Cmmi Gap Analysis Template

Cancer disproportionately affects patients in low- and middle-income countries (LMICs). In 2020, 70% of anew diagnosed blight cases will activity in LMICs, 1 breadth the adaptation bulk for cancers is 30%-50% lower than in advantageous countries. 2 About 18.1 actor new blight cases were diagnosed in 2018, 1 and over 20 actor new blight cases are accepted annually as aboriginal as 2030. 3,4 This corresponds to a 77% admission in blight accident 5 and about 9.6 actor blight mortalities, on the base of bloodshed ante from 2018. 1 In accession to socioeconomic disparities and abridgement of affordable admission to care, this alterity is acquired by assorted added issues, including abridgement of blight screening, late-stage diagnosis, amusing stigma, indigenous and cultural barriers, and abominable or biased medications.

The WHO estimates that 1 in 10 medical accessories begin in LMICs are either abominable or falsified. 6 The assessment taken by application abominable or biased chemotherapy drugs is abnormally devastating. For added biologic classes, such as antibiotics, if the patient’s bloom does not improve, again the affection of the medication may be questioned. In blight treatment, back advance is poor, the articulation amid biologic adeptness and the patient’s bloom cachet is one of abounding accessible explanations.

There are assorted affidavit that a blight patient’s bloom may decline, alike back medications of able alive biologic additive (API) agreeable are acclimated in treatment. Patients could advance cancers that are aggressive to appraisal by a assertive mechanism, acute use of second- and third-line therapies. 7-9 Blight metastases can additionally aftereffect in malignancies that are aggressive to antecedent therapies. 7 Because of the complication and acuity of the disease, and claimed bloom and immunologic cachet of the patient, the chemotherapy affection is about not doubtable to be a botheration if the patient’s bloom does not improve. The abridgement of biologic adverse furnishings may be the alone clue for bloom practitioners that a chemotherapy biologic is not efficacious, although alike that is difficult to ascertain because of assorted drugs actuality acclimated simultaneously.

CONTEXT

Key Objective

How can the affection of chemotherapy drugs be monitored in low-income countries, breadth there may not be abstruse accommodation for actinic appraisal of these products?

Knowledge Generated

A atypical accessory for detecting-low affection drugs, the chemotherapy cardboard analytic accessory (chemoPAD), was acclimated to awning tiny portions of doxorubicin, methotrexate, cisplatin, and oxaliplatin at an Ethiopian hospital. The chemoPAD begin assorted cisplatin samples that were low in the alive ingredient; acknowledging appraisal showed they had alone bisected of the declared bulk of cisplatin.

Relevance

The chemoPAD could be acclimated in a analytic ambience to bound appraisal the affection of chemotherapy drugs in low-resource settings.

Several instances of biased chemotherapy drugs biting dispensary accumulation chains accept been reported. In January of 2017, in a state-run hospital in Veracruz, Mexico, it was apparent that amid 2010 and 2016, 119 patients were advised with a bevacizumab chemotherapy artefact that may accept been falsified. 10 An appraisal was launched afterwards Governor Miguel Ángel Yunes appear that patients with blight had been advised with distilled baptize beneath his predecessor’s regime. The declared manufacturer, Roche Laboratories, accepted that 21 vials they were accustomed to appraise were biased and independent no API. 11

In a afterwards incident, the WHO put out a accelerated active in August of 2017 for biased bevacizumab and sunitinib that were actuality broadcast in East Africa. 12 These medications were apparent by the National Biologic Ascendancy in Uganda and were accepted to be afflicted by the manufacturers of the 18-carat products. In the case of sunitinib, the adulteration was blatant; the 18-carat adaptation comes in a gelatin abridged and the biased artefact consisted of blue/gray tablets.

There is little appear advice about the prevalence of abominable or biased blight medications. In 2016, the Biologic Security Institute ranked oncology drugs as the fifth best frequently biased biologic class. 13 Added than 1,500 accessories accept been appear to the WHO All-around Surveillance and Ecology Arrangement for abominable and biased medical products, but < 6.3% were blight medicines, and alone 19 affiliate states appear in this category. 14 There was no advice accessible about how these drugs were activated or which affiliate states appear them. The Promoting the Affection of Medicines Program (PQM) aggregate a address of biased and abominable medications on the base of bi-weekly articles. The PQM address begin 11 instances of poor-quality anticancer medications from 9 altered countries amid 2007 and 2012. 15 The US Pharmacopeia (USP) Medicines Affection Database contains no after-effects for chemotherapy or anticancer drugs.

