liwplpoWa

usw

Medical journals are taking action toimprove the quality of their work. TheInternational Committee of MedicalJournal Editors, for example, has estab-lished a requirement that all clinicaltrials be entered in a public registrybefore the onset of patient enrollmentas a condition of consideration for pub-lication. And an increasing number ofjournals use Web-based tools such asCrossCheck, which is used during theeditorial process to identify matchingtext as part of an effort to identifyplagiarism.

But the current system of medical

journal peer review simply isn’t set up to

ith rotating images of innocent teens

aloch

fp“iCcs

Ppauess

Volume , . : October

catch out-and-out fraud, and at presentit’s often very difficult for journals toensure that physicians have institutionalreview board approval for their research.In terms of data manipulation, at somepoint the journal editors have to trust theresearchers who are collecting the data.

“The thing is, and it’s really quiteunfortunate that you have to say this,”Dr. Weingart said, “but the fact of thematter is that you can’t believe every-thing you read.”

Section editor: Truman J. Milling, Jr, MDFunding and support: By Annals policy, all

authors are required to disclose any and all

ection–“Gen HAE”–that shapes the

sf

mHsDtH“sd

tirlpdtfan

ttmrcp

potshiNct

commercial, financial, and other relation-ships in any way related to the subject ofthis article as per ICMJE conflict of inter-est guidelines (see www.icmje.org). Theauthor has stated that no such relation-ships exist.

doi:10.1016/j.annemergmed.2011.08.003

1. Angell M. Drug companies and doctors: astory of corruption. New York Review ofBooks.

2. SAFE Study Investigators. A comparisonof albumin and saline for fluidresuscitation in the intensive care unit.

N Engl J Med. 2004;350:2247-2256.

ame information in more suitable waysor the younger set.

Rival HAE pharma CSL Behringakes its mark with the “All AboutAE,” at its Berinert HAE product

ite. Elsewhere is “HAE Hope” byyax, along with that pharma’s Kalbi-

or HAE therapy Internet offerings.ealth care professionals can peruse the

HAE: Learn About It, Talk About It”ite for insights and discussions on theisease.

Patients have their pick of online siteso partake in their own dialogues and freenteractive accessories–online journals forecording attacks, appointments and re-ated medical information. They can get

Hereditary Angioedema:Massive MarketingCampaigns HighlightNew Therapies ForRare Disease

rintable reports, fact-filled USB flash-

by GEORGE FLYNN

Special Contributor to

Annals News & Perspective

Hereditary angioedema (HAE), aserious but very rare disease, seemsan unlikely candidate for a high-dol-

ar marketing and education campaign target-ng, among others, emergency physicians,ho are publicly criticized by some HAEatients. But the market release of a pha-anx of new therapies–in which multipleharmaceutical companies have hundredsf millions invested–has led to a blizzard of

eb sites, education campaigns and evenn indie film.

“Every Patient Deserves Hope,” thepgraded ViroPharma corporate Webite, projects its theme amid a backdrop

nd active elderly. The “learn more” linksead visitors through a complex networkf relatively new Internet sites for theompany’s Cinryse therapy for patients ofereditary angioedema.

Clusters of demographically balancedaces of patients await on the Cinryseroduct site, peering out from a motto ofPower of Prevention.” Another web stops the “Ryse Above” page presenting theinryse Solutions Program, not to beonfused with the Cinryse Patient Re-ources Program.

Those who don’t visit these Viro-harma sites are still welcome at the com-any’s “HAE and Me” portal, describeds a virtual “online community” thatnites teens and adults with shared HAExperiences. If the youthful crowd wantseparation, they can turn to their own

rives, and customized documents, de-ailed exercise, diet and other potentialactors in their fight against HAE. Therere even custom-made travel cases witheeded medical items for road trips.

This marketing campaign includeshe human touch–24/7 patient coordina-ors and counselors guiding them toedical professionals and caregivers, and

unning interference through compli-ated insurance or financial assistancerograms.

