Diversifying our approach to clinical development


The paradox of cancer research

The paradox of cancer research is that, as our understanding of the disease increases, so does our recognition of its complexity.

For centuries, we have been naming cancer according to the organ initially affected; however, tremendous advances in genetic profiling have led us to identify multiple sub-types, each with their own molecular and, subsequently, prognostic profiles. We now recognise, for example, that lung cancer is not one disease, but has more than ten distinct sub-types, all fuelled by different molecular pathways.1

This understanding has allowed us to start developing treatments that specifically target the molecular mechanisms that drive different cancers, introducing an era of personalised medicine where one size no longer fits all. This shift towards personalised healthcare has contributed to global improvements in cancer survival rates. In Europe, the number of deaths caused by cancer has decreased by approximately 20% since the late 1980s,2 and today many patients diagnosed with cancer can expect to live for over 10 years.3,4

While these trends are encouraging, in order for us to keep delivering innovative treatments to the patients who need them, the way we assess new medicines needs to evolve and keep pace with our growing understanding of cancer biology. 

The categorisation of cancer into many sub-types poses several challenges for clinical development, as we have more sub-types to investigate and smaller patient populations to recruit in clinical trials. Find out how we are re-designing clinical trials to overcome these issues here

The evolution of endpoints

Overall survival (OS) is the length of time a person with cancer lives after starting treatment. It is a measure – or ‘endpoint’ – that has been used in clinical trials for decades and it remains the "gold standard" for measuring a medicine’s efficacy. As people with cancer are now living longer, it can take more time and resources to demonstrate whether a new medicine significantly improves the length of survival compared to an older treatment. Furthermore, patients with cancer today will typically have several subsequent treatments over the course of their disease, which can mean that it is difficult to determine the long-term efficacy provided by a particular medicine that was given in a clinical trial.5

To overcome these impracticalities, endpoints including progression-free survival (PFS)* and overall response rate (ORR)** were introduced. While these endpoints were practically unheard of 30 years ago, today they are commonly used in trials and are widely accepted by regulatory authorities as surrogates for OS.6

*PFS is the length of time people live from the point of randomisation into a study until disease recurrence, worsening or death.

**ORR is the portion of patients whose tumours shrink by a predefined amount (usually around 30 percent), as viewed on medical scans, for a minimum time period. 

Figure 1: Graph representing the number of FDA approvals, 1996 - 2014, based on overall survival as an endpoint compared to other clinical trial endpoints7

A modern era of endpoints

More recently, the development of highly sensitive imaging technologies has enabled us to explore newer, disease-specific ways of measuring a tumour’s response to treatment.

In blood cancer, for example, minimal residual disease (MRD) is a condition where a small number of cancer cells remain in the patients’ blood or bone marrow following treatment. Achieving ‘MRD negativity’ means a patient is in a deep remission and has no detectable cancer cells, even using modern, more sensitive tests.8

Similarly, in early breast cancer, pathological complete response (pCR) can be used to assess the efficacy of a medicine given prior to surgery (in the neoadjuvant setting). Achieving pCR means there are no cancer cells detectable at the time of surgery in the affected breast and lymph nodes. pCR may be measured much faster than traditional endpoints and some studies have suggested its association with improvements in longer-term outcomes.8

For a more detailed explanation of pCR and what it means, watch this short video here.

As the evolving science challenges us to find innovative ways of measuring the clinical efficacy of cancer treatments, our understanding of already established endpoints changes as well. For example, disease-free survival (DFS***) has been recognised for decades as a surrogate for OS in early breast cancer trials. However, in more recent years, an adapted version of this endpoint, known as Invasive Disease Free Survival (iDFS****), has been widely used by investigators, particularly in the adjuvant breast cancer setting. This endpoint is often favoured as it allows for a more precise estimate of a treatment’s effect on the disease.

***DFS represents the length of time a person lives without any signs or symptoms of their cancer after completion of their initial treatment.

****iDFS the time a patient lives without return of invasive disease after adjuvant treatment.

Measuring the response of immunotherapy, a new class of medicines, requires a different approach altogether. In many cases, recruiting the immune system to attack a tumour causes an apparent increase in tumour size early on, followed by dramatic, durable shrinkage due to the dynamic nature of the immune system. So, a new set of response criteria, known as the immune-related response criteria (irRC), has been developed to better capture the response patterns observed with some immunotherapies, allowing a more comprehensive evaluation of their impact.

