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Operation Volcano - The Herceptin Case

September 2015

Publisher: AIFA - Agenzia Italiana del Farmaco
Editor: Domenico Di GIorgio

Project: Pharmaceutical Crime, Fakeshare

Authors:

Italian Medicines Agency

Summary of the biggest investigation on pharmaceutical crime held in Europe in recent years: stolen and falsified medicines, sourced from Italian hospitals and from other illegal chains, were recycled in the EU distribution network. This White Paper was submitted to the EC and published by AIFA.

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OPERATION VOLCANO

THE HERCEPTIN CASE

story, lesson learned, proposals

AIFA | AEMPS | AGES | IGZ | MHRA

OPERATION VOLCANO

THE HERCEPTIN CASE

story, lesson learned, proposals

AIFA | AEMPS | AGES | IGZ | MHRA

http:// www.agenziafarmaco.gov.it | e-mail: d.digiorgio@aifa.gov.it

(including photocopying, microlm, or other methods) without written permission from the editor.

Director of the Publication: Domenico Di Giorgio.

Editorial production: Italian Medicines Agency - AIFA.

Editorial Sta: Annalisa Berselli (AIFA), Gianpaolo Derossi (AIFA), Belén Escribano Romero (AEMPS), Marta Gramazio (AIFA),

Paul Hargreaves (MHRA), Manuel Ibarra Lorente (AEMPS), Marcel Moester (IGZ), Serena Panicale (AIFA),

Andrea Ungersbäck (AGES), Hannes Wuerkner (AGES).

Book design and Illustrations: Gianpaolo Derossi.

Thanks to: Gabriele Angiello (AIFA), Mark Cilia (Malta Medicines Authority), Patrick Costello (EMA), Mark Jackson (MHRA),

Alastair Jerey (MHRA), Ruth Mosimann (SwissMedic), Liv Weingartz (EMA), Marcus Wittstock (BfArM).

Special thanks to the Comando Carabinieri Tutela per la Salute - NAS and to all other administrations and WGEO delegates involved in this

investigation for their unvaluable support.

Hearty thanks to Pavle Zelić (ALIMS) for the support to this publication.

Compiling a book is a complex operation, which requires repeated checking of the text, the gures and the relations between these. Experience

shows that it is practically impossible to publish a book free of errors. We will therefore be grateful to readers who will point out such errors.

AEMPS Spanish Agency for Medicinal Products

and Medical Devices

AGES Austrian Agency for Health and Food Safety

AIFA Italian Medicines Agency

BASG FederalOfceforSafetyinHealthCare(Austria)

CAP CentrallyAuthorisedProduct

DHPC DearHealthcareProfessionalLetter

DRA Drug Regulatory Authority

EMA European Medicines Agency

EU European Union

FIMEA Finnish Medicines Agency

FMD TheEuropeanUnionFalsiedMedicines

Directive 2011/62/EU

GDP Good Distribution Practice

GMDP Good Manufacturing and Distribution Practice

GMP Good Manufacturing Practice

HMA Heads of Medicines Agencies

IWG Inspectors Working Group

MAH Marketing Authorisation Holder

MHRA Medicines and Healthcare Products Regulatory

Agency(UnitedKingdom)

MoH Ministry of Health

MS MemberStatesoftheEuropeanUnion

NUI NonUrgentInformation

OTC Overthecounter

RA Rapid Alert

RAS RapidAlertSystem

WGEO WorkingGroupofEnforcementOfcers

ABBREVIATIONS

The so-called “Operation Volcano”, also known as “Herceptin case”, origi-

nates upon receipt of an alert by a German parallel distributor, soon fol-

lowed by further investigations in respect of which emerged that vials of the

cancer medicine Herceptin (trastuzumab), stolen from Italian hospitals, have

been manipulated and falsied and re-introduced under false credentials by

unauthorized wholesalers into the legal supply chain. Seizures of falsied vials

have been carried out by authorities in Germany, Finland and United Kingdom

(UK). The distribution of the falsied vials to other European Union (EU) Mem-

ber States (MS) was also proved.

Upon further investigation by the Italian authorities, additional medicinal prod-

ucts have been identied as stolen in Italy and, subsequently, re-introduced

under false credentials by a criminal organization connected to Italy.

This has been facilitated through unauthorized wholesalers connected with the

Italian criminal organization, formally based in Cyprus, Hungary, Latvia, Roma-

nia, Slovak Republic, Slovenia and Greece issuing fake invoices to sell the stolen

medicines to authorised Italian and Maltese operators. These authorised oper-

ators have subsequently exported these to other EU markets.

A similar scheme, involving operators from other countries, was also discov-

ered.

The vulnerability of the parallel import channel to this kind of attack and the

lack of enforcement actions with respect to Good Distribution Practice (GDP)

(e.g. inspections to wholesalers) were major causes for the case; strong pro-

tection of the network via strict importing rules for parallel distribution and

traceability systems for medicines, cooperation between enforcement and

health authorities, sharing of information and intelligence knowledge (also via

web tools such as the AIFA/Fakeshare ones) allowed Italy to counteract crim-

inals and to avoid the inltration of illegal medicines and up to July 2015 led

to the arrest of more than 60 people in 8 dierent police operations in Italy,

and to the eradication of the hospital thefts

in Italy (passing from 3 cases per week, until

May 2014, to zero, from June 2014), but were

not enough for preventing further possible

theft/falsication/exporting criminal plot, as

demonstrated by the recent RA issued by Ger-

many and other MS with respect to the possi-

ble inltration of counterfeit medicines in the

same channels targeted in this case.

By explaining the case in detail, summarising

the key lessons learned and the possible pre-

ventive actions, this White Paper calls for a

stronger enforcement eort against phar-

macrime, with more resources at MS level

and an ad hoc coordination at EU level.

Investigation period Enforcement unit Arrested people Seized products

November 2013 Police (Lodi) 20 236 boxes

December 2013 Carabinieri (Caserta) 0 52.251 packages

February 2014 Carabinieri (Naples) 2 404 boxes

April 2014 Police (Bari) 4 680.00 euros

February 2015 Carabinieri (Siena) 9 Non declared (tons)

April 2015 Carabinieri NAS (Milano) 19 16.000 packages

June 2015 Guardia di Finanza (Rome, Naples) 10 68.000 packages

UPDATE AUGUST 2015:

police operations related to the

“Operation Volcano” criminal network in italy.

• November

Police

(Lodi)

2013

20 236

boxes

• December

Carabinieri

(Caserta)

2013

052.251

packages

Arrested

people

Seized

products

• February

Carabinieri

(Naples)

2014

2404

boxes

• April

Police

(Bari)

2014

4680.000

euros

• February

Carabinieri

(Siena)

2015

9ND

(tons)

• April

Carabinieri NAS

(Milan)

2015

19 16.000

packages

• June

Guardia di Finanza

(Rome, Naples)

2015

10 68.000

packages

THE STORY (SO FAR)

I.I Thefts of medicines in Italy

Theft of medicines (from hospitals and in the eld – i.e. from lorries and pharmacies)

had a big increase in Italy after 2011; the number of thefts in hospitals, in particular, was

so big as to become a “media emergency”, with weekly articles and reports, and even

University research (“Transcrime: the thefts of medicines from Italian hospitals”, http://

www.transcrime.it/pubblicazioni/the-theft-of-medicines-from-italian-hospitals/)

being published and promoted on the general press.

