Author: Julia Busch Edited by: Inês Barreiros
The pharmaceutical industry is in a crisis and has been heading towards it since before the world economy crash of 2008. This crisis is no news, nor is it going to be over soon and neither was it unexpected. It is not only a financial one, but also one for drug development strategies that industry, research and patients are facing.
The next decade will witness a lot of change everywhere in the world and likewise the pharmaceutical industry and the drug discovery process will have to change as well. The biggest challenge the pharmaceutical world faces has arisen out of the industry's biggest successes. For as long as this industry has existed it has been reliant on the income generated by sales of a small number of highly demanded substances, effective against common diseases and the exclusive right to produce and sell these substances. These blockbuster drugs come from an age of research when faith in endless innovation was prevalent. The financial security their sales generated nurtured the pharmaceutical industry into the powerful entities they are today, but also provided a false sense of security.
Gone are the days of when the next big discovery was to be found in a garden plant and all that was needed for a successful drug was to neutralise pain receptors or fight off bacteria. The ailments we are facing are more complex in nature, poorly understood, a cure difficult to design. The developed world will not be forever safe from antibiotic resistance and tropical diseases like malaria. The recent spread of Ebola and Zika have shown that research and industry have to rethink their priorities. The pharmaceutical industry has been focusing on high revenue, lifestyle related drugs to facilitate growth. The last decade of blockbuster drugs includes psychotropic drugs and cardiovascular disease prevention medicine.
These are the wells that are running dry now. The so-called patent cliff was reached in 2011 with losses including the likes of Lipitor (a lipid lowering agent used for prevention of heart disease) which brought Pfizer 5 billion dollars a year and the cliff continues on into 2017. Few new blockbuster candidates are on the horizon. A patent lasts for 20 years and on average, the development of a candidate compound to a marketable drug takes 10 years, leaving companies with a lag phase of discovery-to-market of a decade. Drugs like Lipitor come from a time when drug development was more affordable and the financial crisis had not yet struck. Development costs have skyrocketed in the last decade and companies initially tried to fight this by supporting less risky me-too-drugs and cutting down on their research into new target and drug discovery budget.
Development and financing decisions made 10 years ago are starting to catch up with the companies now in form of weak discovery pipelines. Despite the weak pipelines and the enormous increase in development cost, the annual approval rate of drugs by the Food and Drug Administration (FDA) has remained stable. This statistic reflects not a recovery process of the industry, but shows the compromises the FDA has been willing to make in turning the lengthy admissions process easier, to support the struggling industry.
Drug development has to become affordable again and there are a number of strategies companies are already adapting to overcome the challenges.
The strategies for some of the UK’s industry giants such as GlaxoSmithKlein, AstraZeneca and Shire, have been to go down different paths of innovation. All require restructuring and reinvestment. GSK, due to lose one fifth of its total sales with the expiry of the Advair patent in 2016, is diversifying its portfolio with heavy investment in emerging markets, consumer goods and the purchase of the Novartis vaccines division. Many smaller successes in various areas are meant to spread the risk and stabilise the company. AstraZeneca on the other hand are concentrating their resources on their cancer research pipeline and invest heavily in their next blockbuster candidates. Many companies have taken to merge with smaller biotechnology companies to support their weak development pipelines. Shire has chosen to acquire niche market developments and is focusing on products for ADHD, and they are discovering the benefits of investing in rare diseases.
These business decisions are temporary fixes. The bigger problem lies in the scientific discovery and development process of new drugs. The costs are the immediate symptom of a deeper problem. The future of affordable drug development has to lie in scientific innovation.
Even though the initial drug discovery process has become more difficult with more and more chemical space and straightforward targets already explored, the majority of the rising costs of development stem from human trials in phase two and three* at the end of the drug development process. One reason for this is an increase in requirements for new drugs. If a drug for a disease already exists on the market, a new candidate will have to surpass previous study results in phase two and three, which increases cost and the likelihood of failure. In addition, drug safety standards are stricter today. Failure is a big percentage of cost contribution, which means that especially failure in phase two and three trials have to be avoided.
