then deductive learning is usually the best method. This involves proposing an explanation for the change and developing a hypothesis from that explanation. For example, if the market share of a premium-priced therapy is declining, one obvious explanation is that payers are switching to lower-priced options. This leads to the hypothesis that if price is the explanation, then the shares of lowerpriced equivalents should grow at the expense of high-price products. When the data supports that hypothesis, the putative explanation is upheld and becomes new, causal knowledge about how the market works. If, however, the data shows other patterns, such as shift to an equal-priced rival, then other, non-price explanations are needed and a new cycle of hypothesis testing is needed.

Deductive learning is the most obvious learning method. It is the basis of most scientific methodologies. But it is much less common in biomedical markets than you might expect. In part, this is because it is hard to isolate one variable and control for others. Just as often, however, deductive learning is feasible but managers are happier to have faith in their long-held, subjective beliefs rather than to risk them being proven false.

Inductive learning

When market change is messy and hard data is unavailable, and the goal is to unravel what is happening, then inductive learning is the preferred method. Less structured than deductive learning, induction can appear structure-less when, in fact, its process is implicit. For example, prescriber behavioural issues such as adherence to patient pathways can be studied by exploring the experience of multiple prescribers. By structuring that exploration into episodes, such as when adherence persisted or failed, or into crosstherapy comparison matrices within the same group of prescribers, patterns are more likely to emerge. In this example, the research might induce that adherence is inversely proportional to experience and self-confidence, an example of new declarative knowledge. Induction can be a richer, more insightful method than deduction but it is vulnerable to cognitive biases and method design needs to guard against that.

Inductive learning is the most common learning method amongst executives. But because it is pervasive and often implicit it is often not even recognised as a learning method. By recognising when they are inducing new knowledge, managers can make the process explicit, more structured and more effective.

Abductive learning

Between deduction, which tests existing thinking, and induction, which draws out new ideas, lies abduction, which works well when multiple views of the world vie for acceptance. For example, why market access decisions vary between countries

might be explained by rational, quantitative decision making, by variations between country’s health systems or by irrational decision processes, such as internal politics. In this situation, some facts, including decisions and explicit decision processes, are known but other facts, such as internal dissent and implicit decision mechanisms are not. This uneven mix of information ingredients favours abductive learning, which might be best described as the “best fit” method. In this example, abductive learning would start with halfformed hypotheses such as: • If market access were rational, we would expect to see… • If market access were irrational, we would expect to see… • If market access were country-dependent, we would expect to see….

With each hypothesis completed by a description of what facts would fit each explanation.

These tentative hypotheses would then be compared to the findings of structured, inductive methods, such as comparisons of different cases and interviews with decision makers. The hypothesis whose prediction most closely matches the inductive observations is the most likely to be true. In this example, our research found that market access is “boundedly rational”, that is it was rational within the specific context of the country. This combination of two explanations was new insight into how market access decisions are made and is an example of procedural knowledge.

Abductive learning is, in many market situations, the most powerful learning method, yielding actionable insight into important and messy situations. But it is also the method that requires most skill. Deduction requires a systematic approach and induction demands a degree of intuition and sensitivity to the data. Abduction requires a systematic approach, sensitive intuition and the ability to allow rival explanations to compete fairly. When abduction fails, it is rarely the method at fault. More often, it is because some internal political faction identifies with one explanation or another or because firms prefer to rush to easy but unsubstantiated conclusions.

Mixing it up

Inductive, deductive, and abductive learning approaches are not mutually exclusive. They can and should be applied in the same organisation at different times or to different knowledge gaps. But, powerful as they are, sometimes none of the three approaches alone is sufficient. This is the case for the most problematic knowledge gaps, those that start from very limited understanding but which are critical to commercial success. For example, what is the segmentation in this market (declarative), what causes segments’ different behaviours (causal) and how does each segment reach their decision (procedural).