This emergency situation resulted in AIFA (Italian Medicines Agency) Counterfeiting Pre-

vention Unit setting up a project with industry in Italy in order to feed a shared database.

One of the primary functions of this project was for industry to share with AIFA informa-

tion about stolen medicines, i.e. name, manufacturer, “Bollini” number, batch details,

etc.: the database is being fed and the gathered data are analysed in order to understand

the real framework.

Another function was to organise those

information in order to let AIFA both in-

vestigate and respond to theft cases, and

refer to those data against pharmaceuti-

cal crime in general, being the phenom-

enon more complex and articulate than

isolated thefts.

THEFT PROJECT: TIMETABLE

• Beginning 2013:

increase of thefts of medicines in Italy since 2012.

• Spring 2013:

set up of the “Theft project” in order to share the data of

the phenomenon – AIFA, Farmindustria (manufacturers

association), ASSO-RAM (warehousing services association),

Carabinieri NAS (specialised police force), supported by the

Ministry of Health.

• Summer 2013:

set up of a shared database through a platform managed by AIFA.

• Autumn 2013:

gathering of data (from MoH, Industries, Distributors) and analysis.

“Wherearethestolenmedicinesfromthehospitaltheftsandtrucktheftsgoingto?” To

help answer the question were examined and tested six possible scenarios:

AIFA set up indicators for testing the different scenarios:

AIFA developed all listed instruments, and involved Carabinieri NAS, Customs and other

stakeholders in the test verications: the plan was to use these tools for triggering and

“ltering” signals coming from the different involved actors – e.g. customs, police, in-

dustries, health professionals.

1. Black market in the eld 2. Black market on the web 3. New supply to hospitals

National distribution on “grey/black

channels”

(i.e.toprivatehospitals,clinics,etc.ortodoping

network/beautycenters)

Specialised distribution via the Internet

(e.g.athletesnetworks…)

Mere nancial damage

(i.e.creationofashortagetobere-fullled)

4. Black market

to EU/non EU MS

5. Inltration of the legal

supply chain in Italy

6. Inltration of the legal

supply chain in EU

where medicines are cheaper or less

accessible. Transfer (undercover export)

to eastern Europe for distribution

through pharmacies, etc.

National distribution into the legal

network

(i.e.toItalianpharmacies,OTCpharmaciesand

hospitals)

Transfer (overt export) to northern

Europe

(e.g.paralleltrade)

1. Black market in the eld 2. Black market on the web 3. New supply to hospitals

Blacklist of stolen products and

related batch numbers to be shared and

training (police)

Winter 2013

IT intelligence activities (AIFA, private

companies)

Winter 2013

Evaluation of data (low incidence)

4. Black market

to EU/non EU MS

5. Inltration of the legal

supply chain in Italy

6. Inltration of the legal

supply chain in EU

Blacklist of stolen products and

related batch numbers to be shared and

training (customs)

January 2014

Evaluation of data, blacklist and

training (police)

Winter 2013

Watchlist for EU MS, set up of an alert

procedure (DB/signals)

Winter 2013

After some test in the eld, the most probable scenario was considered the last one (6):

a “blacklist” of stolen medicines was prepared and circulated to interested DRAs and

stakeholders in Europe, asking to report AIFA any suspect signal about incidents involv-

ing the listed products.

The database was also made available to industries and operators as a tool for process-

ing signals from the eld: any suspicion about a medicine could be processed by using

also the data regarding stolen medicines.

When in March 2014 the signal arrived, the system helped to identify

it in a timely manner: a manipulation occurred in Germany on

a medicine in AIFA blacklist was forwarded to the Market-

ing Authorisation Holder, that informed AIFA in real time,

since the reported batch number matched an entry of

the database.

I.II The case

A “signal” was received on March 31st, 2014, from a Ger-

man parallel distributor who received Herceptin 150 mg

from a wholesaler in UK, concerning what initially looked

like a defective vial that had been traded in the Parallel Im-

port system.

On March 31st the signal was forwarded to the manufacturer (Roche)

and to AIFA.

As reported in the NUI that Paul-Ehrlich Institute (released on April 2nd), during the de-

livery control of medicinal products from the UK wholesaler the following was observed:

• the batch number of the primary and the secondary packaging differed;

• the products were partially liquid (although it is a powder);

• residue of product was observed on the outside of the vial;

• some products seemed to have been reopened and closed.

Samples from each of the affected batches (H4319B02; H4129B01; H4284B04) were

seized.

Further investigation of the case was performed by involving also the manufacturer and

the AIFA Counterfeiting Prevention Unit: data were evaluated by using also the theft

database tools.

The check determined that the batch number could be related to a theft from a truck in Italy.

The quality signal and the theft data gave a possible explanation to what had been ob-

served: the mix up of batch numbers can be caused by the assembly of single stolen

vials in big packages, easier to replace on the market since importers prefer single batch

numbers; the manipulation may be explained since criminal organisations make

use of inltrators and those, besides stealing intact or “prepared” vials, might

recycle also products’ packages from garbage by relling and sealing

them in a way acceptable to non experts, in order to get more money.

Following the above mentioned initial NUI issued by Paul-Ehr-

lich Institute (April 2nd, 2014), whereby vials of the cancer

medicine Herceptin (trastuzumab), stolen from Ital-

ian hospitals/distributors, were reported to have been

re-introduced under false credentials by unauthorized

operators as falsied medicines into the supply chain,

a number of Member States have taken action where

required.

Seizures of manipulated vials have been carried

out by national competent authorities in Germany,

Finland and UK, while the MHRA inspected the UK

wholesaler and the Carabinieri NAS inspected the

Italian wholesaler who supplied to the UK: AIFA sup-

ported the identication of the products

as “illegally exported”, and “falsied”

with respect to the origin (as for the Dir.

2011/62 denition of “falsied medicine”).

The distribution of similar vials to other

EU MS was also veried.

In the invoices from the UK wholesal-

er two other products were detected,

namely Alimta and Remicade. The evi-

dence pointed rmly at a signicant dis-

tribution channel having been discovered

and not just a one-time case.

Upon further investigation by the Italian

authorities, additional medicinal prod-

ucts were identied as stolen in Italy and

subsequently re-introduced under false

credentials. This was facilitated through

the unauthorized operators operating in

Cyprus, Hungary, Latvia, Romania, Slovak

Republic and Slovenia issuing fake invoic-

es pretending to sell the stolen medicines

legally to authorised Italian operators.

These authorised legal Italian operators

subsequently exported these to other EU

markets.

