Digitally Enabled,Patient‐Centric Clinical Trials: Shifting the Drug Development Paradigm

The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a site‐centric to a patient‐centric model. Merck’s (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck’s digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient‐centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real‐time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure‐response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient‐centric, digitally enabled trials will also be discussed.

The rapidly advancing field of digital health technologies provides an opportunity to transform the pharmaceutical industry and the way clinical trials are conducted. Although the conduct of clinical trials has evolved over the last century to improve the unbiased evaluation of new therapies, there remain several limitations in the current clinical trial paradigm. Pharmaceutical clinical trials are often site‐centric, requiring patients to come to the clinical site for sample and data collection. The need to travel to the clinical site often restricts the trial population to those that live in geographic proximity to the clinical site, and, thus, restricts who participates and limits patient diversity, leaving many patients excluded and underserved. ¹ , ² , ³ , ⁴ , ⁵ The current trial paradigm provides only static snapshots of data (corresponding to the time of the clinical visit), resulting in lost opportunity to monitor end points of disease progression, pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability end points in between clinical visits. Additionally, clinical trial outcome measures may not be particularly meaningful to patients or their health care providers, and end points may be limited by categorical, episodic, subjective assessments that progress slowly, thus requiring large, long, expensive clinical trials to enable detection of meaningful change in the end point. Furthermore, patient medication adherence and persistence to therapy in clinical trials is often low, ⁶ , ⁷ limiting the researcher’s ability to adequately assess the drug’s safety, efficacy, and exposure‐response relationships. Lastly, patients often find the clinical trial language confusing and the trial’s expectation of what they are supposed to do intrusive into their daily lives, limiting the number of patients that participate in clinical trials and threatening the retention of those patients that do consent to participate. ¹ , ² , ³ , ⁴ , ⁵ The potential benefits of digital health and outpatient sampling technologies in clinical trials are tremendous. They can enable increased access to the appropriate patient population, reduced patient burden to participate, augmented, more informed, objective data sets (both in collecting and measuring existing end points at home and in access to new end points that would have been impossible to collect in the past), increased engagement with the patient, and better understanding of the patient experience throughout the trial. All these benefits will ultimately improve the patient experience during the trial and enable improved drug development decisions and understanding of drug and disease effects. ⁸ Despite all these potential improvements, the relative “explosion” in both the number of digital health technologies as well as their capabilities, and an increased adoption of consumer‐grade health‐tracking devices in the marketplace, adoption of use of such technologies in pharmaceutical trials has been lagging by comparison. ⁹ , ¹⁰ , ¹¹ Some of the challenges to pharmaceutical trial adoption include questions around patient privacy, lack of sufficient validation for digital end points, lack of transparency for calculation of end points (“black box” algorithms), challenges related to patient adherence and burden of wearing and using devices, operational and data transfer challenges, and regulatory unknowns. However, use of digital end points in drug development trials, including as primary and secondary end points and to support label claims, is becoming a reality, and “pilot” trials evaluating technologies of interest, often evaluating digital end points in comparison to a traditionally accepted clinical standard end point, are being increasingly conducted. ¹² , ¹³ , ¹⁴ The digitally enabled clinical trials initiative at Merck (Kenilworth, NJ) is aimed at using innovative, digital technologies in clinical trials both at the clinical site and in at‐home settings to reduce patient burden, collect higher quality, enrich clinical trial data sets, and ultimately enable more rapid and informed clinical decisions. We ultimately aim to shift the clinical trial paradigm from one that is site‐centric to patient‐centric. Key areas of focus include (i) collection of at‐home PK, PD, and biomarker samples (outpatient sampling), (ii) use of technologies to monitor and improve patient adherence (smart dosing), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) development and use of data platforms that can acquire the data from digital devices, provide real‐time analytic capabilities, and maintain patient engagement throughout the trial (digital platform; Figure  1 ). Application of these components in clinical trials will lead to access to higher quality and previously unattainable data for more informed clinical decision making.Open in a separate windowFigure 1Areas of focus for digitally enabled clinical trials.This paper describes the four key areas of focus of our digitally enabled clinical trials initiative and reviews corresponding enabling technologies. Furthermore, this paper discusses the synergistic power in implementation of these approaches jointly within a trial to enable a more accurate understanding of adherence, safety, PK, and corresponding exposure‐response relationships of investigational new drugs (INDs) as well as reduced patient burden for clinical trial participation. Obstacles and challenges to adoption and fully realizing the vision of patient‐centric, digitally enabled trials are also discussed.     

