Bad medicine

Mon­i­tor­ing pro­grams tar­get sub­stan­dard drugs

Modern Healthcare - - INTERNATIONAL - Kerry Grens

Pa­trick Luku­lay faced a daunt­ing task this month when he stepped off a plane in Accra, Ghana. Lo­cal clin­ics were re­port­ing that oxy­tocin, a drug used to stop hem­or­rhag­ing af­ter child­birth, was no longer work­ing.

Doc­tors had to dou­ble the dose to have the de­sired ef­fect. Some­times they had to try dif­fer­ent brands be­fore they found one that worked. Luku­lay, vice pres­i­dent of global health im­pact pro­grams at U.S. Phar­ma­copoeia (USP), had trav­eled to Ghana to train staff at African reg­u­la­tory agen­cies to crack down on poor-qual­ity drugs. Ac­cord­ing to the World Health Or­ga­ni­za­tion, 30% of mem­ber states have lit­tle to no reg­u­la­tory over­sight of phar­ma­ceu­ti­cals.

To il­lus­trate how bad the prob­lem can be, a study this year by USP and the Ghana Food and Drugs Au­thor­ity found 90% of oxy­tocin sold “failed qual­ity spec­i­fi­ca­tions,” Luku­lay says, call­ing the re­sults “damn­ing.”

USP, a not-for-profit or­ga­ni­za­tion that sets qual­ity stan­dards for medicines, launched its pro­gram for train­ing over­seas reg­u­la­tors be­cause its pu­rity stan­dards are be­ing rou­tinely vi­o­lated abroad. Sub­stan­dard prod­ucts from poorly reg­u­lated pro­duc­ers are be­gin­ning to af­fect the qual­ity of the U.S. drug sup­ply. Un­like coun­ter­feit, or fal­si­fied, drugs, which are an in­ten­tional ef­fort by crim­i­nals to slip fake prod­ucts into the global drug sup­ply chain, sub­stan­dard drugs are made by le­git­i­mate com­pa­nies that bun­gle the man­u­fac­tur­ing process.

It’s a threat that is likely to grow in the years ahead. Amer­i­can man­u­fac­tur­ers are in­creas­ingly look­ing abroad for their ac­tive phar­ma­ceu­ti­cal in­gre­di­ents and even fin­ished medicines. The hep­arin disas­ter in 2008, when 81 peo­ple died in the U.S. af­ter tainted Chi­nese chem­i­cals en­tered the sup­ply chain, awak­ened sup­ply-chain of­fi­cials to the poor over­sight of for­eign-made goods. Glob­ally, sub­stan­dard medicines in poorly reg­u­lated mar­kets are caus­ing count­less in­juries and deaths and are thought to be a lead­ing cause of grow­ing re­sis­tance to treat­ments for malaria, bac­te­rial in­fec­tions and tu­ber­cu­lo­sis.

“I think sub­stan­dard medicines have been a ne­glected as­pect of the poor-qual­ity medicine prob­lem,” says Dr. Paul New­ton, an in­fec­tious dis­ease spe­cial­ist with the Well­come TrustMa­hosot Hos­pi­tal-Ox­ford Trop­i­cal Medicine Re­search Col­lab­o­ra­tion in Laos.

The man­u­fac­tur­ers of sub­stan­dard drugs are usu­ally in low-in­come coun­tries that rely on generic ver­sions of drugs for com­mon con­di­tions and usu­ally lack reg­u­la­tory rigor over their own drug sup­plies. Roger Bate, an econ­o­mist at the Amer­i­can En­ter­prise In­sti­tute, a right-of­cen­ter think tank, and his col­leagues have sent lo­cal shop­pers into pharmacies to buy medicines in coun­tries such as Uganda. Af­ter test­ing the prod­ucts, they’ve found sub­stan­dard rates as high as 48%.

“From the re­search I’ve done, there’s no doubt that in­come is an in­verse de­ter­mi­nant to how many sub­stan­dard drugs one is likely to en­counter,” Bate says.

Al­though poorer coun­tries bear the bur­den of sub­stan­dard drugs, the prod­ucts can find their way to the U.S. Late in 2011, the In­dian drug­maker Ran­baxy earned ex­clu­sive rights to sell the first generic ver­sion of Lip­i­tor (ator­vas­tatin) in the U.S., “prob­a­bly the big­gest prize any gener­ics com­pany could ask for,” says Amir At­taran, an as­so­ciate pro­fes­sor at the Univer­sity of Ot­tawa.