Apparently, there was a consolidated

scheme: the criminal organisation behind

IDENTIFIED UNAUTHORIZED (“BOGUS”) WHOLESALERS

• CARNELA LIMITED

str. Michalaki Karaoli 8, Nicosia, Cyprus, VAT CY10308068X

• ABLE POWER INTERNATIONAL HOLDINGS

str. Podmaniczky Utca 57. 2/14, Budapest, Hungary

• AVIMAX HEALTH AND TRADE KFT

Fòti U. 4 Szàm, HU-2161 Csomàd, Hungary, VAT HU24206028

• MARS DISTRIBUTIONS KFT

Tompa M. Utca 9, HU-8360 Keszthely, Hungary, VAT HU11779074

• EURORIGA MED Import Export

str. Akademika Mstislava Keldisa Iela 12-158, Riga, Latvia,

VAT LV40103517211

• LATVAMED INTERNATIONAL Imp. Exp

str. Akademika Mstislava Keldisa Iela 12-158, Riga, Latvia,

VAT LV40103572887

• PERSONAL COMMODITY RINGSIDE

Municipiul Arad, str.Tribunal Dobra n.18 Judet Arad, Romania,

Fiscal code RO31031066 dated 19.12.2012

• ZEAPHARMA S.R.L

Municipiul Targu Jiu, Victoriei, bloc196, scara 3, etaj 2, ap. 10,

Judetul GORJ, Romania (note:Zeapharmaisauthorisedas

pharmacy,notaswholesaler)

• EXIMP AZ - sros

Bratislava, Slovak Republic

• PIRAMID D.O.O

Brniceva Ulica 31, 1231 Ljubljana, Slovenia, VAT 61869937

• TAIN D.O.O

Nova Gorica, str. Kridiceva Ulica n.19, Slovenia, VAT 76488632

• HILDONS

Feidiou 3, Thessaloniki, Greece, VAT number EL 800528668

• NIXERTRON IBERICA S.r.l.

via Novara 123, 20153 Milan, Italy, VAT 01063770323

this criminal operation hired local crimi-

nals in Italy to break into hospitals and to

hijack distribution trucks.

The stolen products were transferred to

an Italian licensed wholesalers and it ap-

pears that falsied receipts were creat-

ed for the shipments. Fake non licensed

wholesalers were set up in numerous EU

Member States, e.g. Hungary, Latvia, Cy-

prus, Czech Republic.

Authorised wholesalers in Italy received

(fake) invoices from one of the “bogus

wholesalers” in another country, e.g.

Hungary, and received the stolen medici-

nal products: It is likely that the medicinal

products never left Italian territory during this stage, the unauthorised operators’ mo-

dus operandi was aimed at legitimise the supply chain. The whitewashed shipment was

then sold by the licensed Italian wholesalers, e.g. in the UK.

The non Italian wholesalers, apparently, never asked anything more than the Italian au-

thorisation of the legal wholesaler1; they apparently believed they bought from a genu-

ine wholesaler for selling the medicines to other MS in that belief.

Since organisations in e.g. Latvia, Hungary etc. are unauthorised operators, the products

were considered as “falsied”; due to the falsication of the origin, they were not con-

sidered safe or effective, and consequently quarantined.

1 According to GDP guidelines, wholesalers have to verify only the direct wholesalers they are

buying from (see FMD).

LIST OF OPERATORS WHICH DIRECTLY BOUGHT

MEDICINES FROM THE “BOGUS WHOLESALERS”

• FARMA GLOBAL Srl

Via Boscofangone Snc, 80035 Nola, Napoli, VAT 06474151211

• FARMACEUTICA INTERNAZIONALE Srl

Via Dell’industria Snc, 83030 Pietradefusi, Avellino, VAT

02715470643

• FARMACIA COZZOLINO DI MARIO & CIRO S.N.C.

Corso Italia 15, 80056 Ercolano, Napoli, VAT 02778921219

• FARMACIA DELLA ROCCA

Via Sottotenente Ernesto Cirillo 207, 80041 Boscoreale, Napoli,

VAT 06345681214

• PHARMA-TRADE SPA

Via Roma,12 (Operative site: Via S.Abbondio, 158), 80045 Pompei

(NA), VAT 07034161211

• PHARMASEA Ltd.

11, Dingli Street, Sliema, Malta

With respect to the already investigated products, Italy traced all internal transactions:

the Italian operators that were supplied, directly or indirectly, by the unauthorised

wholesalers mentioned above were also inspected.

Member States were requested by AIFA in a NUI launched on May 14th to contact whole-

salers, relevant organisations and parallel distributors in their territory to temporarily

quarantine medicinal products bought from the unauthorized operators above, until the

outcome of the current investigations provide evidence of their safety and efcacy, and

to inform AIFA of any medicine bought from the Italian operators listed in the NUI, in

order to allow the “validation” of the purchase with the data made available to AIFA by

the Traceability System of the Ministry of Health.

Follow up NUIs were launched by AIFA on 28th of May, 1st and 25th of July and 26th of Au-

gust, aimed at disseminating a list of spe-

cic batches of medicinal products that

were conrmed as affected by the case,

updating the list of involved operators

and proposing specic activities of veri-

cation and inspection, when required, to

the competent authorities of other MS.

Further investigations allowed to dis-

cover that the “undercover distribution

network” sourcing stolen medicines from

Italy was applying similar schemes also in

other MS (a Malta/Romania connection

was demonstrated) and with other kind

of illegal products (falsied Herceptin,

Pegasys, Avastin were spotted between

2013 and 2014, in channels clearly related

to this one).

THE SUPPLY CHAIN MODELS

A) Bogus Operator sells to Italian Operator who sells to German

operator.

B) Bogus Operator sells to Italian Operator who sells to operator in

another MS who subsequently sells to a German operator.

At this stage it is estimated that this has been going on for three

years at least and involves hundreds of medicines.

The list of operators which directly bought medicines from the “bogus wholesalers”

mentioned above was also released as an Annex to NUI issued on the 14th of May, and

updated in the follow up NUIs (see box for the list)

Italian and Maltese authorities are progressing with regulatory action against the whole-

saler authorisations of the above listed operators.

To date, the licence for three of the operators was suspended for three months by the

competent local authority, Regione Campania:

• FARMA GLOBAL (degree n. 161, 29/7/14),

• FARMACIA DELLA ROCCA (n. 160, 29/7/14),

• PHARMA-TRADE (degree n. 162, 29/7/14).

Two of the operators are no longer active:

• FARMACEUTICA INTERNAZIONALE ceased its activities (as stated in the Regione

Campania degrees n. 72, 27/5/14 and n. 111, 3/7/14);

• PHARMASEA license was revoked by the Maltese authorities.

Between April and July 2014, Italian Prosecutors and joint investigation teams coordi-

nated by AIFA and Carabinieri NAS identied the involved operators, the distribution/

export channels and, moreover, even the undercover warehouses of the criminal organ-

isations.

In July 2014 three warehouses were found near Naples; police forces enforced the with-

drawal of the stolen medicines from the exporting channels, and local authorities acted

against the operators which directly bought from the bogus wholesalers.

It is now known that some wholesalers are not adhering to the regulations and this has

permitted falsied medicines to contaminate the parallel import/distribution network.

II.

CASE MANAGEMENT

II.I The verication process

II.I.I Validation of trades

Since the NUIs launched by AIFA recommended quarantining all products sourced by

operators that were “contaminated” by the bogus wholesalers, all EU MS started an

in-depth check of all trading activities which were in connection

with such operators; AIFA, Carabinieri NAS and other com-

petent authorities performed targeted inspections of the

whole supply chain and, after the July 1st NUI, all availa-

ble invoices related to possibly “contaminated” trades

were forwarded to AIFA and EMA for a systematic ver-

ication of the legitimacy of the trades.

The result of this exercise was double:

• AIFA worked on the data disclosed by the com-

petent Prosecutor, following the trades from the

bogus wholesalers to the rst EU MS outside of Italy,

with EMA and other MS followed up the next steps up

to the nal customer (top-down approach: nal goal, RA/seizure of the illegal

quarantined goods).