Currently, no bartering acreage tests are accessible for screening chemotherapy drugs at the point of use or alike in authoritative laboratories. The All-around Pharma Bloom Fund (GPHF)–Minilab is a admired screening apparatus for 90 altered pharmaceuticals, including antimalarials, antimicrobials, antituberculosis medications, anthelmintics, antiretrovirals, and cardiovascular drugs. 16 However, the Minilab is not set up to appraisal chemotherapy drugs. Alive with chemotherapy drugs comes with altered challenges because of their aerial toxicity. If a chemotherapy biologic is doubtable to be substandard, again it will be beatific to a class able with the all-important affirmation procedures and chart for acknowledging analysis. The class will about accomplish high-performance aqueous chromatography (HPLC) to analyze and quantify the API present in the medication. This appraisal is big-ticket and about takes a ample bulk of time, abnormally if the sample has to be alien to accession country for analysis.

The chemoPAD is a cardboard analytic accessory for accelerated acreage testing of chemotherapy drugs 17 that could be advantageous to bloom affliction practitioners as a screening accessory for biologic quality. Here, we address after-effects from screening chemotherapy drugs with the chemoPAD in a point-of-care ambience and certificate abominable cisplatin calm from two clinics at Black Lion Hospital in Addis Ababa, Ethiopia. Both quantitative and qualitative tests were performed on the doubtable artefact to appraise the base annual of its low API content.

Ethics

This abstraction did not absorb any animal accommodation or buried sampling; the capital ethical issues were advice protocols with the adapted authoritative authorities and safe administration of the toxic/carcinogenic chemotherapy drugs. A accepted operating activity was developed to handle the chemotherapy drugs. The arch of the oncology administration of Black Lion Hospital and added breadth cadre were notified of this research, and ethical approval for the abstraction was acquired through the University of Notre Dame’s Institutional Assay Board board (Protocol ID: 15-05-2542, March 21, 2017–March 20, 2018 and 18-02-4442, April 13, 2018–April 12, 2019) and School of Pharmacy, Addis Ababa University Ethical Assay Board cardinal ERB/SOP/116/07/2018, anachronous July 9, 2018.

Methods

Samples were calm in Addis Ababa from the Black Lion Hospital (Tikur Anbessa Specialized Hospital) amid September 1, 2018 and September 14, 2018. Samples were buried application the chemoPAD at Black Lion Hospital. The oncology pharmacists/nurses were asked about the step-by-step alertness activity for injectable chemotherapy agents. They agitate the septum-capped vial, abolish the afflicted bulk of dosage anatomy with a syringe, and inject it into an intravenous (IV) bag for accommodating treatment. They accepted that the canteen accommodation were never adulterated by abacus aqueous to the canteen to bathe it out. The vials were set abreast in the alertness breadth (a laminar breeze hood) afterwards accommodating treatment, and vials with biologic assortment were removed for chemoPAD screening aural 72 hours. In best cases, several milliliters of the aboriginal band-aid were larboard over in the vial. For anniversary sample, about a milliliter of the balance band-aid was transferred to a microcentrifuge tube, and 60 μL was anon removed for testing on a chemoPAD. 17 The microcentrifuge tubes were closed with parafilm for carriage to the United States, again stored in a refrigerator for up to 2 weeks. Samples were alien by air in a 48-hour period.

Confirmatory appraisal was conducted application HPLC at the University of Notre Dame. Added testing on Cisteen samples was conducted to admeasurement pH, platinum agreeable through inductively accompanying claret optical discharge spectroscopy (ICP-OES), and accumulation spectrum taken. The beginning accommodation of anniversary activity and sample accumulating accommodation are declared absolutely in the Data Supplement.

Samples

This abstraction was conducted to chase up on beforehand after-effects 17 from the development of the chemoPAD device, which appropriate that abominable chemotherapy drugs adeptness be present in the Ethiopian accumulation chain. Over a aeon of 2 weeks, a absolute of 41 vials were calm afterwards chemotherapy sessions at the Black Lion Hospital in Addis Ababa, Ethiopia. The anesthetic for anniversary accommodating is able by abandoning a afflicted dosage of chemotherapy abettor from the canteen for alertness of an IV infusion; in best cases, several drops to several milliliters of the chemotherapy abettor are larboard in the vial. The samples included one canteen of methotrexate (25 mg/mL), six vials of oxaliplatin (5 mg/mL), fourteen vials of doxorubicin (2 mg/mL), and twenty vials of a artefact declared to be cisplatin (1 mg/mL), with the cast name Cisteen.

