Bit­ter Pill

Amani Saini, BA’09, wants to es­tab­lish rou­tine ge­netic tests in Canada to com­bat one of the coun­try’s lead­ing, but lit­tle rec­og­nized, causes of death. And for her, it’s per­sonal.

Trek Magazine - - Sorting It Out - BY ALIA DHARSSI, BA(HONS)’09

It hap­pened in the fall of 2010, when stu­dents at UBC were writ­ing their midterms. Amani Saini’s younger sis­ter, a 19-year-old study­ing an­thro­pol­ogy, called her fam­ily’s home in Ab­bots­ford and asked her par­ents to come and pick her up. She wasn’t feel­ing well. Saini knew her sis­ter wouldn’t miss ex­ams un­less she had been stricken with some­thing par­tic­u­larly nasty, but she could not have an­tic­i­pated the rapid and se­vere wors­en­ing of symp­toms a short time later that would lead to a sur­real and ter­ri­fy­ing vigil at Van­cou­ver Gen­eral Hos­pi­tal’s ICU, pray­ing for her lit­tle sis­ter’s life.

Saini’s sis­ter was suf­fer­ing from toxic epi­der­mal necrol­y­sis. It caused her eyes to burn, her body to blis­ter, and her skin to peel off. A doc­tor told the fam­ily to pre­pare for a fu­neral, says Saini, still shaken by the mem­ory.

Al­most as shock­ing as the symp­toms and dire di­ag­no­sis was the cause: an ad­verse drug re­ac­tion to the ibupro­fen in a com­mon over-the-counter med­i­ca­tion she had taken to treat an or­di­nary cold.

Mirac­u­lously, af­ter three weeks in hos­pi­tal, Saini’s sis­ter sur­vived, al­though her qual­ity of life would not be the same. Saini, too, was pro­foundly af­fected. How could a non-pre­scrip­tion cold med­i­ca­tion lead to a life-and-death strug­gle? The doc­tors told her they didn’t know how it might have been avoided, says Saini, who couldn’t let the is­sue go. Now she is on a mis­sion to pre­vent ad­verse drug re­ac­tions (ADRs) like the one that nearly killed her sis­ter.

ADRs, which oc­cur when pa­tients ex­pe­ri­ence a harm­ful and un­in­tended re­ac­tion to a nor­mal dosage of a drug, kill 10,000 to 22,000 Cana­di­ans each year. It’s a num­ber that would place them any­where be­tween the third and fifth lead­ing cause of death in Canada, if they were recorded in the Cana­dian Vi­tal Statis­tics Death Data­base. But too of­ten, ex­perts say, it’s the re­sult of an ADR, such as toxic epi­der­mal necrol­y­sis (TEN), that is recorded as the cause of death, rather than the ADR it­self.

But now, dra­matic drops in the cost of ge­netic test­ing, along with re­search fo­cused on pin­point­ing ADRs in­flu­enced by an in­di­vid­ual’s ge­netic makeup, stand to change that un­set­tling statis­tic. Saini is work­ing closely with re­searchers at UBC and plans to play a cen­tral role by build­ing an or­ga­ni­za­tion to ad­vo­cate for poli­cies to pre­vent ADRs and help those who fall vic­tim to them.

“There are so many rea­sons why peo­ple die – drunk driv­ing, dan­ger­ous driv­ing, sui­cide, Alzheimer’s, can­cers, lung dis­ease – and if you look at these causes, they all have an [as­so­ci­ated] or­ga­ni­za­tion that’s advocating for [their preven­tion],” she says. “It just sur­prised me that, when my sis­ter got sick, there wasn’t re­ally any re­source that we could go to.”

Saini, an arts grad who had shied away from science for years, be­gan read­ing up on ADRs and pos­si­ble treat­ments. She was spurred by anger about the de­creased qual­ity of life ex­pe­ri­enced by her sis­ter, who took a se­mes­ter off from UBC af­ter most of her tear ducts were de­stroyed by TEN and still suf­fers from chronic dry eye. She must spend half an hour each morn­ing car­ing for her eyes, limit her time in front of com­puter screens, and use pricey eye drops ev­ery day.

Her story is not unusual. Hun­dreds of thou­sands of Cana­di­ans ex­pe­ri­ence ADRs each year. The ma­jor­ity sur­vive, but many suf­fer last­ing dam­age to their bod­ies. No one knows how big the prob­lem is. Health­care providers can re­port ADRs to a na­tional data­base, but ex­perts say it’s cur­rently dras­ti­cally un­der­used. For ex­am­ple, only four per cent of TEN cases are re­ported there, ac­cord­ing to a 2004 study from the Univer­sity of Toronto. New leg­is­la­tion en­acted in 2014 – Pro­tect­ing Cana­di­ans from

Un­safe Drugs Act (Vanessa’s Law) – re­quires manda­tory ADR re­port­ing by health­care in­sti­tu­tions, but this will not be en­forced un­til sup­port­ing reg­u­la­tions are pub­lished.

