Clinical Trials

Building Trial Adherence With Packaging As the cost of running clinical trials climbs, compliance formats have gained favor for addressing persistently high non-adherence rates.

By David Vaczek Senior Editor

P alien! nun-adherence is a prevalent concern in clini­cal trials and one reason why clinical trial co~ts arc on the rise. When medication

adherence rates arc low, trials often have to be expanded with more par­ticipants to achieve meaningful results, rtclding to trial costs.

If patients leave off taking the dmg, yet maintain the apperu·ancc of being compliatH, non-adherence may go unrecognized.

Trial invc~tigators will then he lr.d to underestimate the therapy's cllcctive­ness, and the drug may be launched at a higher dose than is therapeutically necessary. If the dose is subsequently reduced posl-umrkcl, the company h<L~

to back-peddle on its revenue forcast. Drug companies running trirtls r~re

tuming LO compliance Jonuats, ns stud­ies dcmomtrate the value of patient­friendly designs in keeping patients on track with smdy protocols.

Sn1dics showing adherence improve­ment when compliance formats are used with commercially available drugs provide insights for di.11ical tr ial packnging, Dr. Knthy Zonra, pntient adherence consultant, C:~i Inc. (www. c3i-inc.com), said in a presentation nt the 1-leah:hcare Compliance Packaging Coundl's Rv\dhcrencc conference.

Zonca recommended that compa­nil:s LHkc these documented n:~ulLs with

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approved drug~ Hnd exteml the lessons lcamcd to the clinical trial setting.

"PHckagiug CHit be both a behavioral and educational support for patients in clinical trinls, acting ns reminders as to whether the medications have or have not been taken, and offering clear directions, instructions in how to accu­rately take the medication in order to f<>llow the trial protocol," Zonca said.

Trials arc growing increasingly com­plex, with increasingly complex patient instructions. A C.u:Lor in non-adherem;e rates, trial complexity is also dri\'ing a slide in patient trial retention rates, Zonca ~aid.

Trial proccdmcs questionnaires and assessments, routine exams, lab proced ures- -add complexity for patients and investigators .. Median total procedures per protocol were 166 pro­cedures in 2001:1- 2011, a 57ll;(, increase from 2000- 2003.

Among patieuts receiving treatment for chronic conditions in clinical trials, average adherence rates arc 42% to 78%, Zonca said.

The patient retention rate ha s dropped precipitous!)'· Less than 2:)'Y.• of patients screened were retained until trial completion in 2010, compared with nearly 50% of patients screened completing the trial in 200 1.

PROACTIVE MEASURES When m.lhercm:c is low in " cliui-

cal trial, researchers have to increase the sample size to m aintain study power. A 20% decrease in medication adherence may rewlt in the need for a greater thnn 50% increase in ~ample size to maintain equivalent power. A tl-ial with 50% mean compliance <'ould require about 4- times as many partici­pants as a h'ial with I 00% compliance, Zonca said.

The trial's goal is for patient adher­ence to the u·ial protocol. For a mar­keted drug, the objcclive is to maintain therapy towards having a healthier patient.

Yet the pronctivc measures for improving adherence work in both scl­tings. They indude: increased contact, reinlinn~menl of the value of partici­pation, and reminders- which include patient fi·iendly packaging with clear, concise labeling, Zunca said.

"Early intervention i\ critical. Effec­tive inte rventions combine education, motivation, support, reminders, and rewards," Zonca said.

Fisher Clinical Services is using more bliswr packaging in trials, as a preferred altcmative to lJotlles. "1-iost importrtntly, the packaging features enhanced graphics <md 'pictures', and more empha~is on patient directions," says Mike :\fCl"J'ear, vice president and global head or clinical supply optil t!Ua­tion services, Fisher Clinical Services (\1'\V\V.Jlsltet·cliuica.lset'\'ices.cottt).

"Fundamentally, a well-planned program thinh about how the paticm will take their medicine and be more likdy to adhere to their dosing regimen. Paticnt-friencUy packag­ing is all about ensuring that a patient dearly understands how the medicine is to be administered. In a lri<~l where a patient may tt~kc multiple medications, a blister pt~ckage helps lay out the protocol," .\rlcNear adds.

Clinical trials often have complex dosing regimens . .tvlany protocols require patients ro take multiple pills fi·om various columus presented iu a hlislt:r card, at dillercnt imervals each day.

Study spuusors wiH look fur cnlmnced graphical elements to help patients understand the correct way to take each scheduled dose, says Ward Smith, director of marketiug, Keystone Folding Box Co.

"Companies are now recognizing that the complexity of a dosing n:ginwn contributt:li to nun-adherence. They look to reduce dosing errorli via package design. fFor examplel they will ask us to use color blocking to visuaHy group pills to be taken at a specific time. Icons of the sun and moon arc commonly printed to designate the time of day each dose is to be taken," Smith says.