Expanding as rapidly is the onlineresence of the US HAE Association. Therganization of patients and advocates–itouts no specific therapy product but isponsored by companies producing them–as grown over the past couple of years tonclude a separate educational Web site.ow it is widening into the political advo-

acy field. The organization mounted a na-

ional tour with 6 regional patient meet-

Annals of Emergency Medicine 19A

I B

ings to introduce them and families to itsmission, the new therapies and the diseaseitself.

Those not going to HAE Associationmeetings will find that the disease–or atleast a definitive documentary on it–mayeven be coming to a theater near themeventually. In May 2011, ViroPharmaannounced the launch of Swell the movie,a 25-minute film of art house quality.Created by the noted Woodshop Films,the movie relies on a cinèma vèritè ap-proach to surpass the stock streamingvideos of patients and medical specialistsnow posted online. Corporate officialstalked of entering Swell in various filmfestival competitions.

Online or in person, the extensivemarketing campaigns, crusades for aware-ness and advocacy are drawing marketingindustry comparisons to the tenacious,high-tech approaches for medical productstargeting far more familiar “ask-your-doc-tor-about” audiences–those suffering fromdiabetes, high-blood pressure, chronic painand more.

A VERY RARE DISEASEnstead, HAE product companies arepursuing markets that are small evenby the standards of the National Or-

ganization for Rare Disorders. It considers adisease rare if it afflicts fewer than 200,000Americans. There are now less than 7,000US residents identified as having HAE. Es-timates range up to 10,000 for the totalnumber with the disease in the US.

While the competitors have estab-lished or are aggressively seeking foreignmarkets, the rarity of the disease has in-tensified the efforts to find and recruitpatients in the US by pharmaceuticalcompanies, which have enormous invest-ments in their HAE therapies. That isaccompanied by the more traditional in-centive-bearing visits by sales reps tophysicians and hospitals.

“The prevalence of HAE patients whichhas been estimated at approximately 1 in10,000 to 50,000 people around the world,has been definitively determined,” Dyaxstates in its investor risk disclosures for theFirst Quarter 2011 filing with the Securi-ties and Exchange Commission. “There canbe no guarantee that any of our programswill be effective at identifying HAE pa-

tients and the number of HAE patients in

20A Annals of Emergency Medicine

the United States may turn out to be lo-wer than expected or may not otherwiseutilize treatment with Kalbitor for all orany of their acute HAE attacks, all of whichwould adversely affect our results of opera-tions and business prospects.”

Filings by other companies make sim-ilar references in assessing worst-case sce-narios for investors. Risks factors includethe ability of patients to secure funding,from insurers or government programs ifnecessary, during a period of potentialconstraints on public assistance for med-ical needs.

Marketing campaigns contrast withcorporate reports and disclosures of im-pressive percentage gains, but they stillcount US customers by the hundredsrather than thousands. Dyax, for example,had a first-quarter 2011 jump of 64% inthe number of patients treating with Kal-bitor. However, that brought them up toa total of 154 patients. (There were largertotals in other categories–742 patientswith prescriptions or start forms for thattherapy, and 435 with Kalbitor placed atUS treatment sites.)

BIG REVENUE, SMALLNUMBERS

ig revenues can come from the rel-atively small numbers, however.Last year, ViroPharma led the way

with a reported $177 million in US salesof Cinryse. General industry projectionsare for overall revenues from the therapiesto reach more than $500 million by mid-decade, and far more when including for-eign markets. (Companies with HAEtherapies and officials of the US HAEAssociation either declined comment ordid not respond to interview requests forthis article.)

The marketing-driven race for reve-nues parallels the drive by patients forexpanded therapy options and researchfor breakthroughs in a disease that haslong baffled the medical community.HAE attacks trigger swelling that cangrossly distort areas such as the eyes, lips,face, feet and hands. Deaths have oc-curred when the swelling chokes off air-ways, and the abdominal form of HAEhas been repeatedly mistaken for otherconditions, sometimes leading to un-needed surgeries and treatments.