• EMA and AIFA led all invoices received by the MS, trying both to reconstruct

the full picture of the illegal trades (since some of the bogus wholesalers related

transactions appeared to be missing in the available seized documentation), and

to validate the legitimate trades, by verifying the origin of the products and the

traceability of the supply (bottom-up approach: nal goal, release of the quar-

antined products non related to the illegal network, and reconstruction of the

full picture of the illegal trades for the next follow up RA/seizures).

On the basis of the data collected and disclosed by Carabinieri NAS and by the com-

petent Prosecutor, AIFA have painstakingly identied the medicinal products that were

supplied via Route A listed above. They are involving other MS in the supply chain review

when one of the 5 authorised Italian wholesalers supplied product to a non-German

wholesaler/PDs (Route B above).

EMA and other involved EU MS authorities supported the verication and trades recon-

struction exercise, nalised at the compilation of the annex to the RA that AIFA issued

on August 8th.

The investigation has identied 100 products that have been supplied via the bogus op-

erators listed in the previous table. The products are listed in the RA issued by AIFA on

August 8th, including an Annex that was updated on August 14th, September 1st and Janu-

ary 29th, 2015. This Annex will be furtherly updated as more information becomes avail-

able.

Italian authorities continued to identify the supply chains for the medicinal products

concerned. On review of documentation from the bogus operators to Italian Oper-

ators (purchasers) it became evident that a large number of various medicines

(but in small volumes) were supplied utilising the same supply chains as for

the rst ve medicinal products identied and listed in the previous

NUIs. It was evident that in most cases the country of nal desti-

nation was Germany.

AIFA proposed recall of the medicines con-

rmed as falsied related to specic

trades, as listed in the RA Annexes, and

not the entire batches. Each Member State

had to search for trades in which they are

the last customer in the supply chain. Once

identied, these trades form the basis of a

specic MS recall.

It is important to note that AIFA proposed recall of the specic trade not the entire batch

referenced.

II.I.II Validation of operators

As part of the general investigation, AIFA and Carabinieri NAS enforced the proposal in-

cluded in the previous NUIs: Italian wholesalers were inspected by Carabinieri NAS and

all invoices related to the “bogus wholesalers” were led, and their trades traced to the

rst non Italian customer, as for the RA annex development process.

This inspection exercise was extended to all Italian operators who bought products from

the operators listed, and all new data regarding trades and operators were disclosed in

real time to all MS, via EMA mail list and AIFA restricted “fakeshare” web platform: the

new bogus operator HILDONS was for instance identied in July 2014 during the inspec-

tion campaign, its nature conrmed through direct contacts between AIFA and Greek

authorities, and the distribution of the information to the network authorised in real

time by the Prosecutor.

After the RAs were issued, a new inspection campaign was launched as a result of the

new data gathered by EMA and EU MS authorities; the results of the new campaign will

be disclosed by AIFA through the same authorisation process and distribution channels

used previously.

The results of this campaign should conrm the security of the distribution network in

Italy, allowing all EU MS to consider as “safe” any trade related to the validated opera-

tors, with no need for further statements by the competent Italian authorities. There are

no illegal activities recorded and conrmed after the third NUI launched by AIFA (July 1st,

2014). Invoices forwarded by EU MS authorities have been conrmed as legitimate.

It is likely that this new campaign, in combination with the RA follow up activities, will

trigger the identication of new actors and trades. For example, Italian authorities

have suspended the licence of another operator (ITAFARM SRL, Strada del Piano 49/E-

51, 06135 Ponte S. Giovanni, Perugia, VAT 04944591009), even if for infringements that

currently seem unrelated to the targeted illegal channels, whilst Italian and other EU

PRODUCTS SOLD MOSTLY TO HOSPITALS

These are products for which the dispensation is exclusively at

hospital level. AIFA contacted the MAHs of these products in order

to verify the distribution chain and validate the data through the

Italian Traceability System of the Ministry of Health. This let AIFA

identify the products sold directly to hospitals

without any wholesalers’ involvement. Hospitals

are not allowed to export or resell these

products: any of these products found at level

of wholesalers’ channel should be regarded as

“suspect” at least, and evaluated further.

BRAND MAH MAH STATEMENT

AFINITOR Novartis Farma S.p.A. Note to AIFA, 3 September

2014

ATRIPLA Gilead Sciences S.r.l. (for Bris-

tol Myers Squibb) Note to AIFA, 8 August 2014

AVASTIN Roche S.p.a. TWIMC 16 May 2014

CAELYX Janssen-Cilag SpA Note to AIFA, 28 August 2014

ECALTA Pzer Italia S.r.l. Note to AIFA, 3 September

2014

EVIPLERA Gilead Sciences S.r.l. Note to AIFA, 8 August 2014

EXJADE Novartis Farma S.p.A. Note to AIFA, 3 September

2014

FASLODEX AstraZeneca S.p.a. Note to AIFA, 6 August 2014

GILENYA Novartis Farma S.p.A. Note to AIFA, 3 September

2014

HERCEPTIN Roche S.p.a. TWIMC 17 April 2014

IRESSA AstraZeneca S.p.a. Note to AIFA, 2 September

2014

MABTHERA Roche S.p.a. TWIMC 16 May 2014

NPLATE (250mg) Amgen S.r.l. Note to AIFA, 11 August 2014

PREZISTA Janssen-Cilag SpA Note to AIFA, 28 August 2014

ROACTEMRA Roche S.p.a. Note to AIFA, 7 August 2014

STELARA Janssen-Cilag SpA Note to AIFA, 28 August 2014

MS authorities are currently investigating

suspect movements connected with the

“bogus wholesalers” activities.

II.I.III Triggers for new signals

One of the key lessons learned during this

phase of the investigation is that since

the counterpart is a criminal organisa-

tion, it is impossible to rely on informa-

tion sourced from the paperwork facade.

Moreover, some of the information relat-

ed to the illegal channels emerged only

after repeated police inspections and

in depth IT verications; and since the

comparison between the number of sto-

len medicines (as for the available Ital-

ian data), the disclosed invoices and the

“Italian sourced medicines” highlighted

visible outliers and unbalances, it is like-

ly that there are still more undercover

channels to be discovered.

In order to generate more signals to be

investigated, AIFA asked MAHs and the

Ministry of Health for support in order to

identify products that were not legally

exported after April 1st 2013: this exercise

was aimed at giving all MS new referenc-

es for identifying suspect invoices and

trades.

AIFA then checked all available tracea-

bility data, and asked MAHs of hospital

medicines listed in the RA annex to spec-

ify if they sold products to wholesalers

(i.e. the only wholesalers legally export-

ing medicines) after April 1st 2013. MAH

declarations were validated using the

traceability data gathered by the Italian

Ministry of Health through the medicines

track & trace system in place in Italy.

On August 26th, a list of products for

which the distribution was intended for

Italian hospitals (which are not allowed to

export these medicines) was released via

NUI: since any trade related to the above mentioned list of products should be regarded

as “suspect” at least, and evaluated further, AIFA asked all operators to send any infor-

mation regarding trades of those products which occurred after 1st April 2013, that were

not already listed in the 8th August RA, and recommends to quarantine the suspect goods

until further verication of the trade.

The goal of this exercise is to support the research of any other illegal channel that is

still out of the investigation: any signal will be evaluated (through traceability data and

verication with MAH) and, if conrmed as “suspect”, forwarded to police/prosecutor for

the follow up activities (e.g. inspections and seizures), in preparation of further update

of the RA Annex.