We need to continue adapting and diversifying our approach to drug development as our understanding of cancer broadens. Having a range of endpoints at our disposal allows us to tailor our clinical trials for each treatment and patient population under investigation,’’
Nana Scotto Disease Area Head, Breast Cancer and Gynaecologic Malignancies.
A good example of what this evolution means in practice comes from breast cancer setting, where we have already made tangible progress. Recognition of the need to bring new medicines to patients quicker led to our close collaboration with both the U.S. Food and Drug Administration and the European Medicines Agency to evaluate evidence for the use of pCR as an endpoint in early breast cancer trials. This, together with our innovative trial designs, has already allowed us to bring a treatment to patients earlier than was ever possible before.”

Measuring what matters

In addition to extending lives, treatments must also aim to sustain or improve a patient’s quality of life (QoL). QoL is measured through patient-reported outcomes (PROs), which are collected via surveys and cover wide-ranging aspects of a person's well-being, from symptoms experienced to the ability to perform daily activities. While subjective, QoL and patient preference are important considerations when it comes to treatment decisions.

Beyond clinical trials, we must not forget that what we call “endpoints” and “outcomes” are very real things which have profound implications for people’s lives. For patients with advanced breast cancer for example, a year without their disease progressing means a year without deteriorating health; a year of putting the brakes on cancer. In the early breast cancer setting, if a patient receives treatment prior to surgery and achieves pCR, it may provide reassurance that the treatment is working. In practice, understanding endpoints may allow patients to emotionally process their diagnosis.

More than a measurement: A personal account from a former breast cancer patient, Ike de Rooij-van Haaren

I felt a lump in my breast and scheduled an appointment with my physician straight away. I was diagnosed with an aggressive form of early breast cancer and that is why I wanted to go to a hospital that would treat me with the latest treatments and/or clinical trials. I was able to take part in a clinical trial, and my treatment consisted of chemotherapy and an experimental targeted therapy, which were given to me prior to surgery. The doctor explained to me that our ultimate goal would be to make sure that the tumour is gone entirely after the six months of treatment.


After the six months my doctor gave me the incredible news that we had achieved our ultimate goal and that the tumour was undetectable [i.e. pCR was achieved]. This also meant a far less invasive surgery was required, which was fantastic news. Even though I still needed surgery, radiation and an additional six months of targeted therapy, we felt the hardest part was behind us. Mentally this made the rest of the treatment much easier. We never could have hoped for such an outcome of achieving pCR. Knowing that treating breast cancer early greatly increases your chance of cure, my family and I feel confident to have high hopes for the future!

Change is happening – now

As we learn more about the molecular mechanisms behind different sub-types of cancer and as we introduce more and more treatment options that prolong survival, demonstrating the benefit of new medicines by traditional standards becomes increasingly difficult and time-consuming. There is pressure on the clinical development process to evolve and diversify.

The evidence supporting newer endpoints for cancer medicines is growing and they are increasingly being recognised as an important way to speed up the assessment process while keeping the same levels of quality and assurance traditionally associated with clinical trials. In order to bring new targeted treatment options to the patients who need them as quickly as possible, we must continue to think innovatively and collaboratively about the way in which we investigate new medicines.


  1. My Cancer Genome. Molecular Profiling of Lung Cancer. March 2016. Last Accessed 15 September 2016.
  2. Bosetti C et al. Ann Oncol 2013; 24(10):2657-71.
  3. Cancer Research UK. England and Wales Survival (2010-2011) Summary. April 2014. Last accessed 15 September 2016.
  4. Verdecchia A et al. Lancet Oncol 2007;8(9):784-96.
  5. Pazdur R. Oncologist 2008;13(2):19-21.
  6. Johnson JR et al. J Clin Oncol 2003; 21(7):1404-11.
  7. www.fda.gov; www.cancerwatch.com; Johnson JR et al. J Clin Oncol 2003;21:1401-11. Data reflect primary endpoints in pivotal trials of anti-cancer medicines, not including preventative or palliative treatments
  8. European Medicines Agency. Appendix 4 to the guideline on the evaluation of anticancer medicinal products in man. December 2015. Last accessed 26 September 2016.