Most recently, clinical trials have begun to la\'or Key­stone's Ecoslide-~"{ package, adopted by Walmart last year for packaging generics in the chain's $4 prescription drug program. As the Ecoslide-lL'\.'s caleudarized design sup­ports adherence, the package offers improvement in fulfill­ment by eliminating the need tor heat sealing.

lu the asseml>ly of the patented Ecoslklc-RX, a small nylon rivet is snapped to the back of the blister . When the blister is loaded iuto the sleeve, the rivet engages with the rar1on to fun ction as a chikl-rcsiwmt lock-and-rdcasc bullon.

The Med-Ic Smart label from Information Mediary Corp. Is custom designed to fit medication blister packages for recording the time each dose Is removed. The removable, reusable electronic content monitor tag that records the activity Is hidden Inside the card.

April 2013 Pharrmccutkdl & ,\IL'<.ikdll'.tckaging New~ • Jmlpncw~.curn

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Clinical Trials

"\'\'e have: seen wide spread interest in the last few months fi·01n clinical trial material package rs. Customers ;m• seeing Ecoslicle-R.tX as a solution that reduces both material and labor co~ts. You can arhicvc dramatically fitstcr throughput as smaller packaging crews Cilll run a higher numLcr of pieces per hour. You eficctivcly reduce your total-dclh·crcd­package-cost," Smith sars.

Companies aJe realizing that the benefits of using adher­ence packaging in clinical trials outweigh the minimal aclcli­Lional costs, says John Nlusaus, ~tubal director, electronic adher<~nce solutions, ::vtWV J lealthcare.

"Cost and speed have been the two hiswrical issues, fwithl clinical trial budgets oftentimes fixed to a certain style of package. Clinical !rial !cams need packaging that is child­resistant and ea~ilr manufactured," :Musaus says.

"But more and more, people arc realizing that the pack­age t·<m aho play an intcgTal rule in assuring thai patients stay on their assigned treatment protocol. Study clata is clcarl>· showing that adherence paekagiu~ used instead of bottles helps people stay on protocol.

"The whole value chain is seeing that it pays to spend a little more time to get the package right. It has a ~mall effect on overall trial costs, and they can get a more accurate trial result,'' l'l'lusaus says.

CAPTURING DOSING HISTORY With so much at stake in a clinical trial, it is little wonder

that smart packaging- packaging that incorporates elec­tronic circuits for tracking patients' usc of a package- is receiving greater interest.

Smart packages provide a means of capturing unbi­asccl information on patient's dosing history. The data can be auali.:cd to help diuical Lrial teams bcucr uuderstand patient adhcrcnn· and exposure to the drug. This dosing information Glll also be used in couuselin~ paticuls to stil)' compliant with the protocol.

ln its drafi guidance, "Enrichment Strategies For C liui­cal Trials" (Docket #: FDA-2012-D-1145-0037) issued in December 2012, FDA cites "smart bottle.~" ns a tactic for eneuuraging patient compliance. M \VV H enlthcare has submitted comments calling on the agency to usc the term "smart packaging," noting that eleclronic mcdicaliuu event monitoring is aho a feature in unit-dose blisters, pumps, syringes, and nthes.

"And we believe the u sc of smart packaging should be more strongly cncountged [as it) offers the ability to r apture robust and high!)' rdiable dosing history data in an unob­trusive and non-invasive manner, and it has been used sur.­ccssli.tlly in hundreds of clinical U'ials in\'olving hundreds of thousands of subjects," 1\H\V Healthcare wrote.

"Smart packages tie right in with the rise of telcmoni­loring <llld tclchcallh that we are seeiug slllrt to come into more common use," Zonra said.

"1 believe Uta! as rcimbmsemem fi>r these sctviccs slarts

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to come into play and as doctors, clinics, and ACO's are measmcd ou oulcomes thal smart packages wiJI be one of the tools they will be looking for to support patients in achieving the best possible outcome.~ li.>r tlwm," Zonra said.

Though trial clinicians generally recognize the benefit of the datn obtained f1·om smnrt packaging, packaging depart­ments aho have 10 buy into il.

"There is Lots of data to support that patients moni­ton~d and counsded are murh more compliant overall . \Vith smart cards, you can measure exactly when patients extract their medicat ion during the tri:tl to help sites undcrstaml the patiems and counsel them appropriately," McNear says.

"\\'c have seen several trials utili.:e the t\'led-ic mmrl card product (from Tnformation Mediary Corp.) over the last two years. Two critical factors arc enabling thi~: the price point has tu be more rcalh!ic, ami [you need) the ability to use it with standard blister card fom1at~ currently deployed in the indusll')'," says 1\k.i\ear.

