Precision medicine clinical trials – How far are we in personalized medicine?

precision medicine

Precision Medicine is a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat a disease1.

It combines pharmacology and pan-omics (the study of genes, proteins, metabolites and their functions) to develop effective, safe medications and medication doses that are tailored to the variations in subject´s transcriptome.

“It can be difficult to predict who will benefit from a prescription, who will not respond at all, and who will experience negative side effects”

With the knowledge gained from the Human Genome sequencing Project, researchers are learning how inherited differences in genes affect the body’s response to medications.

Although the term “precision medicine” is relatively new, the underlying concept that the therapeutic interventions need to be tailored to the patient´s genes, lifestyle and environment, has been a part of medicine for many years.

For example, blood transfusions are not given randomly but the donor’s blood type is matched to the recipient to reduce the risk of complications.

Many drugs don’t work the same way for different populations around the world. For some drugs, such as statins (routinely used to lower cholesterol) as few as one in 50 patients may benefit from regular intake2.

It can be difficult to predict who will benefit from a prescription, who will not respond at all, and who will experience negative side effects (adverse drug reactions).

There are even drugs that are harmful to certain ethnic groups; this is often found out by chance after approval, because of the bias towards the participants of a certain origin in classical clinical trials3.

Therefore, using precision medicine as an aid to plan clinical trials catches much attention in the present era of drug development.

“the personalized strategy was an independent predictor of better outcomes and fewer toxic deaths “

Classical clinical trials yield just a few assessments from larger populations and often indicate a need for yet another study due to differential response patterns in certain sub-populations of participants 4.

For instance, imatinib was found to double the survival rates of leukemia patients with a chromosomal abnormality called the Philadelphia translocation5. Similarly, cetuximab improves the survival of patients with colorectal cancer whose tumor cells carry a mutated EGFR gene but not a mutated KRAS gene6. Direct pharmacologic targeting of HER2 using trastuzumab has been shown to selectively exert anti-tumor effects in cancer models and patients with HER2-amplified breast cancer7.

The particular relevance of these therapies, in awake of the identified genetic biomarkers where the subjects can be stratified according to their genetic profile, is challenging and undeniable8.

A comprehensive analysis of phase II trials, that took place between 2010 and 2012 and used single –agent arms, reveals that the personalized strategy was an independent predictor of better outcomes and fewer toxic deaths9.

Several innovative precision medicine initiatives have launched clinical trials for complex diseases:

Longitudinal cohort studies

Longitudinal cohort studies such as the Breast International Group’s AURORA protocol (Aiming to Understand the Molecular Aberrations in Metastatic Breast Cancer) enables the molecular preselection of patients suitable for enrollment in genotype-driven clinical trials and classifies potential prognostic biomarkers10.

Such studies with a primary endpoint of the proportion of patients that could be entered into the trial of targeted agents are suggestive of the feasibility of a personalized clinical treatment.

Basket trials

Basket trials such as the NCI-MATCH, a Phase II precision medicine trial, use the tumors’ genetic markers to assign subjects with different types of late stage cancers to different treatment arms.

These treatment arms (baskets) are drug combinations that are targeting tumors containing certain molecular anomalies regardless of the cancer types. Baskets include patients who share a certain genetic anomaly.

During this trial the effectiveness of the mode of action of the single combination of drugs to a genetic anomaly will be measured. A major advantage of this study design is that it is very informative about which are the tumor types where single-agent therapy is worth pursuing in phase III trials versus other types where combination treatment strategies should be prioritized.

The first interim analysis (2016) of the MATCH trial has permitted implementation of several enhancements to the structure and logistics of the study, mainly the overall patient size of the trial and the laboratory capacity11.

Umbrella trials

Umbrella trials such as The Lung MAP (Master Protocol- phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer) use two or more enrichment designs.

As per tumor characterization, patients are recommended to sub-trials based on the genomic profiles of the tumor.

The goal of this clinical trial is to rapidly identify new active drugs and bring them as soon as possible in the market through a registration process for patients with squamous cell lung cancer.

This could serve as a paradigm for drug development for malignancies with wide molecular heterogeneity12.

N-of-1 study design

In clinical research fields outside of oncology, the N-of-1 study designs have been more often employed, e.g., trials conducted for patients with musculoskeletal or pulmonary conditions 1314.

The defining characteristic of N-of-1 trial is the recruitment of patients exposed to different experimental agents or placebo in different temporal sequences, with washout periods in between 15.

This type of design practically renders each involved patient to serve as his or her own comparator, through the comparison of the effıcacy seen for the different experimental agents that the patient receives.

This is an approach that could be of help for molecular aberrations of really low prevalence, where randomized studies are extremely challenging.

The Exceptional Responders Initiative

The Exceptional Responders Initiative has been launched to understand the molecular underpinnings of exceptional responses to treatment.

The initiative collects cases in which patients with any cancer had dramatic and long-lasting responses to standard and experimental treatments that were not seen in similar patients who received the same treatment.

This approach will drive the identification of molecular biomarkers that can be integrated into clinical trials and predict response to a specific therapy16.