II.I.IV Restoring of the security of the italian supply chain beyond the Herceptin case

During the crisis period, Italy put in place additional checks and verications that are

currently guaranteeing the safety of the supply chain: NAS inspections, reinforced veri-

cation on MoH traceability data, cooperation with MAHs and wholesalers associations

for data verication and invoices check, support to other MS in invoices verication were

all major triggers for the enforcement of the proper GDP processes validation, with re-

spect to the criminal inltration that was highlighted by the AIFA/NAS investigation.

BRAND MAH MAH STATEMENT

SUTENT Pzer Italia S.r.l. Note to AIFA, 3 September

2014

TASIGNA Novartis Farma S.p.A. Note to AIFA, 3 September

2014

TRUVADA Gilead Sciences S.r.l. Note to AIFA, 8 August 2014

TYSABRI Biogen Idec Italia S.r.l. Note to AIFA, 6 August 2014

VELCADE Janssen-Cilag SpA Note to AIFA, 28 August 2014

VIRAMUNE Boehringer Ingelheim Italia

S.p.a. Note to AIFA, 6 August 2014

VIREAD Gilead Sciences S.r.l. Note to AIFA, 8 August 2014

VOTRIENT GlaxoSmithKline S.p.a. Note to AIFA, 7 August 2014

Since GDP inspections are not specically targeting criminal behaviours, Italy is putting

in place extra verications to be applied in order to avoid the possible resurfacing of this

kind of criminal inltrations: the inspection systems will be strengthened through the

cooperation between NAS and competent authorities, allowing to maintain the degree

of condence on the validation that was conrmed through the extraordinary proce-

dures put in place during the investigation, and the already established procedures for

tracing legal operations will be put in transparency, in order to allow other EU MS to

easily check by themselves the legitimacy of the supplies.

With respect to this, it is important to note that legally distributing/exporting operators

are currently obliged to send to the Traceability System of the Ministry of Health all data

about the medicines they export: products, number of pieces, batch numbers, dates and

MS of destination.

Lack of communication of those data is considered as a relevant infringement, since it

impacts on the traceability of the medicines; specic sanctions are already considered

in the Italian regulation, and could trigger not only administrative nes, but also licence

suspensions.

These data may be automatically correlated by the tracea-

bility system to the MAH supplies, highlighting any suspect

activity (i.e. export non related to previous supplies);

MoH and AIFA will develop a system for giving MSs

access to the validation data and will also prepare

an ad hoc “certication le” that all MS opera-

tors could request from their Italian suppliers,

as an ofcial conrmation that the distribution/

export is traced and legal.

AIFA currently publishes on its website alerts,

blacklists and data about stolen medicines:

the restricted “fakeshare” web platform, ac-

tive since January 2014, was made available to

operators and authorities for the sharing of infor-

mation during the crisis, and will be developed further as a current tool for operators,

whilst the ad hoc “open” webpage (already active: http://www.agenziafarmaco.gov.it/

en/content/falsied-illegal-and-stolen-medicines-0) will be used for the dissem-

ination of guidance documents, such as guidelines (e.g. the “WGEO due diligence” for

wholesalers, a “list of suspect signals for wholesalers” that AIFA is currently developing,

and a list of available web resources for checking the National authorisations of whole-

salers), alert on stolen medicines, and the explanation of the verications on the Italian

supplies for the interested operators.

Some of the measures could be easily implemented at EU level as preventive actions

against the resurfacing of the contamination.

II.II Coordination activities

Upon the rst alerts for Herceptin, BASG/AGES required the parallel distributors, which

are located in Germany, to recall the batches identied (April 16th to 18th, 2014). Within

the recall correspondence BASG/AGES not only asked for delivery data, but also for pur-

chase data (name of the supplier). For getting an overview EMA set up spreadsheets to

collect the delivery routes of Italian-origin Herceptin batches. By checking the spread-

sheets and contacting the relevant DRAs, the original supplier in Italy could be identied

for mostly all quantities of Herceptin which were distributed to Austria within few days.

One route was traced back to a Maltese supplier, and after contacting the DRA in Malta,

an inspection took place which revealed that this supplier sourced Herceptin from an

unauthorized supplier.

In the mid of May 2014, all parallel importers based in Austria were inspected or ofcially

contacted to provide the names and status of their suppliers for special parallel traded

medicinal products. Afterwards a check was done whether the named companies under

suspicion were on the circulated list of the bogus wholesalers.

A focus project was started to collect all purchase data of all medicinal products affect-

ed in this case to check whether all actors involved in the distribution chain possess an

authorization according to Directive 2001/83/EC.

BASG/AGES coordinated and required all data relevant for the Austrian market (e.g.

asked DRA to provide data on suppliers for Herceptin delivered to Austria) and analysed

the data.

A coordination of all investigative measures and outcomes (e.g. collecting the analyses

reports) as well as asking for required data all over Europe (which was partially done by

EMA) and an analysis of the data given with investigative measures to follow on DRA side

would be useful. In this case, analysis of data was done on DRA level only by those DRAs

affected as end user countries – to different extent.

II.II.I Roles of dierent entities during this case

Role of EMA

• Coordination and set up of spreadsheets completed by member states;

• Providing data on parallel distribution notications;

• Coordination activities and requests to affected DRAs from DRA side for CAPs.

Role of WGEO Task Force Volcano (founded in Vienna during the annual WGEO - Meeting)

• Discussion of next steps and recommendations from enforcement side;

• Keeping in mind the broader involvement of other branches of the illegal net-

work in other MS.

Role of AIFA

• Providing data and analysing data, primarily related to the Italian case;

• Linking the prosecutor in Italy to European DRAs and EMA;

• Summarising all information and coordination of discussion/joint activities

between DRAs and investigators (via organisation of webinars, teleconferences,

development of documentation, publication of NUIs, RA and press releases);

• Sharing of information between DRA/enforcement activities through the “fake-

share” web tools (restricted web area, webinar platform, etc.).

Role of DRAs

• Providing data on distribution of medicinal products affected in this case follow-

ing requests from EMA, Italy or other concerned MS;

• Some DRAs are not affected as target country, which may have inuence on

setting priorities in corresponding.

Investigative Coordination

• Is currently done by AIFA for the Italy case which is a heavy workload;

• Information is missing whether further suspicions are addressed/followed-up/

coordinated from enforcement side (e.g. the Romanian/Malta case, the Roma-

nian Herceptin/MabThera/Sutent cases, evaluation of notications of parallel

distributed medicinal products and trade that gain no nancial benet for the

involved companies when legally bought).

III.

KEY LESSON LEARNED

The management of the “Operation Volcano” made it clear that additional enforcement

resources are necessary to tackle any cross-border illegal trafcking of this magnitude.

These resources have to be allocated within DRAs to handle such cases adequately in

order to protect public health.

GMDP inspections are mostly focused on the pharmaceutical quality system. Empiri-

cally, signals of criminality cannot be found that way. Although irregularities might be

addressed by GMDP inspectors, further enforcement investigations are necessary to

tighten the suspicion. DRAs are well staffed with personnel to narrow down the risk and

danger to public health caused by falsied medicines. GMDP personnel is competent

to set up guides and measures to prevent falsied medicines entering the legal sup-

ply chain, but when this occurs many different professional experiences in the phar-

maceutical area have to be considered before a case can be xed. Only specialised DRA

enforcement personnel are trained to address and prove irregularities especially of the

provisions of FMD. Coordinated surveillance of the market and communication between

these two groups is necessary. Finally, each other’s experiences have to be implemented

in prevention programs to secure public health.