Microbiological culture analysis of the tongue anaerobic microflora in subjects with and without halitosis

Objective:  Determination of the microflora present on the tongue dorsum of subjects with and without halitosis using conventional microbiological culture methods.
Methods:  Twenty-one halitosis and 20 control patients were recruited using a strict clinical protocol. Samples were collected from the posterior dorsum of the tongue using a sterile brush. Each sample was vortex mixed for 30 s and serial 10-fold dilutions to 10⁻⁷ were carried out. Samples were plated onto fastidious anaerobe agar (FAA) and FAA enriched with vancomycin. These were incubated under anaerobic conditions for 10 days at 37°C. Strict anaerobes were identified by metronidazole sensitivity and bacteria were identified to genus level by a combination of colony morphology, Gram staining and biochemical and enzymatic tests (rapid ID 32 A).
Results:  The predominant species in test and control groups were Veillonella sp. and Prevotella sp. Greater species diversity was found in the halitosis samples compared with controls. The halitosis samples contained an increased incidence of unidentifiable Gram-negative rods, Gram-positive rods and Gram-negative coccobacilli.
Conclusions:  There was no obvious association between halitosis and any specific bacterial genus. The increased species diversity found in halitosis samples suggests that halitosis may be the result of complex interactions between several bacterial species. The role of uncultivable bacteria may also be important in contributing to this process.     

Improved survival of children with sepsis and purpura: effects of age,gender, and era

Background  

To gain insight into factors that might affect results of future case-control studies, we performed an analysis of children with sepsis and purpura admitted to the paediatric intensive care unit (PICU) of Erasmus MC-Sophia Children's Hospital (Rotterdam, The Netherlands).     

Demographic characteristics and prevalence of serologic markers among donors who use the confidential unit exclusion process: the Retrovirus Epidemiology Donor Study

BACKGROUND: Most blood centers utilize a confidential unit exclusion (CUE) process, intended to reduce the risk of transfusion-associated infectious diseases by allowing high-risk donors confidentially to exclude their blood from use for transfusion. The effectiveness of this method remains controversial. STUDY DESIGN AND METHODS: Confirmatory or supplemental test results for antibodies to human immunodeficiency virus, human T-lymphotropic virus type I, and hepatitis C virus, as well as hepatitis B surface antigen and syphilis and screening test results for antibodies to hepatitis B core (antigen) and alanine aminotransferase levels were obtained for approximately 1.8 million units donated during 1991 and 1992 at five blood centers within the United States. The prevalences of these infectious disease markers in units that the donors confidentially excluded (CUE+) and units that the donors did not exclude (CUE-) were calculated and examined within demographic subgroups. RESULTS: Units that were CUE+ were 8 to 41 times more likely to be seropositive for antibodies to human immunodeficiency virus and hepatitis C virus, hepatitis B surface antigen, and syphilis and three to four times more likely to react for antibody to hepatitis B core (antigen) or to have elevated alanine aminotransferase levels than units that were CUE- (p < 0.001). The positive predictive value of CUE (the percentage of CUE+ units that were confirmed seropositive for any marker) was 3.5 percent, and the sensitivity of CUE (the percentage of confirmed-seropositive units that were CUE+) was 2.3 percent. CONCLUSION: The current CUE process has low sensitivity and apparently low positive predictive value, and in many cases, it appeared that donors misunderstood it. Yet, CUE was not a “random process,” as CUE+ units were more likely to be seropositive for any infectious disease marker than CUE- units. This suggests that efforts to improve the CUE system may be warranted. As risk factors for transfusion-transmitted infection become more difficult to identify by history-based screening, however, such efforts may have limited effect.     