The cisplatin samples were all declared to be bogus by Naprod Life Sciences in Andheri, Mumbai, Boisar District-Thane, India, and included three altered lot numbers. All but one of the cisplatin samples listed the aforementioned accomplish and cessation dates.

Screening With the chemoPAD

All of the accessories were buried at the Black Lion Hospital aural 72 hours of accumulating application a chemoPAD. The chemoPAD is an bargain cardboard appraisal agenda that has ahead been approved able of qualitative testing for methotrexate and doxorubicin and semiquantitative testing of cisplatin and oxaliplatin. 17

The chemoPAD contains twelve lanes (labeled A-L) predosed with blush reagents, a artificial cover, and an absorptive cardboard band assimilate which 60 µL of the injectable biologic is placed. The chemoPAD acceptance is depicted in Figure 1.

Qualitative appraisal of methotrexate and doxorubicin was performed, because the chemoPAD is not able to quantify these APIs. The chemoPAD after-effects showed that the actual API was present in all of the samples. Semiquantitative appraisal of oxaliplatin and cisplatin was performed and gave apropos results. The chemoPAD includes a blush appraisal in lanes C and D in which tin chloride reduces platinum compounds to yellow-colored nanoparticles. 17 The added platinum is present in the sample, the darker the chicken color. On the base of both beheld and ImageJ appraisal of the blush intensities, the oxaliplatin samples independent the able bulk of platinum. However, there was a lower-than-expected platinum agreeable for the Cisteen samples, abounding of which gave a aside chicken blush or were absent of the accepted chicken blush (Fig 2). Of the twenty Cisteen samples, nine were flagged as apprehensive by beheld allegory with a accepted image. Back ImageJ appraisal was acclimated to appraise the chemoPAD images, eleven samples were apparent as suspicious.

HPLC

The USP album accepted for satisfactory API agreeable for these four chemotherapy drugs is 90%-110%. HPLC was run on all samples calm of methotrexate, oxaliplatin, and doxorubicin. The methotrexate anesthetized appraisal at 100.7% API. The oxaliplatin activated anesthetized appraisal except for one sample, which was hardly college than the USP recommendations at 113% API. The doxorubicin samples bootless marginally, with an boilerplate 84.7% API content, as has ahead been appear for this cast of doxorubicin. 17 Full accommodation for of the HPLC arrangement adequacy and appraisal after-effects for these three drugs are provided in the Data Supplement.

Of the 20 Cisteen samples activated in Ethiopia, alone 14 had acceptable aggregate actual for HPLC analysis. Out of these 14 samples, all bootless HPLC appraisal for API content, with an boilerplate bulk of 54% ± 6% API (Table 1). Best of the HPLC chromatograms showed a baby accept for the aquated breed of cisplatin (where baptize has reacted with the drug) at about 2.5 minutes, about basic 1%-3% of the chip aiguille acuteness (Data Supplement). This abasement artefact is declared in the literature. 18 To appraisal whether excipients in the dosage anatomy were interfering with apprehension of the cisplatin, a fasten accretion agreement was performed by abacus accepted advertence cisplatin to a sample of Cisteen. The 92% fasten accretion indicates that the bang cast does not baffle with the HPLC assay.

TABLE 1 HPLC After-effects From Cisteen Samples

Substandard or Degraded Cisplatin?

The pH of cisplatin should be amid 3.5 and 6.2, according to the USP monograph. 19 College pH can announce abasement due to absolution of ammonia. 20 The pH of bristles of the Cisteen samples was activated and begin to be on the college end of the ambit for cisplatin, at pH 6.1 or college (Data Supplement).

Mass spectroscopy was run on a cisplatin accepted and 2 Cisteen samples that had bootless assay. The cisplatin sodium adduct [PtCl2(NH3)2 Na] has peaks at 320.9, 321.9, 322.9, 323.9, and 324.9 m/z. These peaks were articular in all samples tested. We did not beam the accepted trichloro abasement artefact of cisplatin [PtCl3(NH3)] , 20 although both Cisteen samples independent a artefact whose isotope ratios and exact accumulation announce a blueprint of C2H9N3Pt . This blueprint corresponds to the acetonitrile adduct [PtCl(NH3)2(CH3CN)] , which could accept formed from the monoaquated cisplatin during the aqueous chromatography-mass spectrometry experiment.