Another evidence stands out: there is no common procedure for handling in a coordi-

nated way transnational enforcement cases in healthcare. The “Herceptin case” proved

how spread and interconnected illegal activities in Europe are, while the operations set

in motion proved the importance of sharing a common procedure at a European level to

tackle such activities which have European impact and require proactive measures to

identify signals by all involved MS.

Training of GMDP inspectors should attract more attention to nding signals of irregu-

larities/illegal practices and criminalities, which can never be found by using standard

procedures. Every inspector should be aware, that no criminal case is like the last one.

The supply chain to parallel importers and distributors can be complex and there is cur-

rently no system that enables visibility of the full audit trail, even in MS where existing

regulations support traceability.

Looking closer to complex criminal cases will mostly end up in nding several other non

compliant activities conducted by well known and inspected authorised companies, like

the fact that vials were detected during delivery control as manipulated but no notica-

tion was carried out to the National Competent Authorities or buying from not author-

ised wholesalers.

The same illegal structure can be driven in another country at the same time, following

the same set up, like the Romanian signals indicate. Awareness raising and the will to

preserve condence in the parallel trade system can strengthen the ambition for com-

pliance.

IV.

PROPOSALS

IV.I Enforcement coordination

The medicines supply chain is constantly being challenged by criminal activity and this

paper and associated proposals appear to be a positive step towards managing this risk.

It is clear from the lessons learned that well-coordinated, effective and efcient en-

forcement collaboration by member states is key in ghting medicines crime. It is there-

fore suggested that, in complex cross border cases involving more than two member

states, an ad hoc medicrime enforcement taskforce, comprising of staff from enforce-

ment departments within drug regulatory agencies and associated bodies, should be

formed.

The formation of an enforcement taskforce will enable members to share information

and partake of intelligence and best practice, as well as gauge enforcement capabilities/

limitations and provide assistance in capacity building and training. Tools and guidelines

can also be developed, for example the WGEO due diligence document, and shared with

appropriate stakeholders. The ad hoc enforcement taskforce will also endeavour to co-

operate with competent international bodies such as EMA, EUROPOL, INTERPOL, and

others at eye level.

One of the primary roles of the medicrime enforcement taskforce will be to gather intel-

ligence by collection and analysing each signal and supporting national competent au-

thorities such as police, DRAs and customs with concrete questions to be able to conduct

investigations in a timely and efcient manner, share information and focus on evidence.

The team should also adopt proactive measures and move away from the traditional

reactive enforcement activities, which stand the risks of losing relevant evidence and

investigative leads

In terms of setting up and implementing the taskforce the following issues will be ad-

dressed:

• A task force leader similar to a Rapporteur shall be appointed.

• Reassure that the WGEO SPOC system is in place in each country.

• Support from the highest level (HMA) must be provided to inuence member

states to provide requested data within the set time frame and to actively col-

laborate.

• Members shall be assigned to prioritise their work on the taskforce in order to

protect the public health within Europe.

• Financing for the taskforce personnel should be guaranteed and provided by the

respective agency.

• Training is available for specic enforcement duties.

• A joint communication strategy should be agreed.

• Cooperational meetings, webinars and telecons can be performed.

• Mapping and structured intelligence gathering can be guaranteed.

• Recommend actions for member states affected will be documented.

• A focused enforcement project shall be set up to proactively collect and docu-

ment all data in the case (as done during this case by using the AIFA/EC “fake-

share” platform and tools).

IV.I.I Further proposals

The MHRA collaborated with AIFA, and other agencies, to produce this document with a

view to formalising a process that would allow effective joint working in relation to com-

plex, European, cross border investigations. In terms of enforcement coordination, the

MHRA support the formation of an ad-hoc taskforce approach to manage this type of

enquiry.

In relation to regulatory coordination, the MHRA support the closer cooperation with the

EMA GMDP Inspectors Working Group in relation to improving the due diligence require-

ments for wholesale dealers and enhanced cold chain provisions.

The paper clearly addresses matters from an “enforcement” perspective which would

include collaboration in relation to the investigative strategy. However, an area that

does not seem to be clear, and that the paper may benet from, is in relation to the

management of the higher level strategic issues. The question arises, should there be a

strategic group that sits above the operational taskforce to ensure appropriate coor-

dination of the issues?

It is suggested the group could maintain an overview of the emerging issues, draw up

terms of reference for the operational taskforce, ensure sufcient resources are availa-

ble, consider transnational risk and strategic linkages with other agencies. This strategic

group could also review progress of the taskforce and would provide a useful structure

to escalate critical issues.

Depending on the nature and the scale of the event, it would be drawn from the member

states most affected by the incident.

It is suggested to pull a steady strategic group out of senior DRA enforcement ofcers

alongside the active WGEO taskforce, whose members would change case by case. Only

a few of the European agencies could facilitate a bigger operational group with their re-

sources. Smaller countries could handle cases better with the supervisory help of both

the strategic group and the active colleagues involved in the taskforce. Financing and

resources for both strategic group and WGEO taskforce have to be ensured in order to

better tackle criminal activities at a European level.

IV.II Regulatory approach

The current regulations and controls are clearly insufcient with regard to due diligence

by wholesalers in order to prevent the criminal penetration of the legitimate supply chain.

It is recommended that the EMA, GMDP IWG and HMA-WGEO be requested to develop

common position documents to explain how to apply the due diligence requirements in

the EU GDP Guide by wholesalers and strengthen its compliance providing examples of

how to carry out this activity, e.g. requiring nancial credit checks, conrming VAT num-

ber, checking Duns number, conrming EORI number and conrming that the address is

a registered business premise, like listed in the WGEO Due Diligence paper.

The creation of the EMA GMDP database will help resolve the problem of wholesale deal-

ers unknowingly purchasing from unlicensed sources. However, it will take approximate-

ly ve years for the database to be fully operational as it depends upon the inspection

of wholesale dealers and the issue of a GDP certicate. One possible proposal could be

for an enhanced inspection programme by all MS with a commitment to complete the

database within an agreed time limit. This would have signicant resource consequences

for most MS and may detract from their GMP inspection programmes.

In order to make out of the thefts’ database a useful tools at a European level, there

should be legal obligations for all stakeholders to report stolen medicines to the DRA.

The “Operation Volcano” highlighted the importance of such a tool in support of inves-

tigations.

Ways should be sought to see if a quicker implementation of the serial number system

introduced in FMD would be possible, along with the permission to use this structure for

all medicines and medical products.

Lastly, in order to ensure the quality of products, it is recommended that the Commis-

sion, through the auspices of the EMA GMDP Inspectors Working Group, be requested

to review the current requirements in the EU GDP Guide for cold chain medicines and

determine whether the current requirements can usefully be strengthened by requir-

ing a temperature data logger (or similar) to accompany all shipments so as to assure a

complete temperature audit trail.

IV.III Preventive measures

Prevention can only be based on tools to gather and share information among author-

ities involved in law enforcement. The following tools currently appear to be the most

useful ones:

• A constantly and timely updated database (similar to EudraGMP) and/or web

platforms of thefts of medicines where data about stolen medicines are pub-

lished: AIFA already started a project on this involving authorities, administra-

tions, associations and operators in the pharmaceutical and healthcare elds.

