Biopharmaceuticals and monoclonal antibodies in oncology trials--a cross-sectional analysis

Abstract

Protein engineering has led to a significantly improved understanding of the biophysical properties of proteins and, importantly, of the molecular mechanisms of disease. Moreover, it has enabled scientists to modify the molecular characteristics of peptides and proteins, leading to improved pharmacokinetics and pharmacodynamics of protein therapeutics. Consequently, biopharmaceuticals, such as monoclonal antibodies (mAbs), interferons/cytokines or vaccines, contribute increasingly to clinical practice. Some of these new treatments have dramatically changed the outcome of specific diseases. However, treatment options remain limited in many conditions, particularly in malignant disease, despite a much-improved understanding of the molecular mechanisms underlying cancer. With the successful pre-clinical development of therapeutic biomolecules, the most significant barrier prior to implementation into clinical practice is proof of concept in humans. This is in part addressed by clinical trials that evaluate the toxicology, dose response and efficacy of the molecules. This observational study summarises the current state of biopharmaceuticals in clinical trials and provides a particular focus on oncology trials. It identifies those cancer types that are most likely to benefit from the efforts made in pre-clinical protein science and establishes evidence that engineered proteins and peptides are set to play a growing role in clinical practice. This study was based on the 95,254 trials registered on the National Institute of Health Clinical Trials Database by 31 August 2010. Of these, 25,525 trials assigned to cancer conditions, including leukaemia and lymphoma, were further analysed, with a particular focus on the 3653 interventional trials that were based on biological interventions. The inclusion criterion for the analysis was registration on the Clinical Trials Database by the above date. No other trials were included. Biopharmaceuticals were the more prevalent intervention in cancer trials (14%) compared with trials in non-cancer conditions (6%). Further subgroup analysis based on the 20 cancer subtypes with the highest mortality revealed that biological therapeutics comprise 43% in malignant melanoma trials and more than 20% in five other cancer types. Two-thirds of all monoclonal antibody are registered in cancer trials (1033, 4.6% of all cancer trials). The subgroup analysis demonstrated a predominance of lymphoma and leukaemia trials for antibody interventions, with 204 and 163 trials registered, respectively. In non-cancer conditions only 503 (0.9%) trials investigate monoclonal antibody interventions. A retrospective longitudinal analysis of the trials demonstrated that monoclonal antibody trials are increasingly frequently registered in non-cancer as well as cancer conditions. However, biopharmaceutical trials continue to be registered more frequently only in non-cancer conditions, but have come to a plateau in cancers. This study is limited by analysis of data from one database only. While the NIH Clinical Trials Database used is the most comprehensive and internationally recognised of its kind, it is possible that the results may have been modified if other databases were also included. Protein engineering has paved the way for biopharmaceutical clinical interventions. A cross-sectional analysis of trials registered on the NIH Clinical Trial Database shows that biological interventions are increasingly entered into clinical trials. While oncological diseases used to lead this effort, biotherapeutic trials in non-cancer conditions have now become more frequent in comparison. Monoclonal antibodies, however, are still mainly investigated in oncological conditions. Haemato-oncological diseases are most frequently investigated for mAb interventions, although they are not among the eight most common causes of cancer mortality. This may reflect the fact that pre-clinical research, understanding of molecular mechanisms and target identification in other malignancies and diseases is less developed.

Fig. 1

Subgroup analysis of all trials registered on the NIH Clinical Trials Database by 31 August 2010. The fig. provides data for all non-cancer conditions (A and B) and all cancers, including leukaemia and lymphoma (C and D). There are more than 2.5 times as many trials registered for non-cancer conditions compared with cancers (69300 vs. 25525); however, there are more biological interventions under investigation for all cancers (3653 vs. 3397). Forty open access studies of cancer trials were not included in the analysis. A number of trials are registered for two interventions and the total in B and D, therefore, deviates from the numbers provided in A and C.

Fig. 2

Illustration of the proportional contribution of non-cancer conditions and cancer trials to different trial subgroups. 26.8% of all trials are cancer trials; however, the proportion increases over different subgroups to 62.3% of all trials that investigate mAbs (data provided in Table I.)

Fig. 3

Trends of trial count start dates registered over the last decade. (A) There are an increasing number of trials registered in non-cancer conditions. The number of trials registered for cancers has been almost static since 2006. (B) Biological trial registrations have increased annually in non-cancer conditions, but have fallen since 2008 in cancers and are now at the level of 2004. (C) mAbs have consistently been more relevant to trials in cancers compared with non-cancer conditions. Counts for mAb trials have been rising since 2004 for both subgroups. Table II summarises all data. The counts for 2010 are extrapolated from the counts available by the end of August. There were no start dates available for 73 cancer and 211 non-cancer trials.

Fig. 4

Cancer mortality in the UK in 2008. Data from Cancer Research UK.

Fig. 5

Trial counts and fractions of biological and mAbs trials for the 20 most common cancers. (A) Most biological cancer intervention trials are registered for leukaemias and non-Hodgkin lymphoma. Lung cancer, the cancer with the highest mortality, ranks only sixth in this statistic. (B) Biological interventions are registered for 6% of non-cancer trials. This fraction is higher for all of the 20 most common cancers and more than twice as high for 18 out of those 20. The fraction is more than 3 times as high for 10 cancer conditions still. (C) Non-Hodgkin lymphoma and leukaemias also have the highest count of mAb trials among the 20 most common cancers. (D) As for biological interventions, in general mAbs play a more important role in all 20 cancer conditions compared with non-cancer conditions. Table III lists a comprehensive set of data relating to the subgroup counts for the 20 cancers analysed in Figs 4 and 5.