Re-engineering pharmaceutical research for better patient outcomes

A so-called ‘productivity crisis’ has been ascribed to the pharmaceutical research and development industry. Despite increases in investment and funding, this has not corresponded to increases in the approval of novel drugs. Why do so many drugs fail to receive approval, and what other means should we be focusing on for the benefit of patients?

Following development of a therapeutic hypothesis, candidate drug discovery and the pre-clinical workflow (lab bench and non-human studies), novel drugs are taken through a series of clinical trials in humans (phases I, II and III) before they can be reviewed and approved by authoritative bodies.

Aaroon Hingorani ESMH scientistProf. Aroon Hingorani, Professor of Genetic Epidemiology at University College London: “Currently about 9/10 drug programmes fail and this failure has a knock-on consequence for drug pricing. A high proportion of the overall costs is essentially what is called ‘sunk cost’ i.e. the costs that can’t be recovered from failed programmes”.



The majority of drugs do not make it onto the pharmacy shelves, mostly due to lack of efficacy (e.g. not reaching the primary efficacy endpoint), safety concerns (e.g. an unfavourable risk-benefit profile in certain patients), or commercial reasons, while for others it unfortunately remains undisclosed.

Undisclosed data

Transparency of clinical trial results is paramount to progress research and treatments, and researchers and sponsors have a responsibility to inform the public, healthcare professionals, and patients (particularly those who participated in the trial). Sense About Science, an independent campaigning charity, have been advocating for clinical trial result transparency through their AllTrials campaign.

Sile Lane ESMH scientistDr Síle Lane, head of international campaigns and policy at Sense About Science: “There is an EU rule that every clinical trial registered onto the EU register must report results on the register within 12 months of the end of the trial. The EUTrialsTracker Tool is an interactive website, built by Dr Ben Goldacre’s team at the University of Oxford and part of the AllTrials campaign, that pulls in information from the EU’s clinical trial register and displays which clinical trials are due to have reported results”. Dr Lane informs that in December 2019, “around a third of European clinical trials have failed to report results and are breaking the rules”. Dr Lane adds, “We know that often it is trials that give so-called negative results that most often goes undisclosed, so not only does the evidence base for our medicines have gaps, it is also biased”.

Why are drug development programmes failing?

It is estimated that only around 14% of all drug development programmes lead to approval. One reason for failure may be inappropriate application of pre-clinical (non-human) models to predict outcomes in humans. “These [pre-clinical] models can be poor predictors of success. For example, cells and tissues are single isolated systems, not whole organism systems, and animal models are not always representative [of humans]”, remarks Professor Hingorani. “In biological sciences” continues Professor Hingorani, “it is well known that there is a high rate of false discovery, leading to the so-called reproducibility crisis. This arises for example from inferences being inappropriately drawn from experiments”.

Denis Lacombe ESMH ScientistDr Denis Lacombe, Director General of the European Organisation for Research and Treatment of Cancer (EORTC): “As the drugs go through the development process, they first start off with very selected patients in the first trial, the ‘perfect’ sample to demonstrate a response rate. In the second, phase 2, trial, the sample size and population will be enlarged a bit, and response rate might be a bit lower. Then at the phase 3, when the population sample is widened again, the response rate is lost.

Re-shaping clinical trials

The classical clinical trial design entails study protocols with pre-set outcomes to examine and measurements to assess, with fixed trial lengths and participant numbers, with no or little flexibility to adjust. Simply, the trial is planned, executed, and analysed. One alternative methodology is the adaptive trial design. The essence of an adaptive clinical trial design is that it can use results from interim analyses to adjust the trial, in accordance with pre-specified criteria. For example, a dose arm could be disregarded, or the sample size could be re-defined. On a similar note, ‘pragmatic trials’ refer to those that focus on comparing interventions under real-world conditions. Dr Lacombe explains, “[pragmatic trials] are performed in populations that are as representative as possible of the general public and which ask clinically relevant questions such as duration of treatment, survival, or quality of life. They are characterised by relaxed eligibility and could be conducted and randomised within the healthcare system”.

