A Guest Blog by Jesús Zurdo Ph.D., Head of Innovation, Biopharmaceutical Development at Lonza

Challenges Faced by the Pharma Industry

Last year a post made by Forbes took social media platforms by storm by suggesting a new (and some believe, more realistic) way of calculating the true cost of developing new drugs. The results were staggering; with some companies portrayed to spend, on average, between four and eleven billion US dollars for every new therapeutic treatment eventually commercialised (1).

The reason for this? Fundamentally an extraordinarily high rate of drug failure. Approximately 90% of drug candidates will fail during their clinical development stages; maybe over 99% if one includes preclinical stages of development as well (2). The ‘valley of death’ in pharmaceutical development spans late discovery through early clinical development. It is substantially longer and more deadly than in other industries and, over the years, has been the end of many promising therapeutic approaches and the companies developing them. Developing new therapeutics is more than ever becoming a business for the ‘brave’.

The result? A dwindling pipeline of new drugs coming up into the market with a growing price tag. A recent paper published in Blood, by a group of over a hundred oncology experts, made headlines by claiming that the exorbitant prices charged for some of the key oncology drugs could be out of reach for a substantial number of patients, and in the medium and long run, will not be affordable to either payers or patients (3). This shines a light on a growing concern in the industry: even for those few products that are eventually registered, payer constraints will have a significant impact on the reimbursement of new therapeutics (4). The unsustainability of this business model is clear to everyone. On one hand, the current paradigm for drug development relies primarily in the development of blockbuster drugs to soak up the enormous level of failure and high costs associated with it. On the other, neither payers nor patients will be able to keep footing an always escalating healthcare bill, particularly when healthcare costs are already the primary cause of bankruptcy in the US(5,6).
The main cause of this issue is a very long, highly inefficient and inflexible drug development process. One of the suggested reasons for such a low efficiency is the fact that pharmaceutical development uses a rigid hierarchical model that does not allow moving to the next level in development until the previous one has been fully completed. In turn, this hierarchical model has historically favoured the generation of fully independent functions that are linked to specific stages of development (7). These functional ‘silos’ make it very difficult to implement an integrated approach to drug development and are a significant obstacle to new initiatives, such as translational medicine.

A Potential Risk for Everyone. The Cost of Failure.

The tragic consequence of this fragmented approach to drug development is that elements that are essential for the success of new therapeutics can be left out during the design and selection of drug candidates. These gaps can cause significant problems that are often only discovered quite late in development. And can cause, at their best, severe delays and require additional investment or, in worse cases, trigger the discontinuation of an entire drug development programme.

In this context, the financial impact of preclinical and clinical attrition is often overlooked. From a biopharmaceutical development perspective, a significant financial commitment is made for the development of a qualified manufacturing process well before the product has even been cleared for its assessment in clinical trials. In fact, fully commercially defined processes are usually developed for prototypes (drug candidates) that, in a majority of cases, will fail at some point during their development cycle. This investment is obviously at risk subject to success at various preclinical and clinical development stages. In addition, potential manufacturing or safety concerns can also have a major financial impact in several other ways:

• Extend already long development timelines (reducing market exclusivity period)
• Require additional investment in process development, repeated work or implementation of corrective measures.
• Stop a programme in its tracks, preventing it from entering clinical development.
• Cause the failure of a programme during clinical trials, requiring a repeat of the trials or prevent final commercial approval due to quality or safety concerns.

These issues can be worth many millions in lost opportunities or investments lacking a return. In this context, it is desirable to select or design a successful candidate early on by asking the right questions.

Why Do Drugs Fail During Development?

The reasons behind drug failure during development remain highly debated and elusive, primarily due to the lack of detailed and up-to-date data on the subject. Still, a publication from Kola and Landis covering drug development between 1980 and 2000 (8) and partial analyses published since, suggest a collection of different causes for drug attrition. These include purely commercial or strategic issues, a lack of efficacy, problems with bioavailability or pharmacology, safety (toxicology, immunogenicity, etc.) or manufacturing and quality issues.

The failure of new drug candidates during later stages of clinical development is primarily due to shortcomings related to the expected biological activity, efficacy, pharmacology as well as commercial reasons. However, early attrition observed during preclinical and initial stages of clinical development fundamentally reside in problems with manufacturing, stability, pharmacology or safety issues.

The Three Pillars of Developability

Any new therapeutic candidate needs to answer the following questions: Can it be made (at the right cost)? Is stable? Can it be formulated for intended route of administration? Is it safe to patients? Can it access the desired tissue at the required dose for the required time? Will it exert the desired biological activity and show adequate effectiveness?