In such cases, a mixed-method approach is usually required, which means using more than one learning method but combining them for complementarity. In our market segmentation case, for example, we might begin with inductive methods to understand the motivations that underlie segmentation, deductive methods to find the causes of their behavioural difference and abductive methods to unravel their decision processes. The three methods can be used to build on each other in stages, known as a sequential mixed-method approach, or independently to verify or “triangulate” each other, which is known as a convergent mixed-method approach. Predictably, mixed methods approaches require more resources and demand more skill than pure, single-method approaches but they tend to produce better answers to harder questions. As in everything else, the quality and quantity of organisational learning is proportional to the effort applied to it.

Ignorance is expensive

Our rapidly changing marketplace makes it more necessary than ever for biomedical companies to learn and to use their new knowledge to sustain their competitive advantage. The exemplar companies in our industry -those that persist on the top company lists for decades - pride themselves on their ability to do this. Yet, at the same time, those market changes places greater pressure on those individuals who must lead organisational learning. Buried under an avalanche of data and armed with evermore powerful information technology options, it is tempting to rely on analysis, chopping up our data in ever more arcane ways. But analysis alone never leads to learning. Any effective approach to learning relies on synthesis, the combination of different sources of information. Inductive, deductive, abductive and mixed-methods are, like cooking, different ways to combine information and whilst analytically dicing the individual ingredients ever more finely has some value it rarely creates new knowledge.

The ultimate lesson from my research then is that organisational learning is essential to long-term survival in a changing market. The learning processes it requires are undoubtedly more difficult and more expensive than the datacrunching that replaces learning in some, lesser firms. But, as the saying goes, if you think knowledge is expensive, you should try ignorance.

AUTHOR BIO

Brian D Smith is a world-recognised authority on the evolution of the life sciences industry. He welcomes comments and questions at brian. smith@pragmedic.com

Bachem

Expanding into oligonucleotides

Torsten Wöhr, Head of Oligonucleotides, Bachem AG, Switzerland

The global market for oligonucleotide therapeutics is expanding rapidly. What is Bachem’s strategy in entering this competitive environment?

I think it is important for our customers to understand that the decision of the Bachem leadership to enter the field of oligonucleotide manufacturing was well-prepared and ultimately taken in line with the company’s long-term growth plan.

We are operative since 2019 and are gradually expanding our expert resource pool, capabilities and capacity for oligonucleotides.

We have been lucky to forge strong partnerships on the customer as well as on the supplier side and have been able to hire great oligonucleotide chemists to accelerate our organisational learning.

Despite having set ambitious goals we go step by step. Having said that, more and more we are shifting our focus from closing the oligo-specific technology gap to building a solid foundation for future growth.

Our large-scale facility will come online later in 2021. We took the time to thoughtfully design an equipment train featuring some innovative engineering solutions for increased utilisation flexibility and improved process control.

Then, later on our way to become a first-choice manufacturer for oligonucleotides, we hope to make our own contributions to advancing the drug class by making oligonucleotide API production more scalable and cost-effective.

The CMO environment, in particular for oligonucleotides, is developing quickly. How do you see your chances of success and what do you think are the major hurdles?

The progress in oligonucleotide-based drug development directly translates into a growing number of granted marketing authorisations. We actually might be seeing additional approvals before the end of the year. In addition, there is a strong interest in the therapeutic application of antisense technology and non-coding RNA biology, which is reflected in an ever growing number of clinical programs in operation and in a global project portfolio that is spreading across a broader range of indications.

We therefore anticipate the demand for oligonucleotide custom manufacturing services to remain strong in the foreseeable future.

As for challenges: mastering oligonucleotide chemistry is not trivial, and building a track record of successfully completed scale-up projects is another major hurdle for every CMO entering the market.

In addition, building large-scale manufacturing facilities for oligonucleotides, meaning facilities with an output of 1-Mol per batch or more, is very expensive. At Bachem, a sizeable CAPEX budget has been granted to purchase special equipment and to build the necessary infrastructure.

