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.

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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
Schering-Plough 520 III Insomnia Org 50081 NCT00561821
Schering-Plough 211 III Insomnia Org 50081 NCT00750919
Pfizer 165 NA Depression Sertraline NCT00406952
Wyeth 40 III Hemophilia BeneFIX NCT00364182
Takeda 908 III Gastric reflux Devlansoprazole MR NCT00251745
Takeda 908 III Gastric reflux Devlansoprazole MR NCT00251758
Takeda 947 III Gastric reflux Devlansoprazole MR NCT00321984
Univ. California-Irvine 40 NA ADHD Ritalin NCT00573859
Centre d’Etudes et de Recherche (France) 50 NA Diabetes Pre-, postprandial injections NCT00934336
Pfizer 185 NA Fibromyalgia NA NCT00819624
AstraZeneca 114 0 COPD Behavioral NCT00788645
GSK 300 II Hot flashes GSK232802, Premarin NCT00604825
SkyePharma 350 III Asthma Fluticasone, formorterol NCT00394199
Depomed 378 III Neuralgia, postherpetic Gabapentin NCT00335933
Boehringer Ingelheim 886 III Sexual dysfunction Flibanserin NCT00360529
Boehringer Ingelheim 1584 III Sexual dysfunction Flibanserin NCT00360555
GSK 506 IV Asthma Fluticasone, formorterol NCT00353873
Depomed 450 III Neuralgia, postherpetic Gabapentin NCT00636636
Orphan Medical 320 II Fibromyalgia Xyrem NCT00087555
Univ. Pittsburgh, NIH 198 NA Obesity Behavioral NCT00277771
Savient Pharmaceuticals 350 II HIV, peripheral neuropathy Prosaptide NCT00286377
Takeda 445 III Esophagitis, reflux Devlansoprazole NCT00321737
SkyePharma 440 III Asthma Fluticasone, formorterol NCT00393991
SkyePharma 556 III Asthma Fluticasone, formorterol NCT00393952
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
Schering-Plough 2152 III Contraception Nomegestrol, Drospirenone NCT00511199
Planned Parenthood 82 NA Contraception Behavioral NCT00733707
Sanofi Aventis 550 II Joint disease Hoe140, Icatibant NCT00303056
Univ. California-Irvine 80 NA ADHD Nicotine NCT00573248
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."

Problematic Paper

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."

For the next few Tuesdays, we'll be publishing new installments in our ePRO series. The second installment can be found here. The third article in the series is here. The fourth article is here. Questions? Contact .(JavaScript must be enabled to view this email address)

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