But within a year, all hopes of dom­i­nat­ing the mar­ket for generic ator­vas­tatin crashed when a ma­chin­ery fail­ure al­lowed bro­ken glass to wind up in bot­tles, forc­ing Ran­baxy to pull the drug from the mar­ket. “They screwed it up,” At­taran says. Other com­pa­nies rushed in to fill the void, and Ran­baxy quickly lost its ator­vas­tatin fran­chise.

Just last week, Ran­baxy agreed to plead guilty in U.S. fed­eral court and pay $500 mil­lion to re­solve al­le­ga­tions of shoddy fac­tory in­spec­tions and poor qual­ity con­trol. The com­pany agreed to plead guilty to seven felony counts of in­tro­duc­ing “adul­ter­ated” drugs into in­ter­state com­merce and mak­ing false state­ments to the U.S. Food and Drug Ad­min­is­tra­tion. All of the drugs were pro­duced at com­pany plants in In­dia.

While there are scant data on the preva­lence of sub­stan­dard medicines, many ar­gue that the prob­lem is grow­ing. In poorer coun­tries, it’s more a mat­ter of in­com­pe­tence on the part of drug com­pa­nies or dis­trib­u­tors. “The phar­ma­ceu­ti­cal in­dus­try glob­ally has blos­somed over the past 10, 15 years, and qual­ity con­trol has not kept up,” New­ton says. For ex­am­ple, Bate says he’s found 284 anti-malar­ial drugs be­ing sold in Nige­ria alone. “That’s not a di­verse com­pet­i­tive mar­ket, that’s in­san­ity,” he says.

In de­vel­oped coun­tries such as the U.S., the prob­lem stems more from an in­creas­ing re­liance on over­seas sup­pli­ers, cou­pled with a labyrinthine sup­ply chain. Drugs used to be made pri­mar­ily in the U.S. and from ac­tive phar­ma­ceu­ti­cal in­gre­di­ents pro­cured in the U.S.

But now, “80% of what goes down an Amer­i­can’s throat comes from abroad,” At­taran says. Glob­al­iza­tion of drug man­u­fac­tur­ing is a “good thing,” he says, but it has also opened up op­por­tu­ni­ties for qual­ity to be­come com­pro­mised, ei­ther by a lack of know-how or pres­sure to re­duce costs by cut­ting cor­ners.

The hep­arin tragedy five years ago is the poster child for what can hap­pen. The wide­spread poi­son­ings oc­curred af­ter Bax­ter pur­chased in­gre­di­ents con­tam­i­nated with a cheap prod­uct that im­i­tated some of the drug’s properties. A sub­se­quent in­ves­ti­ga­tion by the FDA listed nu­mer­ous chem­i­cal sup­pli­ers in China con­nected with pro­vid­ing the poi­soned hep­arin or prod­ucts used in mak­ing it. Ac­cord­ing to the FDA’s web­site, the pres­ence of the con­tam­i­nant sug­gests that some­where along the sup­ply chain it was “added in­ten­tion­ally to hep­arin for fi­nan­cial rea­sons be­cause it is a very cheap ma­te­rial pre­pared by a sim­ple syn­thetic process.”

The in­ci­dent sent shock­waves through the ranks of U.S. sup­ply-chain of­fi­cials, who have to

scram­ble when­ever there is a ma­jor re­call, es­pe­cially of widely used drugs. “Some­times there are no al­ter­na­tives avail­able,” says Deb­o­rah Tem­ple­ton, vice pres­i­dent of sup­ply chain ser­vices at Geisinger Health Sys­tem, Danville, Pa.

Drug short­ages are also an in­di­rect ef­fect of sub­stan­dard medicines. “Among the causes of drug short­ages are man­u­fac­tur­ing is­sues, qual­ity is­sues,” says Kasey Thomp­son, vice pres­i­dent of pol­icy, plan­ning and com­mu­ni­ca­tions at the Amer­i­can So­ci­ety of Health-Sys­tem Phar­ma­cists.

Thomp­son says the glob­al­iza­tion of drug man­u­fac­tur­ing, and the in­abil­ity of reg­u­la­tors to over­see ev­ery step of the process, is “by far the big­gest chal­lenge fac­ing us to­day, and it’s only go­ing to grow.”

The most di­rect way to pre­vent sub­stan­dard medicines from en­ter­ing the sup­ply chain in the first place is to strengthen reg­u­la­tory over­sight abroad. That’s Luku­lay’s goal as he launches the Cen­ter for Phar­ma­ceu­ti­cal Ad­vance­ment and Train­ing in Ghana this month. The pro­gram, funded by USP, will ed­u­cate reg­u­la­tory agency staff in African coun­tries. “Hu­man re­source ca­pac­ity is the ma­jor is­sue in th­ese coun­tries, (es­pe­cially) high staff turnover. Reg­u­la­tory agen­cies are (staffed) with new­com­ers that do not have ex­pe­ri­ence,” he says.

