Patient-Focused Drug Development Perfetto, Eleanor M.; Burke, Laurie; Oehrlein, Elisabeth M. ...
Medical care,
2015-January, Letnik:
53, Številka:
1
Journal Article
Recenzirano
CONTEXT:Patient-Focused Drug Development (PFDD) is a new initiative from the Food and Drug Administration (FDA) intended to bring patient perspectives into an earlier stage of product development. ...The goal is that patients will be able to provide context for benefit-risk assessments and input to review divisions, and also aid in the development of new assessment tools, study endpoints, and risk communications. This paper provides a summary on what is known to date about FDA’s PFDD initiative and describes implications for patients, researchers, payers, and the biopharmaceutical industry. It also provides a roadmap for stakeholders to consider in defining their role in and in shaping PFDD’s direction, and for expanding PFDD principles to conditions beyond the current 20 under FDA consideration.
METHODS:A search was conducted of the peer-reviewed and gray literature using PubMed and Google. This included laws, FDA guidance documents, the peer-reviewed literature, and FDA presentations for content relevant to the search term “patient-focused drug development.”
FINDINGS:Currently, FDA activities within PFDD are limited to gaining patient insights through 20 disease-specific meetings. However, many stakeholders see the initiative much more generally as representing a broad shift toward patient centeredness in biopharmaceutical product development.
CONCLUSIONS:Depending upon the trajectory taken and whether or not all PFDD aims are eventually addressed, the initiative has the potential to change product development in fundamental ways. Further research should explore how patient input on disease manifestation and treatment options is best ascertained from patients and documented before initiating and during drug development.
PURPOSE:To evaluate custom fast cross-linking (cfCXL) treatment of keratoconus.
METHODS:“Custom fast cross-linking” or “cfCXL” is a keratoconus treatment algorithm featuring no epithelial disruption, ...15 minutes of corneal presoaking with a riboflavin–vitamin E TPGS solution, and a 370-nm ultraviolet A radiation beam centered on the most highly curved corneal region. Ultraviolet A radiation beam fluence, total energy, and exposure time are significantly less than those in the Dresden protocol. In this study, refraction, spectacle-corrected distance visual acuity, Kmax, and corneal hysteresis were monitored in 81 eyes of 81 patients for 7 years with 100% follow-up. Pretreatment Kmax and patient age averaged 53.01 ± 4.87 D and 25.9 ± 4.7 years, respectively.
RESULTS:Average refractive cylinder magnitude was reduced by 26.1% at 1 month postoperatively and by 44.2% at 7 years postoperatively. Logarithm of the minimum angle of resolution average spectacle-corrected distance visual acuity (best spectacle-corrected distance visual acuity) improved from +0.26 ± 0.34 (20/36.4) to +0.15 ± 0.23 (20/28.25), +0.05 ± 0.20 (20/22.4), and +0.06 ± 0.20 (20/22.96) at 1 month, 1 year, and 7 years postoperatively, respectively. Best spectacle-corrected distance visual acuity improved in 54.3%, 74.1%, 84.0%, 87.7%, 84.0%, 84.0%, and 82.7% of patients at postoperative months 1, 3, 6, 12, 24, 48, and 84, respectively. Kmax did not increase in 96.3% of patients at 1 month, 97.5% at 1 year, and 98.8% at 7 years postoperatively, with average corneal apex flattening at 1 month and 7 years of −2.79 ± 1.70 D and −4.00 ± 2.40 D, respectively.
CONCLUSIONS:Custom fast cross-linking, epi-on, rapid, narrowed beam apex-centered treatment of keratoconus with riboflavin–vitamin E TPGS produced a significant, rapid, and lasting cone progression stoppage, astigmatism reduction, and visual acuity improvement.
PURPOSE:To report the clinical outcomes with 24-month follow-up of transepithelial cross-linking using a combination of a D-alpha-tocopheryl polyethylene-glycol 1000 succinate (vitamin ...E-TPGS)-enhanced riboflavin solution and abbreviated low fluence UV-A treatment.