German internist and surgeon Hei-

nrich Quincke was credited with the for-

mal discovery of the disease in 1882,which was initially known as “Quincke’sEdema.” The hereditary nature of mostcases was revealed in the case of an 18-year-old German woman whose familyhad suffered HAE attacks for 5 genera-tions.

It was not until early in the 1960s thatresearchers linked HAE to the C1-INHgene deficiency. A decade later, attenuatedandrogens–anabolic steroids–emerged asthe standard response for managing attacksof the disease. The new waves of approvedtherapies include ViroPharma’s Cinryse, aC1 inhibitor that can be infused at homeabout twice weekly to help prevent attacks.It was approved in late 2008. Others thatfollowed were Kalbitor, by Dyax, whichis injected during acute HAE episodes.CSL Behring’s Berinert is an intravenoustherapy for abdominal and facial attacks.

An advisory panel for the FederalDrug Administration recently gave posi-tive reviews of clinical trials for Shire’sFirazyr, which is seeking approval forpatient self-administration for treatmentduring attacks. More therapies remain inthe development or approval pipelines.One seeking US approval is Rhucin, a C1inhibitor protein that is derived from themilk produced by genetically altered rab-bits.

These rapidly expanding therapies andresearch, marketing and the escalating at-tention have helped coordinate medicalspecialties in new ways. In April, theAmerican College of Emergency Physicians(ACEP) joined a partnership with otherfields seeking to improve the standard ofcare for HAE patients. The program, called“HAE: Learn About It, Talk About It,” wasdescribed as an “innovative, peer-drivencampaign designed to unite the disparatespecialties” treating HAE.

“As the first line of contact with undi-agnosed and diagnosed patients in manycases, emergency physicians and physicians’assistants can play a role in improving carefor patients by quickly recognizing HAEsymptoms, understanding new disease man-agement paradigms, and referring patients toan HAE-treating physician for appropriatemanagement,” the joint announcement said.

The American Academy of Nurse Prac-titioners is the newest member of the part-nership, which began in 2010. It now in-cludes ACEP, the Society of Emergency

Medicine Physician Assistants, the Ameri-

Volume , . : October

I

Fsdwsmrs

HtbTfi“pvpwrlns

Arpf2Pfrmnf

can College of Allergy, Asthma andImmunology, American Gastroenterologi-cal Association, and the World Allergy Or-ganization. The program, supported byViroPharma Inc., features a new Web site,LetsTalkHAE.com. It has listings of areaallergists, iPhone apps, an HAE Webinar andother tools to teach emergency physiciansabout the disease, its detection and manage-ment.

EMERGENCY PHYSICIANSCRITICIZED

nformation for emergency physiciansincludes statistics from a 2007 surveyof HAE patients–they may account

for 15,000 to 30,000 ED visits annually.(To put that in context, the Centers forDisease Control reported that in 2008,there were 123.8 million overall visits toEDs, with 42.4 million visits related toinjuries.) Deadly aspects of the diseasewere apparent in the statistics reportingthat up to 30% of undiagnosed HAEpatients had mortality related to asphyx-iation from laryngeal edema.

The site tells emergency physicians ofthe frustrations of patients by emergencyphysicians and others who “often ordercourses of treatment that patients knowwill be futile.” Amid the increasing massof marketing materials and advocacy on-line sites for HAE, there are mentions–mainly by those with HAE–that charac-terize emergency physicians in less thanpositive ways.

The US HAE Association includes arevolving “Patient Stories” feature for itsnewsletter and online archive. One ofthose first-person accounts came from apatient named Elmer but known as Red.He tells of finally identifying his diseaseand the “miracle” of his first treatment.Elmer goes on say he had a recent attackone night and went to a local hospital’sED “with medicine in hand,” but person-nel there were clueless about HAE or thedrug. “It was like driving into an oldwest town that only has horse and bug-gies, and there I am in a new car, and noone wanting to hear my side of the story.I left after 3 hours and no infusion.”