Adaptive Trials

Adaptive Trials as exemplified by the BATTLE trial focusing on patients with metastatic non-small cell lung cancer (NSCLC)17 or the I-SPY trial focusing on patients in the neoadjuvant setting of breast cancer treatment18 evolve dynamically depending on the efficacy data obtained during the trial.

For example, some of the treatment arms can be dropped; biomarker selection strategy can be changed even when the treatment assignment remains the same.

These studies will spawn a new era of treatment trials that will carefully select the patients that may respond best to investigational therapy.

“The idea of precision medicine holds great promise but this new era of trials also comes with its own difficulties.”

The terms ‘precision’ and ‘medicine’ already hint at some of the regulatory challenges that will become essential.

The EU-funded cervical cancer study (BIO-RAIDs) highlights the need for facilitating and standardizing the regulatory processes as the first step in the precision medicine era19.

The study emphases on the challenges such as a lack of uniform international legal and ethical standards, complexities in clinical and molecular data management, and difficulties in determining the best technical platforms and data analysis techniques.

Simultaneously it is even more critical to protect the participants’ privacy and the confidentiality of their health information, with the abundance of highly detailed health data on such a large number of patients20.

If precision medicine approaches are to become part of routine healthcare, healthcare providers will need a constant update on molecular genetics and biochemistry. Medicine practitioners will need to interpret the results of genetic tests on ongoing basis in order to understand how that information is relevant to treatment or prevention approaches, and convey this knowledge to their patients. Data gathered from health care institutions, research projects and routine care need to be linked to the right individuals across their lifetime21.

Moving deeper in achieving affective treatments by means of precision medication will trigger research advances that will also enable better calculation of disease risk, understanding of disease mechanisms, and estimation of optimal therapy for many more diseases.

It is unclear how long it will take to build an infrastructure that maintains momentum up on all fronts such as ethical standards, funding stability, data privacy, patient engagement and provider support for best establishment of precision medicine.

Picture: @vitstudio /


Get the latest articles as soon as they are published: for practitioners in clinical research

  • Read about ideas & tools for effective clinical research

  • Follow today’s topics in clinical research

  • Knowledge base: study design, study management, digitalization & data management, biostatistics, safety

  • It’s free! Sign up now!

Anmeldeformular Newsletter / Clever Reach / EN
  1. National Cancer Institute. NCI Dictionary of Cancer Terms. Personalized Medicine. Accessed January 29, 2017.
  2. Mukherjee, D. & Topol, E. J. Prog. Cardiovasc. Dis. 44, 479–498 (2002).
  3. Currie, G. P., Lee, D. K. & Lipworth, B. J. Drug Saf. 29, 647–656 (2006).
  4. Uryniak, T. et al. Stat. Biopharmaceut. Res. 3, 476–487 (2011).
  5. Druker, B. J. et al. N. Engl. J. Med. 344, 1038–1042 (2001).
  6. Karapetis, C. S. et al. N. Engl. J. Med. 359, 1757–1765 (2008).
  7. Romond EH, Perez EA, Bryant J, et al. N Engl J Med. 2005; 353: 1673-1684.
  8. De Bono J.S. & Ashworth A. et al. Nature 543 (2010).
  9. Schwaederle M: JCO 2015; 33: 3817-3825.
  10. Zardavas D, Maetens M, Irrthum A, et al. Br J Cancer.2014; 111: 1881-1887.
  11. Conley BA, Doroshow JH. Molecular analysis for therapy choice: NCI MATCH. Semin Oncol. 2014; 41: 297-299.
  12. Steuer C et al. Innovative Clinical Trials: The LUNG-MAP Study. Clin Pharmacol Ther. 2015 May; 97(5):488-91.
  13. Louly PG, Medeiros-Souza P, Santos-Neto L. Clin Ther. 2009;31:1007-1013.
  14. Scudeller L, Del Fante C, Perotti C, et al. BMJ. 2011;343:d7653.
  15. Duan N, Kravitz RL, Schmid CH. J Clin Epidemiol. 2013;66(8 Suppl):S21-S28.
  16. Wagle. N et al. Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib. DOI: 10.1158/2159-8290.CD-13-0353.
  17. Edward S. Kim. The BATTLE Trial: Personalizing Therapy for Lung Cancer. DOI: 10.1158/2159-8274.CD-10-0010 Published 3 April 2011.
  18. Printz C. I-SPY 2 may change how clinical trials are conducted: researchers aim to accelerate approvals of cancer drugs. Cancer. 2013; 119: 1925-1927.
  19. Ngo et al. From prospective biobanking to precision medicine: BIO-RAIDs – an EU study protocol in cervical cancer. BMC Cancer. 2015; 15: 842.
  20. Y. Erlich, A. Narayanan. Routes for breaching and protecting genetic privacy. Nat Rev Genet, 15 (2014), pp. 409–421
  21. Dzau VJ, Ginsburg GS. Realizing the Full Potential of Precision Medicine in Health and Health Care. JAMA. 2016 Oct 25; 316(16):1659-1660.