• Real time alert on stolen/illegal medicines (AIFA will start using new ad hoc pag-

es for that - http://www.agenziafarmaco.gov.it/it/content/furti-di-medicinali,

and will promote the use of the AIFA/EC “fakeshare” platform as tool for inves-

tigators).

• Development of risk proles on suspect offers as included in the HMA-WGEO

due diligence document in Annex VI.

• Guideline for wholesalers how to proceed when a batch listed in the “Stolen

Medicines Database” is offered.

• Training for DRA enforcement employees and for GMDP inspectors.

All of these measures should be discussed by involving the appropriate international

fora (e.g. Inspectors Working Party – EMA, PIC/S, PDA, ISPE etc.).

RAs and NUIs

RAs issued by AIFA

August 8th, 2014 | IT - Italian Medicines Agency (AIFA)

AIFAtriggeredawiderecallofillegallymedicinesthroughalistofveriedtradeswheretheprimary

sourcewasaboguswholesaler.ThedocumentwasupdatedonAugust14th,September1st2014,

January 29th 2015 and on July 2nd 2015.

Other RAs

April 2nd, 2014 | DE - Paul-Ehrlich-Institut (PEI)

SuspectedcounterfeitofHerceptin(Trastuzumab)150mg.ThedocumentwasupdatedonAugust12th.

April 8th, 2014 | FI - Finnish Medicines Agency (FIMEA)

Suspect counterfeit herceptin.

April 11th, 2014 | European Medicines Agency (EMA)

Herceptin150mgPowderforconcentrateforsolutionforinfusion.

April 17th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

FalsiedRemicadebatchesandtheactionstakeninGermany.

May 23th, 2014 | CZ - State Institute for Drug Control (SUKL)

NoticationofaQualityDefect/Recall.ThedocumentwasupdatedonJune26th.

July 1st, 2014 | DE - Paul-Ehrlich-Institut (PEI)

ConcerningfalsiedsyringesofGardasil.

July 28th, 2014 | DE - Federal Institute for Drugs and Medical Devices (BfArM)

Recall,noticationforparallelimportedmedicinalproductsoftheCompanyCC-PharmainGermany.

July 28th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Recall,noticationforparallelimportedmedicinalproductsoftheCompanyCC-PharmainGermany.

August 4th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Recall of batches of products of Italian origin.

August 6th, 2014 | DE - Federal Institute for Drugs and Medical Devices (BfArM)

ConcerningfalsiedViramune.

August 8th, 2014 | N – Norwegian Medicines Agency

Recalloffalsiedmedicinalproducts(Ipstyl,Orifarm).ThedocumentwasupdatedonAugust11th.

August 14th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

ConcerningthecompanyHaematoPharmaGmbh,regardingrecallsofbatchesofproductsofItalianorigin.

August 14th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

ConcerningthecompanyInophaGmbH,regardingrecallsofbatchesofproductsofItalianorigin.

August 19th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

RecallsofparalleldistributedmedicinesofItalianorigin(RACC-Pharma).

August 19th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

RecallofsuspectedmedicinalproductsofItalianorigin(Remicade100mg).

August 19th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

RecallofsuspectedmedicinalproductsofItalianorigin(Humira40mg).

August 26th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Recallofillegalproductsofitalianorigin(RAOrifarm).

August 26th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

RecallofillegalproductsofItalianorigin(RAMilinda).

August 26th, 2014 | DE - Federal Institute for Drugs and Medical Devices (BfArM)

Recall,noticationforparallelimportedmedicinalproductCelebrex200mgoftheparalleldistributer

CC-PharmainGermany.

August 26th, 2014 | DE - Federal Institute for Drugs and Medical Devices (BfArM)

Recall,noticationforparallelimportedmedicinalproductViramune400mgoftheparalleldistributer

CC-PharmainGermany.

August 26th, 2014 | DE - Federal Institute for Drugs and Medical Devices (BfArM)

Recall,noticationforparallelimportedmedicinalproductsoftheparalleldistributerOrifarmGmbHin

Germany.

August 27th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

RecallofillegalproductsofItalianorigin(ClexaneeRemicade).

August 29th, 2014 | DE - Federal Institute for Drugs and Medical Devices (BfArM)

Qualitydefect,ClassII,medicinalproductCialis20mgtabletsoftheMAHEliLillyNiederlande,parallel

distributionbyOrifarmGmbH,DE.

September 9th, 2014 | DK - Danish Health and Medicines Authority (SST)

Illegalsupplychain(ZonegranandIpstyl).

September 25th, 2014 | FI - Finnish Medicines Agency (FIMEA)

Truvada parallel trade.

November 5th, 2014 | UK - Medicines and Healthcare Products Regulatory Agency (MHRA)

SuspectedFalsication,SymbicortTurbohaler320/9.ThedocumentwasupdatedonNovember6th.

May 18th, 2015 | DE – Federal Institute for Drugs and Medical Devices (BfArM)

Recallofsuspectedcounterferitmedicinalproductsofitalianorigin(SpirivaRespimat)

May 18th, 2015 | DE – Federal Institute for Drugs and Medical Devices (BfArM)

Recallofsuspectedcounterferitmedicinalproductsofitalianorigin(Clexane40mg)

NUIs

April 4th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Follow-upinformationonsuspectedcounterfeitofHerceptin150mg.

May 14th, 2014 | IT - Italian Medicines Agency (AIFA)

Identicationofthe“boguswholesalers”andrstlistofoperatorshavingtradedillegalmedicines.

May 28th, 2014 | IT - Italian Medicines Agency (AIFA)

Listofinvolvedbatchesforsomeoftheproductstradedbytheboguswholesalers(Mabthera,Avastin,

Herceptin).

July 1st, 2014 | IT - Italian Medicines Agency (AIFA)

Updateofthelistofinvolvedoperators,proposalofinspectionandvericationsaimedatdiscovering

other possible channels and triggering new signals.

July 25th, 2014 | IT - Italian Medicines Agency (AIFA)

Updateofthelistofoperatorsandsummaryofthecase.

August 26th, 2014 | IT - Italian Medicines Agency (AIFA)

UpdateonthestatusoftheItaliandistributionnetwork,summaryoftheongoingvericationsand

proposal of follow up.

October 14th, 2014 | IT - Italian Medicines Agency (AIFA)

Update on the status of the Italian distribution network.

RAs related to similar patterns

September 3rd, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Counterfeit/manipulatedMabthera500mg(Bactch:H0656B03)withromanianorigin.

September 9th, 2014 | RO - National Agency for Medicines and Medical Devices (ANMDM)

Notication-productsdistributedbyChemomedIntertrading.

September 11th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Notication-productsdistributedbyChemomedIntertrading.

October 2nd, 2014 | DE - Paul-Ehrlich-Institut (PEI)

Recall,illegallytraded/counterfeitedmedicinalproductAbilify;wholesalerChemomedinRO,

manufacturerhvdmedicalGmbHinDE.

October 8th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

RecalloffalisiedmedicinesbyparalleldistributorInophaGmbH.

October 22nd, 2014 | DE - Paul-Ehrlich-Institut (PEI)

NoticationonTarceva150mg.

November 19th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

FalsiedAvastinRomanianorigin.

December 4th, 2014 | DE - Paul-Ehrlich-Institut (PEI)

SuspectedfalsiedMabTheraofRomanianorigin.