The ‘druggable genome’ to identify which drug target is important in which disease

On the other side of things, Professor Hingorani is interested in the application of our human genome to improve drug target identification and validation. In summary, he remarks, “the druggable genome approach […] uses natural DNA variation in hundreds of thousands of people to understand which variants in the genome influence the expression or function of different proteins – so as to understand which proteins are important in which diseases, given that proteins are the molecular targets of most medicines. This approach […] has had increasing use and interest in the last 5 years. Drug companies are starting to undertake collaborations with academia and using large population datasets to gain valuable insight […] by better identifying which drug target is important in a certain disease,”. This approach may also have beneficial cost effects, “If we can improve [clinical trial] success rates by more reliably identifying the correct therapeutic targets this should reduce cost-pressures in drug development”.

New drugs are not the only answer

There is a substantial consensus that the assumption of novel drugs equating to better treatment is not valid – only a small number of drugs approved since the 1970s demonstrate real benefit over existing therapies (about 15% of them). Dr Lacombe argues we should not be preoccupied by the low approval rate of novel drugs, “stop as many drugs as needed – but those that we do have, let’s assess them independently, and build key treatments that will be clinically meaningful to society.” “We should be more ambitious for the patients from the beginning”, continues Dr Lacombe, “There are too many ‘me too’ drugs with no public health benefit.” These ‘me too’ drugs refer to those that are very similar to existing drugs with only minor differences. Dr Lacombe argues, “the problem is that we don’t know how to fully optimise the drugs we already have – there are probably maybe even enough drugs out there already to double cancer patients’ survival rates but with so many drugs coming on the market we are killing true innovation. We should be utilising drugs and combinations of drugs to their best potential effect based on our biology and understanding. So many questions remain surrounding our current drugs regarding their optimal duration of use, side effects, and toxicity. Everyone is searching for these ‘breakthrough drugs’ that happen very rarely, while we could be using what we already have to a much better degree.”

The potential role of the EU

Dr Lacombe emphasises the potential positive impact the EU can make in drug development by providing “the means to answer questions in a robust manner, and make decisions based on these, where clinical trials, randomised clinical trials, and real world data can be discussed. We are not ambitious enough at the beginning of drug development, resources are being spoilt and things are not being addressed correctly. Billions are spent on immuno-oncology treatment while it has still not been answered how long the optimal treatment [of these drugs] should last. Simply, an EU manifesto should exist where key public health questions are identified, and the money is put on the table to answer them, and this would in fact save a lot of money.” These thoughts have been solidified in a manifesto developed by EORTC which has been signed by several Members of the European Parliament and other organisations and associations.

Professor Hingorani also notes the great potential of the EU to provide opportunity for collaboration, “A lot of the value [of the druggable genome] is dependent on having very large population and patient datasets with genome analyses and disease endpoints. There is a great opportunity in the EU for large national biobanks to come together”, he underlines, adding that “something that we must be aware of is how this data is used. As citizens donate blood samples and give consent for their data to be used, it is important that they then see some benefit from this contribution, for example in price reductions or widening of access to new treatments, or possibly even some financial return to healthcare systems. We may need to think about a new model of drug development, with more equal partnership between industry, academia and healthcare systems serving patients and populations”.

A lot of change may be on the horizon in the drug development scene. More focus may be directed into adaptive or pragmatic clinical trials, and into really getting to know the drugs we already have, in order to considerably improve patients’ lives and outcomes. A combined effort at the EU level to place patient interest at the heart of drug development would certainly push things in the right direction on many levels.

Related Content

A scientist’s opinion : Interview with Aroon Hingorani about re-engineering pharmaceutical research
A scientist’s opinion : Interview with Dr Denis Lacombe about re-engineering pharmaceutical research
A scientist’s opinion : Interview with Dr Síle Lane about re-engineering pharmaceutical research

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