In an US HAE Association newslettera month earlier, patient Linda, a motherof 4 children, had a similar story of herrelief at learning about her disease–“Fi-

nally, my ‘weirdness’ had a name!” Her

Volume , . : October

“nightmare” continued, she wrote, intrips to EDs during her swelling epi-sodes. “I had to tiptoe around egos.When I tried to explain anything aboutwhat to expect during my swelling at-tack, their attitude was: Who is she totell us how to approach treatment?”Linda said the answer was, “[I was] prob-ably the only one among them who ac-tually knew.” Her story went on to praisethe advocacy campaigns and leaders, say-ing she and her children have a choice ofeffective treatments and “don’t have todeal with emergency room egos, pain,shame, or the fear of seeming ‘odd.’”

Such sentiments surfaced in a lengthydiscussion among patient advocates, phy-sicians specializing in HAE and execu-tives of CSL Behring. Titled “Key Is-sues Dialogue: HAE in the US,” theforum was added to the company’s Website in September 2010. Participantstold of patients being subjected to yearsof misdiagnoses, unneeded surgicalprocedures, and even being labeled as“drug seekers” because emergency phy-sicians can’t determine the cause oftheir symptoms during abdominal at-tacks.

H. Henry Li, MD, PhD, who is boardcertified in Allergy and Immunology anddirector of Immunology of the Institutefor Asthma and Allergy in Chevy Chaseand Wheaton, told of one HAE patientwho took matters into her own hands.She set up an appointment with a localhospital’s emergency department Direc-tor to discuss its protocol for HAE attacktreatments.

Bruce Zuraw, MD, certified in Aller-gy/Immunology and Internal Medicineand the head of the University of Califor-nia–San Diego’s Allergy/ImmunologySection, said in the discussion that theED response can add mortality risks be-yond the immediate threat of laryngealattacks. There is the risk, he said, ofbeing given the standard ED “cocktail”–identified as steroids, epinephrine and an-tihistamine–“and then being kicked outof the emergency room. Basically, they’rebeing told, ‘This will take care of yourproblem, we’re busy and you’re out ofhere. I know there have been deaths dueto that exact scenario.”

Despite the clamor for the newer ther-apies, Dr. Li noted in the discussion that

androgen derivatives continue to play an a

effective role in both preventing attacksand in reducing the severity or frequencyof them in HAE patients. He said thereare exceptions, among them groups suchas pregnant women or young women andchildren, and others who experience sideeffects.

The “HAE in the US” discussionlargely avoided blatant marketing sub-jects, with the various panelists offeringup mutual praise for the progress in HAEawareness and advocacy. The HAE Asso-ciaton leader congratulated HAE therapycompanies for living up to their commit-ments to programs that subsidize sizableco-pay costs for patients unable to affordthem.

EXPENSIVE MARKETINGrom a commercial standpoint, thefull-out marketing campaigns addsignificantly to expenses. As Dyax

tated in its first-quarter 2011 SEC riskisclosures, “. . . Our expenses associatedith building up and maintaining the

ales force and distribution capabilitiesay be disproportional compared to the

evenues we may be able to generate onales . . .”.

The digital-dominant marketing byAE companies may reflect a broader

rend toward Internet and social mediay the overall pharmaceutical industry.he global medical marketing consultingrm of ZS Associates produced a 2010AccessMonitor Report” that tracks theharma industry. Based on extensive sur-eys, it said that fewer doctors, nurseractitioners and other drug prescribersere willing to regularly see pharma sales

eps. There was an 18% drop from 2009,eaving only about 58% of prescribersow considered as “rep friendly” withales forces.

That was followed in 2010 by a ZSssociates report of steep job cuts in the

anks of sales reps in the overall USharma industry. Job numbers had fallenrom the total of more than 100,000 in006, to fewer than 75,000 in 2009.harma officials cited the increasing re-

usal of physicians to see sales reps, theelative lack of breakthrough drugs to bearketed, and even the decrease in the

umber of hospitals. However, a majoractor was cited as pharma’s soaring reli-

nce on drug Web sites and interactive

Annals of Emergency Medicine 21A

“

media, including apps aimed directly atphysicians’ needs.