Potential increased risk of virus transmission due to exclusion of older donors because of concern over Creutzfeldt-Jakob disease. The National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study

BACKGROUND: Concern over the theoretical possibility of disease transmission via blood from donors who develop Creutzfeldt-Jakob disease has led to proposals to exclude older individuals from donating plasma for further manufacture into pooled plasma donations. The impact of extending this age-deferral policy to blood donors was examined with respect to the risk for known transmissible viruses. STUDY DESIGN AND METHODS: Demographic characteristics and confirmed prevalence rates (/10(5) first-time donations) and incidence rates (/10(5) person-years for repeat donors) for viral markers were compared for donors < 50 years old (n = 1,259,805 [85%]) and > or = 50 years old (n = 219,856 [15%]) and for donors < 60 years old (n = 1,409,176 [95%]) and > or = 60 years old (n = 70,485 [5%]). Incidence rates were combined with infectious window-period estimates for each virus, to calculate the risk of virus transmission per 10(6) donations. RESULTS: Unadjusted prevalence rates were significantly greater for younger than for older donor groups for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) (p < or = 0.05). Incidence rates (and transmission risk estimates) for HBsAg were significantly higher in the < 50 donor group than in the > or = 50 group (p < or = 0.05), and those for HIV, human T-lymphotropic virus, and HCV were not significantly higher (p > 0.05). Blanket removal of donors over the age of 50 would potentially lead to the following significant increases in the risk of infected units: HIV, 12 percent; HCV, 21 percent; and hepatitis B virus (HBsAg), 22 percent. CONCLUSION: Removal of donors over the age of 60 would not significantly affect the risk of infected units. Deferral of donors > or = 50 years of age from whole-blood donations for unfounded concerns about Creutzfeldt-Jakob disease could have adverse effects on both blood availability and safety.     

Inactivation of human immunodeficiency virus by gamma radiation and its effect on plasma and coagulation factors

The inactivation of HIV by gamma-radiation was studied in frozen and liquid plasma; a reduction of the virus titer of 5 to 6 logs was achieved at doses of 5 to 10 Mrad at -80 degrees C and 2.5 Mrad at 15 degrees C. The effect of irradiation on the biologic activity of a number of coagulation factors in plasma and in lyophilized concentrates of factor VIII (FVIII) and prothrombin complex was examined. A recovery of 85 percent of the biologic activity of therapeutic components present in frozen plasma and in lyophilized coagulation factor concentrates was reached at radiation doses as low as 1.5 and 0.5 Mrad, respectively. As derived from the first-order radiation inactivation curves, the radiosensitive target size of HIV was estimated to be 1 to 3 MDa; the target size of FVIII was estimated to be 130 to 160 kDa. Gamma radiation must be disregarded as a method for the sterilization of plasma and plasma-derived products, because of the low reduction of virus infectivity at radiation doses that still give acceptable recovery of biologic activity of plasma components.     

Reproducibility and effect of posture on impulse oscillation parameters in persons with spinal cord injury

Background

The impulse oscillation system (IOS) offers significant value in the assessment of airway dynamics in persons with spinal cord injury (SCI) because of minimal patient effort but measurement reproducibility in SCI is unknown.

Objective

To evaluate between-day reproducibility and the effect of posture on airway resistance [respiratory resistances at 5 Hz (R5) and 20 Hz (R20)] in subjects with tetraplegia, paraplegia and able-bodied controls.

Methods

Ten subjects with tetraplegia, 10 subjects with paraplegia and 11 able-bodied individuals were evaluated using IOS. Three 30 second trials were obtained in each while in the seated and supine position on Day 1, and repeated on Day 2.

Results

The within-day coefficient of variation (CV%) for R5 and R20 were comparable in the 3 study groups in the seated and supine positions. Compared to controls, the between-day CV% for the combined data was higher in subjects with tetraplegia and paraplegia for R5 seated, and was higher in subjects with tetraplegia for R5 supine.

Conclusions

IOS has applicability to the study of within-day respiratory resistance in SCI. However, performing longer-term studies in subjects with tetraplegia and paraplegia may be problematic because of the greater variability for R5 when compared to able-bodied individuals.