USP also runs a USAID-funded pro­gram in 35 coun­tries to help bol­ster qual­ity con­trol. The pro­gram has helped to es­tab­lish drug mon­i­tor­ing sites where it trains staff to con­duct reg­u­lar test­ing and iden­tify sus­pi­cious prod­ucts for fur­ther scru­tiny.

“USAID and USP fund­ing can­not reach ev­ery cor­ner of the world that needs our help,” Luku­lay says. More­over, some coun­tries don’t put out the wel­come mat for for­eign­ers look­ing to train lo­cal reg­u­la­tors that will take ac­tion against le­git­i­mate, lo­cal drug­mak­ers that pay taxes and em­ploy peo­ple. “We un­der­stand this pres­sure ex­ists,” he says. “I must say it’s prob­a­bly one of the rea­sons why th­ese fa­cil­i­ties (con­tinue to) op­er­ate.”

Tougher reg­u­la­tory over­sight can bring an­other chal­lenge—how to help man­u­fac­tur­ers that serve those mar­kets meet the higher qual­ity stan­dards. Com­pa­nies that sell low-cost generic drugs of­ten lack tech­ni­cal ex­per­tise and cap­i­tal needed to bring their fa­cil­i­ties up to a higher level of qual­ity.

“There are a lot of costs to ad­here to in­ter­na­tional stan­dards,” says Gil­lian Buck­ley, the study di­rec­tor of a re­cent re­port by the In­sti­tute of Medicine on sub­stan­dard and fal­si­fied drugs. Pur­chas­ing equip­ment in over­seas mar­kets re­quires hard cur­rency that can be dif­fi­cult to come by. The IOM com­mit­tee rec­om­mended that de­vel­op­ment fi­nance or­ga­ni­za­tions such as the World Bank or the U.S. Over­seas Pri­vate In­vest­ment Corp. in­vest in im­prov­ing small- and medium-size drug­mak­ers in de­vel­op­ing coun­tries.

Luku­lay, who was one of the au­thors of the IOM re­port, rec­og­nizes it will be a grad­ual process and rec­om­mends en­cour­ag­ing for­eign reg­u­la­tory au­thor­i­ties and com­pa­nies to de­velop five-year plans to reach the higher stan­dards. “I think if you give com­pa­nies suf­fi­cient time to rec­og­nize you are se­ri­ous, that would be the best prac­ti­cal so­lu­tion,” he says. “To just say, ‘any com­pany be­low stan­dards, we’re go­ing to shut them down,’ it’s go­ing to be po­lit­i­cal sui­cide.”

In the U.S., the FDA has rec­og­nized that

“I think sub­stan­dard medicines have been a ne­glected as­pect of the poor-qual­ity medicine prob­lem.”

—Dr. Paul New­ton

sub­stan­dard medicines are a grow­ing threat. In re­sponse, the agency wants to be more proac­tive at pre­vent­ing poor-qual­ity drugs from be­ing pro­duced, rather than try­ing to block them at en­try into the coun­try.

It has stepped up its over­sight of fa­cil­i­ties that feed into the Amer­i­can drug sup­ply chain. For­eign in­spec­tions by FDA per­son­nel climbed from 305 in 2007 to 563 in 2013.

The FDA has also stepped up its ef­forts to stem the sup­ply of sub­stan­dard drugs that is plagu­ing de­vel­op­ing coun­tries in hopes it will also im­prove the drug sup­ply chain in the U.S. Last month, the agency un­veiled a new, hand­held tech­nol­ogy—de­vel­oped un­der the aus­pices of the Pres­i­dent’s Malaria Ini­tia­tive, launched in 2005—that will be tested in Africa to de­tect coun­ter­feit and in­ef­fec­tive anti-malar­i­als.

FDA Com­mis­sioner Dr. Mar­garet Ham­burg said dur­ing a news con­fer­ence that the “FDA hopes the test­ing will demon­strate the ef­fec­tive­ness of this tool and en­cour­age its wide-scale use to sig­nif­i­cantly im­prove the in­tegrity of prod­ucts that end up on the din­ner ta­ble or at the bed­side of pa­tients in the United States and around the world.”