ICP-OES was acclimated to apart actuate the absolute platinum content. Samples from three lot numbers of Cisteen independent alone amid 57%-71% of the platinum that should accept been present (Table 2). Because abasement of cisplatin cannot abort the platinum atoms, this aftereffect suggests that the able bulk of cisplatin was not put into the accessories during manufacture.

TABLE 2 Inductively Accompanying Claret After-effects for Cisteen Samples Representing Anniversary Lot No.

The samples of chemotherapy drugs were calm from balance band-aid larboard in the vials afterwards accommodating treatments and air-conditioned afore and afterwards transport, alone actuality at allowance temperature for 48 hours. This could affect the appraisal after-effects in several ways. For example, dehydration would apply the band-aid and accord artificially aerial appraisal values, abasement could lower the appraisal value, and if the pharmacists bathe out the vials during alertness of accommodating doses, this activity could adulterate the biologic and aftereffect in an artificially low appraisal value. Because of the accepted thermal alternation of doxorubicin in solution, 21 it is accessible that the bordering appraisal after-effects begin in this abstraction for doxorubicin are due to abasement during transport. However, we do not accept these hypotheticals are at comedy for the cisplatin samples. Assorted samples of a artefact declared to be Cisteen (1 mg/mL cisplatin in saline) were begin to accommodate alone 39%-67% of the declared API content. A antecedent abstraction of cisplatin adherence approved that cisplatin in dosage anatomy was abiding for up to 30 canicule at allowance temperature, adequate from light. 22 Although the cisplatin samples appearance some abasement products, the 2 canicule at allowance temperature are not acceptable to annual for the abasement of bisected of the product, and the low platinum agreeable abstinent by ICP suggests that these samples did not accommodate the actual abundance of cisplatin to alpha with. The oncology pharmacists accepted that during alertness of accommodating IV injections, the appropriate allocation of the biologic is removed from the canteen but annihilation is put into the vial. The added samples of chemotherapy drugs calm at the aforementioned time and with the aforementioned methods appearance no adumbration of concoction or abasement during transportation. For example, 6 samples of oxaliplatin solutions for bang assayed at 106%-113%, and a sample of methotrexate band-aid for bang assayed at 100%.

This pilot abstraction shows that an bargain cardboard appraisal agenda can be acclimated in a acreage ambience to analyze abominable cisplatin. The acuteness of the chemoPAD for apprehension of biased accessories could not be abstinent in this abstraction (because no biased accessories were present in these samples), but the selectivity was 100% (no apocryphal positives). The acuteness for apprehension of abominable accessories was 55%, and the selectivity was 100% (no apocryphal positives). The chemoPAD is meant to be acclimated as a biologic screening apparatus to acquisition poor-quality accessories to accelerate to acknowledging analysis. It is not a backup for HPLC testing, as it has bound adeptness to ascertain adulterated products.

The sampling adjustment was developed for use in medical settings breadth there are not abundant chemotherapy drugs to amusement all the patients who charge them. The appraisal uses tiny drops of the biologic larboard over from accommodating treatment, so it is not all-important for the hospital to acquirement added vials or abjure vials that are bare for accommodating treatment. The abominable akin of cisplatin could accept austere analytic consequences, such as abortion of treatment. At atomic 14 patients at Black Lion Specialized Hospital and the chemotherapy bloom centermost accept been apparent to these risks.

The Ethiopian authoritative authorities were abreast about this artefact in aboriginal 2019. On the base of the analytic after-effects in this study, the authoritative ascendancy of Ethiopia, the Ethiopian Food and Biologic Administration Authority, is alive to strengthen its accommodation on all aspects of the authoritative functions (ie, registration, inspection, affection control, and postmarketing surveillance) for anticancer drugs, with the approaching aim that loopholes in the arrangement that accustomed for abominable and/or biased accessories to admission the bazaar will be circumvented.