In BC alone, hos­pi­tal emer­gency de­part­ments treat about 210,000 pa­tients for ADRs each year, ac­cord­ing to 2011 re­search from UBC. In 2015, an­other UBC study found that one in 12 vis­its made by chil­dren to a pediatric hos­pi­tal in Nova Sco­tia was re­lated to prob­lems with med­i­ca­tions, in­clud­ing ADRs. Such hos­pi­tal vis­its, many of which are pre­ventable, come with a sig­nif­i­cant price tag: ADRs cost the Cana­dian health­care sys­tem more than $13 bil­lion each year.

Other coun­tries are al­ready tak­ing ad­van­tage of new re­search and cheaper DNA se­quenc­ing. In Taiwan, eight per cent of the pop­u­la­tion carry a gene vari­ant that can trig­ger TEN when they take cer­tain drugs. Genes that trig­ger TEN are also com­mon among South­east Asians and In­di­ans. (Saini’s par­ents mi­grated to the Lower Main­land from Pun­jab, a prov­ince in North­west In­dia.) Over the last decade, doc­tors in Taiwan, Thai­land and Sin­ga­pore have be­gun rou­tinely test­ing

Hun­dreds of thou­sands of Cana­di­ans ex­pe­ri­ence ad­verse drug re­ac­tions each year. The ma­jor­ity sur­vive, but many suf­fer last­ing dam­age to their bod­ies.

pa­tients for these gene vari­ants be­fore pre­scrib­ing spe­cific drugs that are known to cause TEN in those coun­tries.

Their sto­ries fired Saini up. In late 2015, she con­tacted re­searchers who stud­ied ADRs in South­east Asia to find out more. “That’s when I re­al­ized this is some­thing that can be adopted here,” re­calls Saini, a pol­i­tics nerd who has been ded­i­cat­ing her spare time to hu­man rights causes, such as geno­cide preven­tion and land­mines con­trol, since her teen years.

She soon met re­searchers in Van­cou­ver who were al­ready build­ing the knowl­edge needed to pre­vent ADRs in Canada. They were based in the same place where her sis­ter’s brush with TEN be­gan – at UBC. In fact, med­i­cal pro­fes­sion­als, ge­neti­cists and pol­i­cy­mak­ers in BC have the po­ten­tial to take a lead­er­ship role when it comes to prevent­ing ADRs, ac­cord­ing to Neil Shear, a Toronto der­ma­tol­o­gist who was the found­ing chair of the fed­eral gov­ern­ment’s Cana­dian Ad­verse Drug Re­ac­tion Ad­vi­sory Com­mit­tee.

More than a decade ago, scientists and doc­tors af­fil­i­ated with UBC, in­clud­ing Bruce Car­leton, Michael Hayden, and UBC ge­neti­cist Colin Ross,

BSc’93, spear­headed the Cana­dian Phar­ma­coge­nomics Net­work for Drug Safety (CPNDS), a group of clin­i­cians and re­searchers across Canada that aims to re­duce se­ri­ous ADRs in chil­dren. The net­work has made sig­nif­i­cant head­way, iden­ti­fy­ing can­cer drugs that can cause deaf­ness and heart prob­lems among chil­dren with spe­cific gene vari­ants. They also dis­cov­ered that codeine, a com­mon painkiller, can be life-threat­en­ing for breast­fed ba­bies if their moth­ers me­tab­o­lize it too quickly.

ADRs are “a big­ger prob­lem than most peo­ple re­al­ize,” says Ross, who has fo­cused his ca­reer on us­ing ge­nomics to im­prove the safety and ef­fi­cacy of drugs. He de­vel­oped the first gene therapy to re­ceive reg­u­la­tory ap­proval in the Western world dur­ing his post­doc­toral fel­low­ship at UBC.

Over the years, the net­work has gath­ered DNA sam­ples from more than 40,000 pa­tients. They in­clude those who haven’t, as well as those who have, had ADRs in­volv­ing spe­cific drugs. Most stud­ies re­quire any­where be­tween 50 and 1,000 will­ing pa­tients. Vol­ume and in-depth clin­i­cal data are key. Re­searchers run tests on their DNA sam­ples to iden­tify ge­netic fac­tors that might be linked to par­tic­u­lar ADRs. Typ­i­cally, they try to repli­cate the re­sults with a sec­ond, and some­times a third, co­hort of pa­tients be­fore fol­low­ing up with val­i­da­tion stud­ies us­ing cul­tured cells or an­i­mal mod­els, ex­plains Ross.

To date, ge­netic tests in Canada have largely been ap­plied to per­son­al­ize can­cer and HIV ther­a­pies. Phar­ma­cist and UBC re­searcher Mark Kun­zli, BSc Pharm’07, MBA’11, would like to see the use of ge­nomics ex­panded to more com­mon drugs. He speaks pas­sion­ately about the role of com­mu­nity phar­ma­cists.

Work­ing closely with Ron­ald Reid, a UBC phar­ma­ceu­ti­cal sciences pro­fes­sor, and oth­ers at UBC, Kun­zli tested a model for how phar­ma­cists could use in­for­ma­tion from ge­netic tests to help with med­i­cal pre­scrip­tions in more than 30 com­mu­nity phar­ma­cies across BC. One day, the re­searchers hope, doc­tors and phar­ma­cists will have a data­base con­tain­ing the ge­netic in­for­ma­tion of pa­tients they can use to per­son­al­ize treat­ment plans and re­duce ADRs.

