Back to resources

Hitting the R&D sweet spot with fast in-human studies

Prof. G.M. van Dam, MD, PhD

The R&D sweet spot encapsulates the solution for a cost-effective approach to drug development. Namely, while R&D costs rise and productivity falls, the pressure to achieve return on investment for new innovative drugs is higher than ever before. It requires drug developers to optimize their productivity and redesign the drug development process as we know it today. This can be achieved by utilizing the R&D sweet spot by, for example, conducting in-human imaging small smart Proof of Concept (PoC) studies. These studies allow for a precise and quick decision about the drug delivery as a prediction of drug efficacy during clinical trials, even before Phase I.

The challenges of the current drug development process.

The development of innovative newly marketed therapeutic or diagnostic drugs is a long and a costly process. In general, developing one new drug costs an average $1.4 billion and takes approximately 10-15 years from initial development towards market authorization (DiMasi et al., 2016). As R&D costs continue to increase, it can be said that without a significant increase in R&D productivity drug developers cannot sustain sufficient innovations to replace the loss of revenue due to patent expirations. Moreover, potentially due to the costly clinical regimen, there is a decrease of FDA and EMA approved new drugs over the last decade.

When a new molecular targeting approach is identified, translation towards a clinical setting is made. After extensive preclinical and animal testing, Phase I studies are performed to assess biodistribution, pharmacokinetics, safety and the optimal dosing regimen for the selected drug. In this clinical development phase, mostly healthy volunteers but also patients with the targeted disease are included. These studies, including the translation from laboratory scale towards implementation in clinical trials, normally take approximately two to three years. During the development from feasibility Phase I studies towards Phase II, Phase III and eventually standard of care drug use, a major amount of potential diagnostic or therapeutic drugs are eventually unsuccessful due to the lack of specificity or off-target effects.

After initial promising Phase I results, the success rate decreases to 20-33% of novel drugs in Phase III studies. In the end, less than 10% of all developed drugs will be used in standard of care. Nonetheless, the last clinical development phases are responsible for more than half of the total development costs. Therefore, as suggested by Paul et al. (2010), the ability to improve R&D efficiency and productivity strongly depends on reducing Phase II and III attrition. In other words, a more effective clinical trial design with earlier go/no go decisions is crucial.

The shift to a quick win and fast fail method.

In the quick win & fast fail method, Proof-of-concept (PoC) studies are introduced to accommodate the need for earlier decision making as described above. During PoC studies a small number of patients (n=10-20) with the disease of interest can be included. These PoC studies, or phase 0 studies, are performed prior to Phase I studies. This timeframe is the so-called ‘R&D sweet spot’. See the figure below for a comparison between the traditional process and the quick win, fast fail method.

Optimize the drug development process with the R&D sweet spot

Figure 1 – A comparison of drug development processes adapted from Paul et al., 2010

So, how does the R&D sweet spot ensure a more cost and time efficient clinical trial? With in-human PoC studies the safety, optimal dosage and drug effectiveness can be predicted. This allows for early decision making on whether to proceed with the tested compound into costly phase I/II and eventually phase III studies. Shifting the decision making into the early phase of the development process reduces investments in late-stage trial failures. In other words, you avoid investing time and monetary resources and exposure of study subjects to the new drug  in taking non-efficient compounds into the more expensive clinical trial phases. Moreover, these saved resources can be used to invest in drug discovery, creating an abundance of new innovative new molecular entities. Furthermore, negative PoC results allow pharmaceuticals to return to the drawing table and develop a new targeting strategy in a timely manner.

Hitting the R&D sweet spot with clinical imaging

Optical and nuclear molecular imaging are powerful clinical imaging modalities to hit the R&D sweet spot.  Conjugation of a new molecular entity or therapeutic drug with a radionuclide or fluorophore allows for in- and ex vivo tracking of the drug by these imaging modalities. This provides valuable data about the drug’s biodistribution. Moreover, facilitating an effective in- and ex vivo imaging workflow allows for the evaluation of drugs at multiple timepoints (e.g., the pharmacokinetics of the drug can be determined).

In order to execute such PoC molecular imaging studies an extremely low dose of the labeled drug, so-called microdosing, is used during PoC studies. The doses of the drugs used in microdosing have no direct pharmacological effect. This microdosing/clinical imaging strategy has multiple advantages:

  • The safety risks for the patients are minimalized
  • The translation from the R&D stage to first-in-human is faster
  • It is approved by regulatory authorities for development and commercialization strategies
  • The detection of the labeled drug by both clinical optical and nuclear imaging devices is sensitive enough to allow for highly adequate drug distribution data.

Microdosing is a cost- and time effective novel attribute which can eventually replace testing in numerous animal models for validation and healthy volunteers. These clinical PoC studies show the biodistribution and the targeting of the tested drug to the tissue of interest. If a non-specific targeting has been shown, a fast go / no-go decision can be made based on realistic in- and ex vivo data. This strategy prevents companies from large investments and therefore costs in non-effective clinical trials in the future. At TRACER, we already provided multiple optical and nuclear imaging PoC studies in a variety of (oncological) diseases with microdosing of fluorescent- and radiolabeled antibodies. During these studies, rapid inclusion of patients allowed for data of 10-30 patients within a few months. Based on this quick collected imaging data, early decisions regarding expansion of the clinical trial towards healthy volunteers and a Phase II trial can be made.

References.

  1. DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics47, 20–33. https://doi.org/10.1016/j.jhealeco.2016.01.012
  2. Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R., & Schacht, A. L. (2010). How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nature Reviews Drug Discovery9(3), 203–214. https://doi.org/10.1038/nrd3078

Other blogs

| See all blogs
Blog

How to get your first-in-human trial approved in The Netherlands

Prof. Go van Dam, MD, PhD
Blog

Microdosing with and without molecular imaging

Milou Noltes, MD, PhD
Blog

Does a Phase 0 study influence your Phase 1 trial?

Maarten Brom, PhD