There is currently no alternative to human trials, and rigorous testing is, after all, in the patient’s best interest. Avoiding end stage development failure of a drug candidate means improving the first stages of development and discovery. Improving a drug’s initial design to incorporate, for example, more advanced predictions of toxicity and bio-availability could reduce time and money spent on failing candidate molecules.
In an ideal world, efficient and side-effect free drugs would be invented on a drawing board. We would have a perfect understanding of the molecular mechanisms and systemic impact of the diseases we are attempting to cure. We would also know exactly which target a chemical is a perfect fit for and how to prevent the chemical from also interacting with other targets. We would fully understand what dosage is needed and be able to immediately design a compound that is easy to synthesise, has just the right solubility and is stable over decades in any condition.
Are we really that far off from the ideal world scenario? We already use conveniently fast and cost efficient computational drug design techniques to help predict some of these factors. The reliability of these methods has seen a huge surge in recent years and is expected to improve as programmes and computational power advance. Our scientific knowledge of the mechanisms of diseases is ever growing with academic research contributing to our understanding of cellular mechanisms and life itself. If industry and academic scientists could work closer together to bridge gaps of knowledge more directly and incorporate considerations from broader aspects of the systems in question into drug design, a purely design driven drug discovery process might be possible in the future.
Such academia-industry collaborations are currently in formation. It is a relatively new sort of relationship that has to be established and various extends of these partnerships are in a testing phase. Both the UK’s Medical Research Council and the Wellcome Trust fund such collaboration efforts. One hurdle to overcome in academia-industry relations is ‘opposing goals’. Both sides aim to find a cure for the disease, but what they want to get out of their successful research is fundamentally different. While the right to exclusively produce and sell the compound is paramount to a pharmaceutical company, an academic researcher gains access to funding through publishing far-reaching results.
An attempt at solving this conflict of interest would be an uncoupling of the two groups. This sounds counter-intuitive at first, since industry and academic research need to nourish each other to facilitate better knowledge exchange. The idea behind open source research associations, like the Structural Genomics Consortium or the Mario Negri Institute, is to generate specialised knowledge about interesting targets and drug candidates and make them openly accessible as quickly as possible. This way industrial researchers can pick up academic research insights as soon as available and develop the resulting ideas into fully-fledged products independently. This serves both the publish-or-perish culture of academic research and allows companies to keep their part of the development process exclusive. This approach relies heavily on an ideal transition of knowledge from the scientific journal article to industry.
Public domain projects likewise receive input from the pharmaceutical industry. The Open Source Malaria project was made possible through GSK opening up its hit datasets to researchers to proliferate the development of drugs for this neglected disease. Particularly, drug development for niche diseases could benefit from this approach. The project has seen very successful open source collaborations of researchers all over the world with transparent research updates. A last hurdle projects like this will have to tackle is finding partners to test promising candidates in clinical trials.
The future will see many advances that will make testing on living organisms safer if not obsolete. Biotechnology companies make up hubs of innovation, which is a breath of fresh air for the industry. Unconventional ideas have a chance to bring true innovation to research and industry within these independent hubs,. An example is an attempt to 3D print tumour cell clusters and organ-like cell cultures. This technology would open up a way to test systemic effects of drugs currently only observable in animal testing. Advances in analytical techniques will improve chemical synthesis processes and advanced screening robots with machine learning capabilities will make it possible to speed up and greatly optimise cell based screening and drug design pipelines.
Advances in drug development will, ultimately, deliver better drugs to the patients but there are other avenues of improvement that have to be pursued. The case of Exubera, an inhalable insulin, which was approved in 2006 but withdrawn from the market in 2007 for lack of demand, exemplifies one such avenue. The 2.8 billion dollar loss made through the misjudgement shows how important the needs and opinions of patients can be for the success of a drug. This is decidedly a factor that has been underestimated and will need to play a more prevalent role for future development. As the market and research become more competitive, patients will benefit from the pressure for excellent products and the exploration of niche markets.
Biotechnology companies are the emerging driving force of pharmaceutical development and scientific innovation in this era. Above all, closer collaborations between academia and industry are reforming the drug development process.
*The term 'Phase 2 trials' refers to the testing phase of a drug of interest on a small (around 100) group of individuals for side effects and dose determination. Phase 3 are when the drug is tested on a much larger (1000s) group of individuals.