Nuclear halo of a 177 MeV proton beam in water: theory, measurement and parameterization

The dose distribution of a monoenergetic pencil beam in water consists of an electromagnetic "core", a "halo" from charged nuclear secondaries, and a much larger "aura" from neutral secondaries. These regions overlap, but each has distinct spatial characteristics. We have measured the core/halo using a 177MeV test beam offset in a water tank. The beam monitor was a fluence calibrated plane parallel ionization chamber (IC) and the field chamber, a dose calibrated Exradin T1, so the dose measurements are absolute (MeV/g/p). We performed depth-dose scans at ten displacements from the beam axis ranging from 0 to 10cm. The dose spans five orders of magnitude, and the transition from halo to aura is clearly visible. We have performed model-dependent (MD) and model-independent (MI) fits to the data. The MD fit separates the dose into core, elastic/inelastic nuclear, nonelastic nuclear and aura terms, and achieves a global rms measurement/fit ratio of 15%. The MI fit uses cubic splines and the same ratio is 9%. We review the literature, in particular the use of Pedroni's parametrization of the core/halo. Several papers improve on his Gaussian transverse distribution of the halo, but all retain his T(w), the radial integral of the depth-dose multiplying both the core and halo terms and motivating measurements with large "Bragg peak chambers" (BPCs). We argue that this use of T(w), which by its definition includes energy deposition by nuclear secondaries, is incorrect. T(w) should be replaced in the core term, and in at least part of the halo, by a purely electromagnetic mass stopping power. BPC measurements are unnecessary, and irrelevant to parameterizing the pencil beam.Comment: 55 pages, 4 tables, 29 figure

Opportunities for Improving the Drug Development Process: Results from a Survey of Industry and the FDA

In the United States, the Food and Drug Administration (FDA) agency is responsible for regulating the safety and efficacy of biopharmaceutical drug products. Furthermore, the FDA is tasked with speeding new medical innovations to market. These two missions create an inherent tension within the agency and between the agency and key stakeholders. Oftentimes, communications and interactions between regulated companies and the FDA suffer. The focus of this research is on the interactions between the FDA and the biopharmaceutical companies that perform drug R&D. To assess the current issues and state of communication and interaction between the FDA and industry, we carried out a survey of industry leadership in R&D and regulatory positions as well as senior leadership at the FDA who have responsibility for drug evaluation and oversight. Based on forty-nine industry and eight FDA interviews we conducted, we found that industry seeks additional structured and informal interactions with the FDA, especially during Phase II of development. Overall, industry placed greater value on additional communication than did the FDA. Furthermore, industry interviewees indicated that they were willing to pay PDUFA-like fees during clinical development to ensure that the FDA could hire additional, well-qualified staff to assist with protocol reviews and decision-making. Based on our survey and discussions, we uncovered several thematic opportunities to improve interactions between the FDA and industry and to reduce clinical development times: 1) develop metrics and goals at the FDA for clinical development times in exchange for PDUFA like fees; 2) establish an oversight board consisting of industry, agency officials, and premier external scientists (possibly at NIH or CDC) to evaluate and audit retrospectively completed and terminated drug projects; and 3) construct a knowledge database that can simultaneously protect proprietary data while allowing sponsor companies to understand safety issues and problems of previously developed/failed drug programs. While profound scientific and medical challenges face the FDA and industry, the first step to reducing development times and associated costs and facilitating innovation is to provide an efficient regulatory process that reduces unnecessary uncertainty and delays due to lack of communication and interaction.