Finally, almost the entire equipment train is custom-built. It is important to get the design details right, ideally on the first pass. We are lucky to have a strong engineering team on site to support these critical activities.

What are the major technical challenges for the production of oligonucleotide therapeutics? Where can Bachem benefit from their expertise in peptide synthesis?

Similar to peptides, the manufacture of oligonucleotides requires expert knowledge in solidphase synthesis and protecting group chemistry. Downstream processing typically includes purification by chromatography and isolation by ultra/diafiltration techniques, precipitation and finally lyophilisation. The manufacture of peptide APIs follows the same basic principle. And it is the core technology Bachem has developed over decades.

Still, there are important differences between peptides and oligonucleotides. The synthesis in flow-through columns consumes large volumes of solvents and reagents for which our facility infrastructure will be appropriately expanded.

Furthermore, oligonucleotides are negatively charged and highly water soluble, requiring the handling of aqueous solutions throughout the entire downstream process.

And let’s not forget that oligonucleotide APIs, especially double stranded entities, are considerably larger then peptides and pose challenges also from an analytical point of view.

Overall, it is fair to say that our peptide manufacturing background and our analytical capabilities are certainly very helpful in our quest to build a successful oligonucleotide business.

COVID-19 exposes the weak links in the pharma supply chain. How has Coronavirus affected Bachem and your oligonucleotide development plans?

Indeed, these are challenging times. COVID-19 affects all of us on a personal level, in our daily work life and social interactions.

Early on in the pandemic, Bachem received essential business status from the Swiss authorities, and we remain committed to our partners and patients, who depend on Bachem’s products and an uninterrupted drug supply.

Bachem’s corona task force monitors the COVID19 pandemic closely and implements appropriate measures in a proactive way. In addition, employees are repeatedly trained in preventing infections and reminded not to become complacent in the process.

So far the virus has not impacted Bachem’s ability to produce, and so our oligonucleotide program is still on track. Fingers crossed that we continue navigating this situation successfully and can make a contribution in battling COVID-19.

Torsten Wöhr joined Bachem‘s Sales and Business Development team in 2017 to lead the company’s business with commercial products. In 2019 he accepted his current role to start up Bachem’s oligonucleotide program offering CMC development and manufacturing services for oligonucleotide drug substances. Torsten has more than 20 years of experience in customer-facing roles for chemical contract manufacturing (pharma/biotech) and life sciences companies. He studied biochemistry/molecular biology at the Swiss Federal Institute of Technology in Zürich (ETHZ) and obtained his doctorate in bio-organic chemistry from the University of Lausanne. He also holds a post-graduate degree in Industrial Engineering and General Management from ETHZ.

AUTHOR BIO

Bachem is a leading, innovation-driven company specialising in the development and manufacture of peptides and oligonucleotides. With 50 years of experience and expertise Bachem provides products for research, clinical development and commercial application to pharmaceutical and biotechnology companies worldwide and offers a comprehensive range of services. www.bachem.com

Brexit and Pharmacovigilance

Where may pharmaceutical companies go? What may happen to sick people should medicinal products suddenly not be available owing to Brexit? Some 45 The United Kingdom decided to leave the European Union; million patient packs go to the European this ‘Brexit’ impacts pharmaceutical companies and their Pharmacovigilance systems in the UK and EU. This article Union (EU) from the United Kingdom (UK) every month, with a further 37 million patient packs moving from the describes the consequences for Marketing Authorisations, for EU to the UK. instance ICSRs, aggregate reports, signal / risk management, On 23 June 2016, the UK, together the QPPV and the PSMF. Pharmaceutical companies need to with the British Overseas Territory of be prepared for the results of the ongoing negotiations between the political stakeholders, which will detail future processes Gibraltar, voted with a 51.9 per cent majority to leave the EU. Subsequently, the UK government initiated the official and needed changes for the pharmaceutical companies. EU withdrawal process by triggering Article 50 of the Lisbon treaty. The