METHODS:In a nonrandomized clinical trial, 25 corneas of 19 patients with topographically proven, progressive, mild to moderate keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitamin E-TPGS, topically applied for 15 minutes, followed by two 5-minute UV-A treatments with separate doses both at fluence below 3 mW/cm that were based on preoperative central pachymetry.
RESULTS:During the 6-month pretreatment observation, the average Kmax increased by +1.99 ± 0.29 D (diopter). Postoperatively, the average Kmax decreased, changing by −0.55 ± 0.94 D, by −0.88 ± 1.02 D and by −1.01 ± 1.22 D at 6, 12, and 24 months. Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 months, respectively. Refractive cylinder was decreased by 3 months postoperatively and afterward, changing by −1.35 ± 0.69 D at 24 months. Best spectacle-corrected visual acuity (BSCVA) improved at 6, 12, and 24 months, including an improvement of −0.19 ± 0.13 logarithm of the minimum angle of resolution units at 24 months. There was no reduction in endothelial cell count. No corneal abrasions occurred, and no bandage contact lenses or prescription analgesics were used during postoperative recovery.
CONCLUSIONS:Transepithelial cross-linking using the riboflavin-vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression.
We introduce and quantify a relatively new form of influence: the Answer Bot Effect (ABE). In a 2015 report in PNAS, researchers demonstrated the power that biased search results have to shift ...opinions and voting preferences without people's knowledge-by up to 80% in some demographic groups. They labeled this phenomenon the Search Engine Manipulation Effect (SEME), speculating that its power derives from the high level of trust people have in algorithmically-generated content. We now describe three experiments with a total of 1,736 US participants conducted to determine to what extent giving users "the answer"-either via an answer box at the top of a page of search results or via a vocal reply to a question posed to an intelligent personal assistant (IPA)-might also impact opinions and votes. Participants were first given basic information about two candidates running for prime minister of Australia (this, in order to assure that participants were "undecided"), then asked questions about their voting preferences, then given answers to questions they posed about the candidates-either with answer boxes or with vocal answers on an Alexa simulator-and then asked again about their voting preferences. The experiments were controlled, randomized, double-blind, and counterbalanced. Experiments 1 and 2 demonstrated that answer boxes can shift voting preferences by as much as 38.6% and that the appearance of an answer box can reduce search times and clicks on search results. Experiment 3 demonstrated that even a single question-and-answer interaction on an IPA can shift voting preferences by more than 40%. Multiple questions posed to an IPA leading to answers that all have the same bias can shift voting preferences by more than 65%. Simple masking procedures still produced large opinion shifts while reducing awareness of bias to close to zero. ABE poses a serious threat to both democracy and human autonomy because (a) it produces large shifts in opinions and voting preferences with little or no user awareness, (b) it is an ephemeral form of influence that leaves no paper trail, and (c) worldwide, it is controlled almost exclusively by just four American tech companies. ABE will become a greater threat as people increasingly rely on IPAs for answers.
Improving adherence to medication offers the possibility of both reducing costs and improving care for patients with chronic illness. We examined a national sample of diabetes patients from 2005 to ...2008 and found that improved adherence to diabetes medications was associated with 13 percent lower odds of subsequent hospitalizations or emergency department visits. Similarly, losing adherence was associated with 15 percent higher odds of these outcomes. Based on these and other effects, we project that improved adherence to diabetes medication could avert 699,000 emergency department visits and 341,000 hospitalizations annually, for a saving of $4.7 billion. Eliminating the loss of adherence (which occurred in one out of every four patients in our sample) would lead to another $3.6 billion in savings, for a combined potential savings of $8.3 billion. These benefits were particularly pronounced among poor and minority patients. Our analysis suggests that improved adherence among patients with diabetes should be a key goal for the health care system and policy makers. Strategies might include reducing copayments for certain medications or providing feedback about adherence to patients and providers through electronic health records.