Indicative of the high Internet profilefor HAE therapies, the Pew Internet &American Life Project in late Februaryreleased its “Peer-to-peer Healthcare” re-port, authored by Pew Associate DirectorSusannah Fox in collaboration with theCalifornia HealthCare Foundation. It wasbased on telephone surveys with 3,001adults and online surveys of 2,156 mem-bers of the National Organization forRare Disorders.

INTERNET SAVVYPATIENTS

People living with rare disease, theirown or a loved one’s, have honedtheir searching, learning, and

sharing skills to a fine point,” the reportstated. “They endlessly scan resources forclues to try to cope with and mitigate theinevitable complications and setbacksthat come from rare diseases. What wasonce a solitary expedition for one personor one family, however, has become acollective pursuit taken on by bands ofbrothers- and sisters-in-arms who maynever meet up in person.”

Adults surveyed reported that 70%relied on a health professional for infor-mation, care and support the last time theyhad an issue with their help. Friends orfamily were cited by 54% for those needs,and 20% looked to others with the samehealth condition. When asked about get-ting that same help online, 5% said theyreceived it from health professionals, 13%

turned to relatives or friends, and 5%

22A Annals of Emergency Medicine

sought out others with the same conditiononline.

Survey respondents with rare diseases,however, “far outpaced all other groups,including those living with chronic con-ditions, in tapping the wisdom of theirpeer network.” More than half said theywent online to get that information, careand support from family or friends, andthat same majority reported turning toothers with the same rare disease for suchhelp. Health care professionals remain theprimary source for them. The findingsunderscore how highly polished onlinepharma campaigns–and pharma-spon-sored Web support groups–can be primeplaces to attract potential client/patientaudiences that would be otherwise tooscattered for more traditional marketingapproaches.

HAE’s journey from the shadows toInternet recognition can be tracked bythe images accompanying the new multi-platform marketing and advocacy thrusts.

US HAE Association, explaining thatfew photos had existed of patients duringtheir disfiguring attacks, created an on-line repository and called for members tosubmit pictures and x-rays. They wouldbe available for academic journals, con-tinuing education for health care profes-sionals–and promotional and advertisingmaterials by pharmaceutical companies.(Proceeds would go for the HAE Assoca-tion mission and services.)

Any earlier lack of photos and illus-trations has now been offset by illustra-tions that are summoned up by GoogleImage searches for HAE. The faces and

other body parts of dozens of attack vic-

tims, including before-and-after compar-ative photos, appear along with distin-guished portraits of HAE specialists androws of multi-colored posters and chartsdetailing the medical impacts and causes.Dominating them are the pharma corpo-rate logos and trademark therapies, alongwith the carefully crafted advertisementsfor target audiences. One for Dyax’s Kal-bitor illustrated under-the-skin handsclutching at a woman’s throat–an imagethat gained a prestigious Gold Awardfrom Medical Marketing & Media. TheGoogle images from an HAE search con-tinued for almost 39 pages.

At a panel discussion last year onHAE, advocates for HAE patients out-lined their progress on several fronts, in-cluding a research registry for patients.“We’re not stopping at this juncture sim-ply because there are products on themarket now,” said Janet Long, an HAEpatient who is executive vice president ofthe US HAE Association. “. . . We’vegone from zero to 150 miles an hour inthe last year, and we’re going to keepmoving forward.”

Section editor: Truman J. Milling, Jr, MDFunding and support: By Annals policy, allauthors are required to disclose any and allcommercial, financial, and other relation-ships in any way related to the subject ofthis article as per ICMJE conflict of inter-est guidelines (see www.icmje.org). Theauthor has stated that no such relation-ships exist.

doi:10.1016/j.annemergmed.2011.08.012

Volume , . : October