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.

Assessing the Impacts of the Prescription Drug User Fee Acts (PDUFA) on the FDA Approval Process

Congress enacted and renewed the Prescription Drug User Fee Acts (PDUFA) in 1992, and renewed it in 1997 and 2002, mandating FDA performance goals in reviewing and acting on drug applications within specified time periods. In turn, the FDA was permitted to levy user fees on drug sponsors submitting applications to the FDA. While PDUFA mandated action or review times, its ultimate impacts on actual final drug approval times are unknown. We model and quantify the impact of PDUFA-I and II on drug approval times, since these approval dates are the ones most directly related to new medicines becoming available to benefit patients. In assessing the impacts of PDUFA on drug approval times, it is noteworthy that approval times were trending downwards at 1.7% percent per year prior to implementation of PDUFA. Assuming continuation of that time trend, approval times post-PDUFA would have fallen even in the absence of PDUFA. Our principal finding is that PDUFA accelerated this downward trend so that instead of a counterfactual 6% reduction in approval times from 24.2 to 20.4 months in absence of these acts between 1991 and 2002, there was an observed decline of about 42%, from 24.2 to 14.2 months, following implementation of PDUFA. Thus, of the total observed decline in approval times between 1991 and 2002, approximately two-thirds can be attributed to PDUFA. However, much of this impact occurred in the initial years between 1992 and 1997 (PDUFA-I) rather than during the subsequent 1997-2002 time frame (PDUFA-II). We discuss implications of these findings and how future research might quantify the social value of the observed acceleration in the FDA drug approvals.

Assessing the Safety and Efficacy of the FDA: The Case of the Prescription Drug User Fee Acts

The US Food and drug Administration (FDA) is estimated to regulate markets accounting for about 20% of consumer spending in the US. This paper proposes a general methodology to evaluate FDA policies, in general, and the central speed-safety tradeoff it faces, in particular. We apply this methodology to estimate the welfare effects of a major piece of legislation affecting this tradeoff, the Prescription Drug User Fee Acts (PDUFA). We find that PDUFA raised the private surplus of producers, and thus innovative returns, by about $11 to$13 billion. Dependent on the market power assumed of producers while having patent protection, we find that PDUFA raised consumer welfare between $5 to$19 billion; thus the combined social surplus was raised between $18 to$31 billions. Converting these economic gains into equivalent health benefits, we find that the more rapid access of drugs on the market enabled by PDUFA saved the equivalent of 180 to 310 thousand life-years. Additionally, we estimate an upper bound on the adverse effects of PDUFA based on drugs submitted during PDUFA I/II and subsequently withdrawn for safety reasons, and find that an extreme upper bound of about 56 thousand life-years were lost. We discuss how our general methodology could be used to perform a quantitative and evidence-based evaluation of the desirability of other FDA policies in the future, particularly those affecting the speed-safety tradeoff.

On Hausdorff dimension of the set of closed orbits for a cylindrical transformation

We deal with Besicovitch's problem of existence of discrete orbits for transitive cylindrical transformations $T_\varphi:(x,t)\mapsto(x+\alpha,t+\varphi(x))$ where $Tx=x+\alpha$ is an irrational rotation on the circle \T and \varphi:\T\to\R is continuous, i.e.\ we try to estimate how big can be the set D(\alpha,\varphi):=\{x\in\T:|\varphi^{(n)}(x)|\to+\infty\text{as}|n|\to+\infty\}. We show that for almost every $\alpha$ there exists $\varphi$ such that the Hausdorff dimension of $D(\alpha,\varphi)$ is at least $1/2$. We also provide a Diophantine condition on $\alpha$ that guarantees the existence of $\varphi$ such that the dimension of $D(\alpha,\varphi)$ is positive. Finally, for some multidimensional rotations $T$ on \T^d, $d\geq3$, we construct smooth $\varphi$ so that the Hausdorff dimension of $D(\alpha,\varphi)$ is positive.Comment: 32 pages, 1 figur

Assessing the Impacts of the Prescription Drug User Fee Acts (PDUFA) on the FDA Approval Process

Congress enacted and renewed the Prescription Drug User Fee Acts (PDUFA) in 1992, and renewed it in 1997 and 2002, mandating FDA performance goals in reviewing and acting on drug applications within specified time periods. In turn, the FDA was permitted to levy user fees on drug sponsors submitting applications to the FDA. While PDUFA mandated action or review times, its ultimate impacts on actual final drug approval times are unknown. We model and quantify the impact of PDUFA-I and II on drug approval times, since these approval dates are the ones most directly related to new medicines becoming available to benefit patients. In assessing the impacts of PDUFA on drug approval times, it is noteworthy that approval times were trending downwards at 1.7% percent per year prior to implementation of PDUFA. Assuming continuation of that time trend, approval times post-PDUFA would have fallen even in the absence of PDUFA. Our principal finding is that PDUFA accelerated this downward trend so that instead of a counterfactual 6% reduction in approval times from 24.2 to 20.4 months in absence of these acts between 1991 and 2002, there was an observed decline of about 42%, from 24.2 to 14.2 months, following implementation of PDUFA. Thus, of the total observed decline in approval times between 1991 and 2002, approximately two-thirds can be attributed to PDUFA. However, much of this impact occurred in the initial years between 1992 and 1997 (PDUFA-I) rather than during the subsequent 1997-2002 time frame (PDUFA-II). We discuss implications of these findings and how future research might quantify the social value of the observed acceleration in the FDA drug approvals.

The JCMT 12CO(3-2) Survey of the Cygnus X Region: I. A Pathfinder

Cygnus X is one of the most complex areas in the sky. This complicates interpretation, but also creates the opportunity to investigate accretion into molecular clouds and many subsequent stages of star formation, all within one small field of view. Understanding large complexes like Cygnus X is the key to understanding the dominant role that massive star complexes play in galaxies across the Universe. The main goal of this study is to establish feasibility of a high-resolution CO survey of the entire Cygnus X region by observing part of it as a Pathfinder, and to evaluate the survey as a tool for investigating the star-formation process. A 2x4 degree area of the Cygnus X region has been mapped in the 12CO(3-2) line at an angular resolution of 15" and a velocity resolution of ~0.4km/s using HARP-B and ACSIS on the James Clerk Maxwell Telescope. The star formation process is heavily connected to the life-cycle of the molecular material in the interstellar medium. The high critical density of the 12CO(3-2) transition reveals clouds in key stages of molecule formation, and shows processes that turn a molecular cloud into a star. We observed ~15% of Cygnus X, and demonstrated that a full survey would be feasible and rewarding. We detected three distinct layers of 12CO(3-2) emission, related to the Cygnus Rift (500-800 pc), to W75N (1-1.8 kpc), and to DR21 (1.5-2.5 kpc). Within the Cygnus Rift, HI self-absorption features are tightly correlated with faint diffuse CO emission, while HISA features in the DR21 layer are mostly unrelated to any CO emission. 47 molecular outflows were detected in the Pathfinder, 27 of them previously unknown. Sequentially triggered star formation is a widespread phenomenon.Comment: 18 pages, 13 figures, accepted for publication in Astronomy & Astrophysic