Prevent­ing ADRs on a broad scale is a com­plex chal­lenge, in part be­cause they are so var­ied. Even though, as Kun­zli points out, “there are cer­tain sit­u­a­tions where we know with al­most ab­so­lute cer­tainty that if you have a cer­tain gene vari­ant and you take a cer­tain med­i­ca­tion at any dose, you will have an ADR,” (which is the case with Asians who have spe­cific gene vari­ants that trig­ger TEN), gen­er­ally speak­ing, ADRs are caused by any num­ber of drugs and in­flu­enced by many fac­tors, in­clud­ing age, ge­net­ics, and how some­one’s kid­ney and liver func­tion. They can also range in sever­ity – from an itchy nose to death.

Phar­ma­cists are al­ready trained to ad­just drugs based on a va­ri­ety of fac­tors, rang­ing from what peo­ple eat to how their liv­ers and kid­neys func­tion, says Kun­zli. “Now we’re just try­ing to ad­just drugs and drug pre­scrib­ing based on gene func­tion.”

Martin Dawes, head of UBC’s De­part­ment of Fam­ily Prac­tice, is work­ing on a prac­ti­cal tool to guide phar­ma­cists and physi­cians through the process. He helps run a per­son­al­ized medicine com­pany partly owned by UBC called GenXys, which runs phar­ma­co­ge­netic tests on DNA sam­ples of cus­tomers and sup­plies soft­ware that helps pa­tients and physi­cians make sense of the re­sults.

“The real fu­ture is where you’ve got it on your smart­phone,” said Dawes, en­vis­ag­ing the day when our ge­netic in­for­ma­tion is loaded into an app that helps us make de­ci­sions about over-the-counter med­i­ca­tion.

But, even as the fu­ture holds many pos­si­bil­i­ties, avail­able tech­nol­ogy and re­search have yet to be trans­lated into pub­lic pol­icy. “We’ve been talk­ing about it since 2003 – how [the Hu­man Genome Project] is go­ing to change ev­ery­thing. But it hasn’t,” says Kun­zli. “Why hasn’t it? Be­cause we haven’t been able to get the pol­icy to sup­port it.”

This is what Saini brings to the ta­ble. She holds a mas­ter’s de­gree in pub­lic ad­min­is­tra­tion from Dal­housie Univer­sity and has worked on health pol­icy for two provin­cial gov­ern­ments. Last year, she wrote a pol­icy pro­posal that called on prov­inces to test Cana­di­ans for gene vari­ants that

ADRs are caused by any num­ber of drugs and in­flu­enced by many fac­tors, in­clud­ing age, ge­net­ics, and how some­one’s kid­ney and liver func­tion. They can also range in sever­ity – from an itchy nose to death.

could trig­ger ADRs, ei­ther when they are born or when they are pre­scribed a new drug. In ad­di­tion to sav­ing lives, Saini ar­gues that ge­netic tests to pre­vent ADRs would save the health­care sys­tem bil­lions of dol­lars and ease the rush in emer­gency rooms. In Novem­ber 2016, the Cana­dian Science Pol­icy Cen­tre rec­og­nized her idea with the Science Pol­icy Award of Ex­cel­lence in the youth cat­e­gory, which rec­og­nizes “in­no­va­tive and com­pelling ev­i­dence-based pol­icy that will make a dif­fer­ence to Cana­di­ans” by those un­der 35.

Now, with ad­vice and sup­port from Dawes, Kun­zli, Reid and Ross, Saini is es­tab­lish­ing a non-profit or­ga­ni­za­tion ded­i­cated to prevent­ing ADRs. In ad­di­tion to advocating for tar­geted ge­netic test­ing, Saini plans to push for elec­tronic health records to give health­care providers clear in­for­ma­tion on a pa­tient’s al­ler­gies and gene vari­ants, and sup­port a manda­tory na­tional sys­tem for gath­er­ing data on ADRs.

“If the ev­i­dence isn’t there, you can’t re­ally act upon it,” she ex­plains. Even ev­ery­day in­ter­ac­tions with her sis­ter – like a re­cent Fri­day night when she couldn’t sleep over at Saini’s be­cause she’d left her eye drops at home – are a con­stant re­minder of just how im­por­tant this ev­i­dence can be.

“I’m happy my sis­ter re­cov­ered,” says Saini. “I feel re­ally blessed that she did, be­cause other peo­ple’s fam­ily mem­bers don’t. But it also does make me very up­set to know it is some­thing that is pre­ventable.”

Amani Saini Photo: Paul Joseph

(L-R) Colin Ross, Mark Kun­zli, Ron­ald Reid, and Amani Saini. Photo: Paul Joseph

Amani Saini met with re­searchers from UBC’s Fac­ulty of Phar­ma­ceu­ti­cal Sciences Photo: Paul Joseph

Last year, Saini was rec­og­nized by the Cana­dian Science Pol­icy Cen­tre

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