De­spite the FDA’s ef­forts, the Govern­ment Ac­count­abil­ity Of­fice has ex­pressed con­cerns that the agency is sim­ply un­der­pow­ered to keep a close eye on ev­ery step of the sup­ply chain. Those for­eign in­spec­tions re­flect only a small frac­tion of the fa­cil­i­ties that are sub­ject to scru­tiny. “FDA faces lim­its on its abil­ity to re­quire for­eign es­tab­lish­ments to al­low it to in­spect their fa­cil­i­ties,” the GAO noted in a 2011 re­port, Drug Safety: FDA Faces Chal­lenges Over­see­ing the For­eign Drug Man­u­fac­tur­ing Sup­ply Chain. “Lo­gis­ti­cal is­sues pre­clude the FDA from con­duct­ing unan­nounced in­spec­tions, as it does for do­mes­tic es­tab­lish­ments,” ac­cord­ing to the re­port.

The AEI’s Bate says FDA in­spec­tions are im­por­tant, but that they are not the so­lu­tion. “It’s go­ing to come down to com­pa­nies them­selves,” he says. The drug in­dus­try also in­spects the plants they use to make the ac­tive in­gredi- ents in phar­ma­ceu­ti­cals, but Bate says it’s im­pos­si­ble to be per­fectly thor­ough.

Imag­ine the chal­lenge: mul­ti­ple sup­pli­ers of raw in­gre­di­ents feed into pro­duc­tion of the ac­tive and in­ac­tive in­gre­di­ents. To fully keep an eye on the en­tire sup­ply chain would have to in­clude th­ese sup­pli­ers, the fa­cil­i­ties where the drug is for­mu­lated, and the plant where it is pack­aged. Check­ing on them once does not mean they will be in the same con­di­tion the next time round, Luku­lay says.

“You can’t run ev­ery test on ev­ery chem­i­cal be­cause you’d run out of money,” Bate says. He pro­poses an au­dit­ing sys­tem that pools re­sources from com­pa­nies to form a stronger over­all in­spec­tion pres­ence abroad. None is planned, ac­cord­ing to a spokesman for the Phar­ma­ceu­ti­cal Re­search and Man­u­fac­tur­ers of Amer­ica, the drug in­dus­try’s ma­jor trade group.

Mean­while, the generic drug in­dus­try con­tends that sub­stan­dard medicines are not a prob­lem for the U.S. mar­ket. “There just isn’t a sub­stan­dard is­sue here” in the U.S., says David Gaugh, se­nior vice pres­i­dent for sciences and reg­u­la­tory af­fairs at the Generic Phar­ma­ceu­ti­cal As­so­ci­a­tion.

Gaugh points to the rig­or­ous test­ing cri­te­ria re­quired to im­port drugs for sale in the U.S. But as Luku­lay notes in the case of hep­arin, “just be­cause there are good man­u­fac­tur­ing prac­tice au­dits con­ducted, there is no fool-proof way to say you can’t end up with a bad API sup­plier.”

Tem­ple­ton at Geisinger says her group re­lies on the qual­ity-con­trol mea­sures by man­u­fac­tur­ers and “as­sumes that we’re get­ting good qual­ity prod­ucts.” But she says it’s also in­cum­bent upon doc­tors and other users to take ac­tion when some­thing doesn’t ap­pear right.

As much as glob­al­iza­tion might in­tro­duce risk, Bate says it can’t be stopped, nor should it be. “If we stop buy­ing from th­ese coun­tries we’d have many more (drug) short­ages than we do and prices would go up a lot,” he says.

At­taran is hope­ful that the prob­lem might work it­self out over time by com­pa­nies’ re­fus­ing to put up with poor-qual­ity prod­ucts. Ran­baxy quickly eval­u­ated its prob­lems and put in cor­rec­tive mea­sures to pre­vent a re­cur­rence. While the com­pany has since re­newed sell­ing ator­vas­tatin, “this was a blem­ish in our over­all cor­po­rate com­plex­ion,” says Chuck Caprariello, a spokesman for the com­pany. Ran­baxy never re­cov­ered its pre­vi­ous share of the mar­ket.

Bax­ter never re­sumed sell­ing hep­arin and sold the di­vi­sion that made the drug. “Com­pa­nies will make the cal­cu­la­tion,” At­taran says. “Is it worth the dam­age to one’s brand, is it worth the PR night­mare, the set­tle­ments to in­jured per­sons, to save a lit­tle money by sourc­ing from un­re­li­able lo­ca­tions?”

MOD­ERN HEALTH­CARE GRAPHIC

Source: U.S. Food and Drug Ad­min­is­tra­tion

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