The purpose of the study was to determine the decrease in pachymetry of very thin corneas with advanced keratoconus due to corneal compaction from the ultraviolet-A (UV-A) irradiation phase of ...transepithelial (epi-on) cross-linking.
Twenty removed corneal buttons were obtained from patients who underwent penetrating keratoplasty for advanced keratoconus. Removed corneal buttons selected from among the post-surgical specimens for this study had intact epithelium, no scarring or surgical cautery, endothelial cell density >2500 cells/mm2, and average pachymetry over the measured points of below 400 μm. Corneas were mounted in a Franz chamber. Each epithelial surface was soaked in isotonic riboflavin and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Ribocross® IROMED Group, Italy) for 15 min. Pachymetry was measured at three points over both the shielded and unshielded corneal halves for each corneal button. Surfaces were then washed in saline to remove the Ribocross®. Shields from UV-A irradiation over half of each cornea were then fixed to stand 5 mm above the test corneas. UV-A irradiation using the custom fast cross-linking (CF-CXL) protocol was then performed for the typical 10 ± 1.5 min, for a total energy of 1.08 ± 0.6 J/cm2 after which pachymetry was re-measured.
The average percent change in pachymetry was −0.43% ± 0.38% (maximum −1.06%) in the shielded half. Pachymetry change was −6.2% ± 2.2% (maximum 12%) in the cross-linked halves.
In conclusion, we estimate that the change in corneal thickness from corneal compaction due to the cross-linking reaction itself was −5.8% ± 2.2%. Scanning electron microscopy of cross-linked corneal segments showed stromal fiber contraction.
This study was designed to determine whether genotype testing for patients initiating warfarin treatment will reduce the incidence of hospitalizations, including those due to bleeding or ...thromboembolism.
Genotypic variations in CYP2C9 and VKORC1 have been shown to predict warfarin dosing, but no large-scale studies have prospectively evaluated the clinical effectiveness of genotyping in naturalistic settings across the U.S.
This national, prospective, comparative effectiveness study compared the 6-month incidence of hospitalization in patients receiving warfarin genotyping (n = 896) versus a matched historical control group (n = 2,688). To evaluate for temporal changes in the outcomes of warfarin treatment, a secondary analysis compared outcomes for 2 external control groups drawn from the same 2 time periods.
Compared with the historical control group, the genotyped cohort had 31% fewer hospitalizations overall (adjusted hazard ratio HR: 0.69, 95% confidence interval CI: 0.58 to 0.82, p < 0.001) and 28% fewer hospitalizations for bleeding or thromboembolism (HR: 0.72, 95% CI: 0.53 to 0.97, p = 0.029) during the 6-month follow-up period. Findings from a per-protocol analysis were even stronger: 33% lower risk of all-cause hospitalization (HR: 0.67, 95% CI: 0.55 to 0.81, p < 0.001) and 43% lower risk of hospitalization for bleeding or thromboembolism (HR: 0.57, 95% CI: 0.39 to 0.83, p = 0.003) in patients who were genotyped. During the same period, there was no difference in outcomes between the 2 external control groups.
Warfarin genotyping reduced the risk of hospitalization in outpatients initiating warfarin. (The Clinical and Economic Impact of Pharmacogenomic Testing of Warfarin Therapy in Typical Community Practice Settings MHSMayoWarf1; NCT00830570).