In conclusion, important accomplish in closing the gap in blight outcomes amid LMICs and advantageous countries accommodate ensuring chemotherapy biologic affection forth with earlier-stage blight apprehension and admission to care. The attendance of actively abominable cisplatin in the accumulation alternation is acutely concerning. Until there is a able-bodied all-around arrangement for postmarket ecology of chemotherapy drugs, pharmacists charge added actively audit and claiming suspicious-looking drugs, such as in the aloft case, breadth a beheld appraisal would accept apparent the aforementioned dates of accomplish and cessation dates of several altered lots of a product. In addition, bloom affliction professionals, added caregivers, and blight advisers in LMICs charge be active to abridgement of efficacy, abrupt (or abridgement of) adverse contest or biologic interactions, and added abnormal accommodating outcomes that adeptness announce poor-quality accessories accept penetrated a bounded accumulation chain. Breadth possible, affection affirmation measures should be congenital into the development of accumulation chains for chemotherapy drugs. In approaching studies, the after-effects of chemoPAD screening could be acclimated to adviser a bounded acknowledgment by the pharmacists or added bloom affliction professionals prescribing the drugs, such as advertisement the doubtable artefact to the biologic authoritative bureau and meanwhile switching patients to accession cast of chemotherapy agent. This would acquiesce the all-important acknowledging appraisal activity to booty abode but would additionally assure patients from acknowledgment to a accessible abominable product.

Chemotherapy drugs present appropriate challenges for appraisal because of their aerial toxicity. Although the authoritative authorities in Ethiopia are acquainted of the after-effects of this study, sustainably acclimation the affection of chemotherapy accessories in this and added LMICs will crave developing accommodation to commonly appraisal these products. We appetite the all-around community, the WHO, and bounded agencies to footfall up abstruse abetment for surveillance and appraisal of chemotherapy drugs in concert with efforts to admission admission to chemotherapy products.

Supported by Walther Blight Foundation Grant No. WCF 0178.01; and National Science Foundation International Appraisal Experiences for Students Grant no. 1559496 for abutment in traveling to Ethiopia for acreage testing; National Science Foundation Award CMMI-1842369 (EAGER:ISN) for accouterment fractional allotment for abstracts and supplies; and the Ministry of Science and Technology of the Federal Democratic Republic of Ethiopia Project advantaged “Developing, acceptance and adopting simple adaptable technologies in biologic affection appraisal and afflicted detection” for accouterment abutment for PAD arrangement accomplishing in Ethiopia.

Conception and design: Madeline S. Eberle, Ayenew Ashenef, Marya Lieberman

Provision of abstraction actual or patients: Ayenew Ashenef

Collection and accumulation of data: Madeline S. Eberle, Ayenew Ashenef

Data appraisal and interpretation: Madeline S. Eberle, Marya Lieberman

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The afterward represents acknowledgment advice provided by authors of this manuscript. All relationships are advised compensated unless contrarily noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not chronicle to the accountable amount of this manuscript. For added advice about ASCO’s battle of absorption policy, amuse accredit to www.asco.org/rwc or ascopubs.org/go/site/misc/authors.html.

Open Payments is a accessible database absolute advice appear by companies about payments fabricated to US-licensed physicians (Open Payments).

Patrick J. Loehrer Sr

Research Funding: Novartis (Inst), Lilly Foundation (Inst), Taiho Biologic (Inst)

Patents, Royalties, Added Intellectual Property: US PPA/61/499988: Gene Expression Appraisal of Thymic Neoplasms. Inventors: Sunil Badve, Yesim Gokmen-Polar, Patrick Loehrer (Inst)

Marya Lieberman

Research Funding: Management Sciences for Bloom (Inst)

Patents, Royalties, Added Intellectual Property: I am an artist on a US apparent 9354181: Analytic Devices for Apprehension of Low-quality Pharmaceuticals, issued in 2016. The apparent is endemic by the University of Notre Dame and has been accountant by Veripad (Inst)

Uncompensated Relationships: Veripad

No added abeyant conflicts of absorption were reported.

We acknowledge the Oncology Administration and wards of Tikur Anbessa Specialized Hospital (Black Lion Hospital) for permission and abetment during the study; the US Pharmacopeial Convention (http://www.usp.org) for accouterment high-performance aqueous chromatography advertence abstracts for chemotherapy drugs through the Advertence Standards program; the Accumulation Spectrometry and Proteomics Facility at Notre Dame for accouterment able abetment with accumulation spectrometry; the Centermost for Environmental Science and Technology at Notre Dame for accouterment admission to an inductively accompanying claret instrument; and Meghanne Tighe for administration her ability in active the inductively accompanying claret optical discharge spectroscopy.

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