"The key for any technology advancement is volume. As volume used goes up, Ute price point goes lower. ln my opinion, smart packaging technology will increase signifi­<:antly over the next several years in clinical research as well as perhaps specialty commercia l markets," 1\kNear adds.

MWV's smart package portfolio includes t\ardcx Solu­tions' l\IEMSCap, the child-resistant Cerepaek, and the Helping Hand pncknge, which measure~ the instances when the blister card is slid in and out of the package.

"Interest and adoption of smart packaging ha~ increased dramatically as researchers and stati~ticians begin to fully appreciate the utility of the patient usage data collected by the package. Adh~rence data collected thro ugh ~mart pack­aging is now being used as an additional vital sign ," Musaus says ..

UNBIASED DATA SETS The data collected via smart packa ging is unbiased,

unlike data obtained from pill counts and patient diaries that rlepcncl on patient recall and arc sul~jcet to patient manipulation.

Studies b y l'viWV ami o!her:s have related patiems' dosin~ patterns measured with smart packages with their phanna­cokinetie (PK) pro liles, d emo11strating significant correla­tion. Pat ient dmg dosing history captured by the package is measured anti compared with the f>K values obtained fi·um monthly blood work visits.

"We have published slUdy da ta from trials showing that acccs~ing the medicine through the pack is equivalent- with high statistical reliability- to blood level serum conccntra­liom. So we can show how the d osing pruftle con-elates with how the blood level rose anrl fell during the course of the u·ial,":says !'l'iusaus.

"The utility of smart packaging for illuminating patient beha\•ior is hard to over~tatC'. Jf you are not measuring the

pmpncws.wm • l'hannat:culil'dl & M~"<lkall'.ttkaging Nc1v~ April 2013

adherence, you ha\'e no concept of what is happening with dosing behavior in between visits," he adds.

In a recent soon-to-bc-publi5hcd stud)' funded in Europe, the authcJrs reviewed and analyzed thr litr raturc on 79 dinical trials puhlishcu from 1995 to ~0 11, where tlleilica­tion ndhcrcnce wns il~Sesscd through clcctronicnll)' compiled drug dosing histories.

One study analysis showed an 8.8% increase in aclller­cncc when the intr.rvcnrion included feedback ro the patient of t.hcir n :ceut uusillg history. A seco11u analysis 011 a subset of ~tudics showed double the adherence improvement in palicuts receiviug lltis lccJback.

"The ~tud)' shows that having a healthcarc professional wu11scl a patie11t bascJ ou the inJiviJual's Jrug Josiug his­tory collected via electronic packaging is the mo~t successful technique for increasing adherence rates in triaL~. as com­pared with mc thotb such as textiug aud rcmimkrs.

"The clinicit~n at the trit~l site is taking the patient's own data and pointiug out how the>' can dmnge their behavior," .Musaus says.

NEW MODELS Though larger dinical trials have hccn tt trend of recent

}'cars, newer models have emerged as drug companies fC.Jcus on making trials both more efficient and informative.

"The mt:g<t trial seems to be dropping lmck Lin liwor ol) more 5tudics, more l>tudy starts, and fewer patient~ in many cases. Sponsors are getting more sophisticated with fore­casting aud developing techniques to predict curolment," .:vlcNear sa)'s.

"We're seeing this wilh adaptive desigu dini<.:al trials fwhere the trial study design changes as cl:ua accumulatcsl, hut abo where compauies are looking 10 get a 'go, no-go' decision in the quickest possible manner," he says.

Direct-to-patient or "virtual" clinical trials ht~vt~ fin· rear.h­ing potential to improve trial costs by avoiding the need for patient); to visit clinics and doctors' offices. In this home­based model, patients are screened for enrollment on line and participnnts rr.ccivc th eir meclications in the mail. Patients report fi·om their homes using smart phones and computers a~ they arc remotely assessed by investigators. Tht~ modd lws been held up as promising 1>pcedier study

n :cruitlllCill aud CHrollmeHl. 1nueased patient compliauce and retention rates arc seen as another potential benefit, as patients f(,Jiow their regimens iu the comlun of home.

Pfizt•r notably tested rhc direct-to-patient concept with the overactive hladder drug Detro! in ~011 iu the lirlit-evcr FDA-approved virtual clinical trial.

"The direct-to-patient model- if it comes to fruition will pul ever more OJtus on packaging design to he sclf-ex­plnnntOty nnd to ensure compliance ;mel npproprintc usc of the medication. Packaging that feature~ euhm~t.:cd iustnu.:­tion and more me of graphics would be a stand-in for visits hy trained mcdicalper~onuel,").kNcar says. •

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