Sigmund Freud, Alfred Kinsey, E.O. Wilson, and others have suggested that social pressure suppresses natural tendencies for humans to express bisexuality, the apparent norm for one of our two closest ...genetic relatives, the bonobo. An analysis of data obtained from a new online sample of 1,150,938 people in 215 countries and territories (63.9% from the United States, United Kingdom, and Canada) who completed the English version of a validated questionnaire of sexual orientation lends support to this idea. A histogram of scores from 0 (exclusive opposite-sex inclinations) to 18 (exclusive same-sex inclinations) forms a near-normal distribution. Although this distribution was likely caused to some extent by sampling bias, it may also reflect the unusual honesty people show when taking online tests anonymously, as an increasing body of evidence demonstrates. We present a formal mathematical expression of a social pressure theory of sexual orientation, along with empirical evidence and computational explorations that support the theory. We also present an analysis of the new data set. Among other findings: sexual orientation labels corresponded to broad, skewed, overlapping distributions of scores. Self-labeled gays/lesbians and, to a greater extent, self-labeled straights, reported that the larger the mismatch between their sexual orientation label and their actual sexual inclinations, the more distress they felt regarding their sexual orientation, a finding that is predictable from cognitive dissonance theory. Educating the public about the true nature of sexual orientation might quell the often rancorous public debates on this topic, as well as give comfort to a large number of mislabeled people.
PURPOSE:To improve the safety, reproducibility, and depth of effect of corneal cross-linking with the ultraviolet A (UV-A) exposure time and fluence customized according to the corneal thickness.
...METHODS:Twelve human corneas were used for the experimental protocol. They were soaked using a transepithelial (EPI-ON) technique using riboflavin with the permeation enhancer vitamin E–tocopheryl polyethylene glycol succinate. The corneas were then placed on microscope slides and irradiated at 3 mW/cm for 30 minutes. The UV-A output parameters were measured to build a new equation describing the time-dependent loss of endothelial protection induced by riboflavin during cross-linking, as well as a pachymetry-dependent and exposure time-dependent prescription for input UV-A fluence. The proposed equation was used to establish graphs prescribing the maximum UV-A fluence input versus exposure time that always maintains corneal endothelium exposure below toxicity limits.
RESULTS:Analysis modifying the Lambert–Beer law for riboflavin oxidation leads to graphs of the maximum safe level of UV-A radiation fluence versus the time applied and thickness of the treated cornea. These graphs prescribe UV-A fluence levels below 1.8 mW/cm for corneas of thickness 540 μm down to 1.2 mW/cm for corneas of thickness 350 μm. Irradiation times are typically below 15 minutes.
CONCLUSIONS:The experimental and mathematical analyses establish the basis for graphs that prescribe maximum safe fluence and UV-A exposure time for corneas of different thicknesses. Because this clinically tested protocol specifies a corneal surface clear of shielding riboflavin on the corneal surface during UV-A irradiation, it allows for shorter UV-A irradiation time and lower fluence than in the Dresden protocol.
Study Objectives. To review the labels of United States Food and Drug Administration (FDA)‐approved drugs to identify those that contain pharmacogenomic biomarker information, and to collect ...prevalence information on the use of those drugs for which pharmacogenomic information is included in the drug labeling.
Design. Retrospective analysis.
Data Sources. The Physicians' Desk Reference Web site, Drugs@FDA Web site, and manufacturers' Web sites were used to identify drug labels containing pharmacogenomic information, and the prescription claims database of a large pharmacy benefits manager (insuring > 55 million individuals in the United States) was used to obtain drug utilization data.
Measurements and Main Results. Pharmacogenomic biomarkers were defined, FDA‐approved drug labels containing this information were identified, and utilization of these drugs was determined. Of 1200 drug labels reviewed for the years 1945–2005, 121 drug labels contained pharmacogenomic information based on a key word search and follow‐up screening. Of those, 69 labels referred to human genomic biomarkers, and 52 referred to microbial genomic biomarkers. Of the labels referring to human biomarkers, 43 (62%) pertained to polymorphisms in cytochrome P450 (CYP) enzyme metabolism, with CYP2D6 being most common. Of 36.1 million patients whose prescriptions were processed by a large pharmacy benefits manager in 2006, about 8.8 million (24.3%) received one or more drugs with human genomic biomarker information in the drug label.
Conclusion. Nearly one fourth of all outpatients received one or more drugs that have pharmacogenomic information in the label for that drug. The incorporation and appropriate use of pharmacogenomic information in drug labels should be tested for its ability to improve drug use and safety in the United States.
PDF