Developability looks at the different aspects that confer a given therapeutic candidate its desired characteristics in three main categories:

1. Manufacturability: productivity (yield), stability of the product, degradation and impurity profile, formulability
2. Safety: immunogenicity, immunotoxicology, specificity, etc.
3. Pharmacology / Biological Activity: bioavailability, half-life, formulability for intended route of administration, immunomodulation, etc.

Interestingly all these categories are related. For example, low stability can cause aggregation and thus safety issues (immunogenicity) and the ability of a product to be formulated for a specific route of administration can have indeed an important impact in the bioavailability and pharmacology (and by extension the efficacy) of a given candidate. For a review of the subject of developability, please go to (9,10).

Developability. A Three-Stage Process to Implementing a ‘True’ Quality by Design (QbD)

Developability assessment can be considered a truly integrative approach to Quality by Design (QbD) methodologies. Developability is not about listing every single type of problem that can negatively impact a given therapeutic candidate, but about assessing and managing risk by identifying the most significant risk factors, and implementing adequate corrective measures.

Traditional implementation of QbD strategies in biopharmaceutical manufacturing has primarily focused on process validation and process robustness. This practice ignores perhaps the single most important aspect of ‘designing’ product quality: the process of designing and optimising desired quality attributes in the molecular structure of a given therapeutic product.

Developability can be applied to early de-risking and seamlessly integrated with discovery and process development activities. A developability assessment programme consists of three different stages:

1. Risk Assessment

The simplest and most cost-effective way of assessing risk is by implementing computational approaches able to predict specific developability features by using the sequence of the biopharmaceutical candidates as single input. These methodologies can have an extraordinarily high throughput and are relatively simple to implement.

Still the probability of occurrence of a given event (i.e. a degradation pathway) must be balanced by its impact (i.e. the process, biological or clinical consequence if this event ever occurred). The combination of the two can provide a measure of the ’criticality’ of the event and suggest whether it is advisable to introduce a corrective course of action (mitigation strategy) for this event. This type of approach fits well with traditional RMA (risk mitigation assessment) utilised in QbD strategies (11).

Criticality = Probability of Occurrence x Impact

2. Implementing a risk-mitigation strategy. Select alternative candidate / re-design candidate / modify process

Predicting potential problems serves no purpose if it is not accompanied by adequate corrective actions or mitigation strategies to address them. Depending on where in the process the risk assessment has taken place there are different courses of action that can be considered. When process development (i.e. cell line development) has not yet started, two different routes can be taken: (a) selecting alternative candidates with more favourable risk fingerprint, and (b) re-design a candidate to correct those issues identified in the risk assessment stage (12).

Once the product has already been taken into process development, or in cases where re-engineering is not an option, process-related interventions can help ameliorate the behaviour of a given product. Strategies ranging from screening larger numbers of clones during cell-line development to utilisation of specific downstream process conditions to minimise degradation pathways or introduction of more stringent purification protocols to reduce aggregated species are amongst the different approaches that could be potentially explored.

3. Validation of course of action

The developability risk-mitigation cycle is finished by completing appropriate validation studies. For example, in the case of immunogenicity of biopharmaceuticals, candidates can be re-engineered to eliminate the occurrence of specific T-cell epitopes in the sequence and then tested using relevant cell-based assays that make use of blood samples from human donors. This approach makes it possible to assess the impact of different allotypes or disease background in the observed response.

Conclusion and Future Trends

In summary, developability assessment can be defined as a way of implementing QbD methodologies early in candidate development. Incorporating this assessment introduces quality risk management (QRM) to address aspects of product design which contribute to manufacturing and safety concerns that could ultimately impact the success of a new therapeutic candidate.

Is developability introducing additional work and therefore slowing down development? In fact, quite the opposite is true. The purpose of introducing a developability assessment very early on in development (during lead design, selection and optimisation) is to remove bias in decision making by incorporating criteria that will be important in the eventual success of a drug candidate. This could potentially reduce the time spent to thoroughly validate the robustness of processes by making them more predictable; potentially resulting in a smoother path for drug development. It will also help to prevent unwanted ‘surprises’ that could derail or at the very least delay progression to the clinic.

Such an approach should not be restricted to small molecules or biopharmaceuticals. New medical platforms such as Cell Therapy could also benefit from the implementation of early risk assessment approaches to increase the robustness of product and process early on in development. This would help to develop a smoother path toward commercialisation which is largely absent in most of the products currently in development.