For some sponsors, patient-reported outcomes (PRO) are one of many discretionary novelties in the repertoire of the modern clinical trial, optional curiosities that might be deployed. Or not.
For all the warm speeches at industry events about patients "at the center" of modern clinical science, "at the heart" of every study, those phrases can ring hollow. A small mountain of other data can obscure the mundane daily experiences of patients underneath lab work, radiological images, genotyping assays and subjective nurse or physician impressions.
Putting Patients First
But for other sponsors, new appreciation of the potency of electronic versions of PRO—handheld diaries as well as telephone-based self-assessments—is putting the patient squarely back in the center of clinical development. In part, that is because U.S. and European regulators behind closed doors are guiding the sponsor community away from paper diaries. Government is starting to comprehend some of the troubling and incontrovertible data quality issues around paper diaries, and to appreciate some of the data integrity features that have always been incorporated into the devices.
In the midst of this quiet reassertion of the centrality of the patient, the electronic PRO (ePRO) technology is recording the primary and secondary outcomes of the trial. What's more, ePRO tools are being used by both the largest and smallest firms in the industry; both types of companies believe the quality of ePRO data warrants the additional cost and logistical complexity of such trials.
So in an increasing number of cases, interactive voice response (IVR) or Palm-based diaries are not gadgets. Instead they are as integral to pushing the boundary of medical knowledge as the radio telescope is to 21st century astronomy. As with any scientific field, new instruments yield new insights.
42 ePRO Trials
The sponsor community is using electronic diaries far beyond the traditional strongholds of ePRO—pain and allergy studies that have long relied on the experiences of patients recorded by patients. In the table below, we scanned the National Library of Medicine's ClinicalTrials.gov (CTG) registry for all trials with the phrase "electronic diary."
There are plenty of trials in pain and allergy. But there are also studies in many other therapeutic areas, including cancer (run by the MD Anderson Cancer Center and the U.S. military), multiple sclerosis (Bayer), HIV (Savient Pharmaceuticals), depression (Pfizer) and metabolic disorders (separate projects from Pfizer, the University of Pittsburgh and the French Centre d’Etudes et de Recherche pour l’Intensification du Traitement du Diabète).
One of the most compelling aspects of the table is that five sponsors (Boehringer Ingelheim, Depomed, Schering-Plough, SkyePharma, and Takeda) are running two concurrent Phase III trials of the same drug with the same indication. If the trials succeed, it's safe to assume the diary data will be one element of the resulting regulatory submissions. In such cases, the patient is indisputably at the center of the science.
ePRO In Ascendance
|Sponsor||# of Patients||Phase||Condition||Intervention||NCT Number|
|Bayer||800||IV||Multiple sclerosis||Interferon, BAY86-5046||NCT00251745|
|Boehringer Ingelheim||388||II||Asthma||Tiotropium bromide, salmeterol||NCT00350207|
|GSK||288||IV||Allergic rhinitis||Fluticasone furoate||NCT00609674|
|Children's Mercy Hospital||20||NA||Pediatric pain||NA||NCT00884780|
|Lilly||144||II||Arthritis knee pain||LY545694||NCT00790790|
|MD Anderson, Pentagon||622||NA||Cancer (breast)||Behavioral||NCT00386620|
|Takeda||908||III||Gastric reflux||Devlansoprazole MR||NCT00251745|
|Takeda||908||III||Gastric reflux||Devlansoprazole MR||NCT00251758|
|Takeda||947||III||Gastric reflux||Devlansoprazole MR||NCT00321984|
|Centre d’Etudes et de Recherche (France)||50||NA||Diabetes||Pre-, postprandial injections||NCT00934336|
|GSK||300||II||Hot flashes||GSK232802, Premarin||NCT00604825|
|Boehringer Ingelheim||886||III||Sexual dysfunction||Flibanserin||NCT00360529|
|Boehringer Ingelheim||1584||III||Sexual dysfunction||Flibanserin||NCT00360555|
|Univ. Pittsburgh, NIH||198||NA||Obesity||Behavioral||NCT00277771|
|Savient Pharmaceuticals||350||II||HIV, peripheral neuropathy||Prosaptide||NCT00286377|
|Thomas Jefferson Univ., JNJ||25||NA||Migraine||Soy isoflavones||NCT00203255|
|AstraZeneca||450||II||Acid reflux||AZD3355, Magnesium, Simethicone||NCT00703534|
|Boston Medical, MIT, Stanford Univ.||40||I||Cancer||Behavioral||NCT00207181|
|Hamilton Health||120||NA||Hypertension||MyBP electronic self-management||NCT00758238|
|Mayo Clinic, NCI||3||NA||Hot flashes||Physiological testing||NCT00427531|
|Mayo Clinic, NCI||25||NA||Hot flashes||Physiological testing||NCT00427622|
|Schering-Plough||2320||III||Contraception||NomacE2, drospirenone, estradiol||NCT00413062|
|Sanofi Aventis||550||II||Joint disease||Hoe140, Icatibant||NCT00303056|
|Univ. Pittsburgh, NIH||300||NA||HIV||Behavioral||NCT00222716|
|Trials (completed, ongoing and future) with electronic diaries listed in the ClinicalTrials.gov registry as of July, 2009. Schering-Plough's trials were originally filed by a company it acquired: Organon. Placebos have been omitted for reasons of space. To sort the data, please click the green triangles at the top of each column. © ClinPage 2009.|
About The Numbers
There can be no assurance that our compilation of ePRO studies reflects all of the projects that have been finished or are currently under way. So at 335, the median number of patients in our table is an arbitrary calculation. There are probably additional ePRO studies in ClinicalTrials.gov that did not use the phrase "electronic diary." And other trials may not be logged in the federal database at all.
But 335 patients is impressive all the same: these are not tiny projects. It's also interesting that a smattering of academic and government projects are using ePRO. Thirty industry-sponsored studies had a median of 442 patients; twelve government- and academic-run projects had a median of significantly fewer—just 40 patients.
On an anecdotal level, there are other signs of change. Valdo Arnera, the Europe-based general manager of electronic diary supplier PHT, is a physician and a longtime observer of the industry. He says that tolerance for paper-based patient-reported outcomes is ebbing among regulators in Europe. "I met two representatives from quite high in the national agencies," Arnera says. "They both told me, 'We hope paper will disappear one day.' She said, 'Oh, this is fantastic. Paper should not be used any more.' It was the first time I have heard that in my life."
In Europe, two regulatory guidance documents (for asthma and steroid contraceptives) strongly encourage but do not require the usage of electronic forms of patient-reported experiences. A final version of a U.S. guidance document spanning all therapeutic areas has been rumored to be on the verge of publication for several years, and could emerge tomorrow or never, depending on the vagaries of the legal process inside an FDA with relatively new appointed political leaders.
Sponsor firms are understandably skittish, in some cases, about revealing competitive aspects of their research programs. So Arnera is limited in what he can say. But he says he was surprised by one recent dermatology project for a sponsor that had never used ePRO before. They chose the technology needing little education. "The primary end point was really coming from the patient," he says. "They had done their homework."