VI.

WGEO DUE DILIGENCE

by wholesalers and other actors involved in the purchase and sale of

medicinal products in the legal supply chain

VI.I Introduction

The legal supply chain of medicinal products has become increasingly more complex

during recent decades, with more and more actors being involved. Brokers are intro-

duced and more than one distributor is usually involved in the purchase and sale of

the same batch of product. Consignments of medicinal products are often

moved across several countries’ borders before entering the market they

are intended for. One important reason for this being the large extent

of movement/change of production sites producing medicinal prod-

ucts from Europe to third countries.

This ever increasing complexity calls for a well regulated and mon-

itored supply chain. As the saying goes “a chain is as strong as its

weakest link”, and to this end every player, every actor in the sup-

ply chain has a crucial responsibility and role to play to ensure that

the right medicines of the right quality reach the right market and

thereby also ensuring that no falsied medicines penetrate the legal

supply chain. Falsied medicines enter the legal supply chain either by

someone’s criminal intentions, by negligence of actors in the legal distribu-

tion chain or by both. So though one cannot eliminate the former, which will be dealt

with through the enforcement systems of the respective countries, there is much room

for improvement in the latter.

One of the key issues one has to address in order to ensure a safer supply chain is to

exercise appropriate due diligence. Due diligence involves ensuring that the person with

whom wholesalers are dealing and thus sourcing (in case of purchases) and supplying

to (in case of selling) are duly authorised in line with required legislation to handle (re-

ceive and supply) the medicinal products involved in the transaction. Though this might

seem as a simple and quite straight forward task, experience has shown that this is often

overseen or poorly adhered to.

VI.II Scope

The scope of this document is to list a set of questions with recommended answers which

will help wholesalers to highlight the risk areas and thus exercise necessary due diligence

when entering into deals especially with new potential suppliers and/or customers.

VI.III Questions and Answers

Q. Do you have a procedure available for Qualication of Suppliers?

A. A procedure delineating how a potential supplier should be assessed before becoming

an approved supplier from the point of view of your business operations should always

be available and followed up. A person should be identied within the company, ideally

the Responsible Person, who should be responsible for the execution of this procedure

and thereby approving new suppliers.

Q. What should be checked before a new supplier can be approved?

Does the company actually exist? Was the verication documented?

A. To ascertain that the company does indeed physically exist, ask for the UID or VAT

number and check this against appropriate country registers, before documenting that

the verication has taken place.

Alternatively, or additionally, search for the number on:

(www.ec.europe.eu/taxation_customs/vies/vatRequest.html). In this way you will at

least ascertain that the company is actually a registered one (and thus a legal entity

subject to legal proceedings). Open source checks on the internet can often be very use-

ful too.

What is the licensing status of the company?

A. Once the company has sent you a copy of their licence or a GDP-certicate, then the

authenticity of the document and the validity of the authorisation are very important.

This verication can be done by checking the website of the competent authority issuing

the licence or if it is registered in the EUDRA-GDP/GMP database as GDP/GMP compli-

ant. If the licence has an expiry date and it is expired, or if it has no expiry date and was

issued more than 3 years ago, check if it is still valid. The process of how and when such

verication is to be done should be described in your procedure and the verications

documented. It is crucial that the company licence status is conrmed before you issue

a purchase order.

Was an audit performed of the supplier?

A. You should have a policy of auditing your suppliers, especially new suppliers with

whom you have not previously had any business dealings with and which are not known

as trusted sources to your medicinal supply trading network. There should be a docu-

mented policy of audits including whom and when to audit based on a risk assessment

approach. Frequency of such audits is also to be listed. An audit should, as a minimum,

include a check of the supplier’s procedure for supplier qualication, ensuring that the

supplier has a process in place to verify that licences/certicates are checked prior to

any purchase orders being issued.

Q. Is the product offered a new product for your company?

A. Verify that the product has a Marketing Authorisation in an EEA country. You have to

consider if this product by nature or by source may be falsied. If so, do not assume that

the Marketing Authorisation number on the packaging is authentic/legitimate, check

with MAH or with the competent authority of the destination country to conrm the

products marketing status. Your quality system should have a procedure which incor-

porates a mandatory provision to notify the authorities in cases of suspicious products.

Q. Is the product being offered available in quantities or volumes unusually high or is

the price being offered considerably lower than the usual price?

A. If the answer to any of these questions is ‘yes’, as part of due diligence, the wholesal-

er accepting the deal should investigate the reason why, to try to establish a plausible

explanation before entering into a transaction. This holds true especially for products

which one does not usually come by in large quantities, or it is a known fact that cur-

rently there is a shortage of a particular product (example GMP problems in a site / sites

where the product is manufactured). Low prices should also raise a red alert and the

wholesale dealer should enquire the reason as to why such a low price is being offered.

Q. Is the supply chain of this transaction transparent?

A. The supply chain, i.e. the movement of goods from the storage of your supplier until

they reach your warehouse should be as transparent as possible. Is the complete chain

accountable? If not, it may pose a risk. A risk assessment should be conducted in this

regard to establish whether all points and handlers involved in the consignment journey

are known. If brokers are involved, check whether these brokers are adequately regis-

tered with the competent authority where they are established. Brokers must register

with the competent authorities of the country in which they are situated. If a broker

involved who is situated in the EEA is not registered, you should not enter into an agree-

ment but notify the competent authority.

Q. What will be the method of transportation? Will there be groupage?

A. The transport of the consignment should be well planned and it should only be han-

dled by shipping/transportation companies with whom there are written agreements

and with whom you have experience and condence in. Another important point to con-

sider is whether there would be groupage. If this is the case this should be known prior to

shipping so that adequate measures are taken by the handlers/shippers not to leave the

consignments exposed which increases the risk of someone tampering with the consign-

ment. For products requiring special storage conditions such as cold chain medicines the

transportation has to be well planned in advance.

VII.

OFFICIAL WEB RESOURCES

allowing to check if a wholesaler is authorised to trade in medicines by the

competent authorities of the MS where it is established

EMA

The Community database EUDRAGMDP may not be fully populated as Member States

are currently working to bring it into operation so the database can be complimented

with further information from the sources listed above and even through direct contact

with the concerned National Competent Authorities if no listing can be found.

• http://eudragmdp.eudra.org/inspections/logonGeneralPublic.do

AUSTRIA

• http://www.basg.gv.at/inspektionen/good-manufacturingdistribution-practice/

arzneimittelbetriebe/

CYPRUS

Cyprus Regulatory authority, Pharmaceutical Services/Ministry of Health, has published

a catalog of all authorized wholesalers in Cyprus. Here is the relevant link:

• http://www.moh.gov.cy/MOH/phs/phs.nsf/All/

B67DD58A5E16809AC2257B2E0026D869?OpenDocument

All authorized wholesalers are also registered in the EudraGMDP database.

DENMARK

Information about Danish companies with a valid WDL can be found at the link:

• http://sundhedsstyrelsen.dk/en/medicines/regulation/company-

authorisations-and-registrations/wholesale-distribution

By clicking at “Companies authorized to distribute medicines by wholesale in Denmark”

an excel le will be downloaded.

Another list for companies authorized to manufacture and import medicines and inter-

mediates in Denmark can be downloaded here:

• http://sundhedsstyrelsen.dk/en/medicines/regulation/company-

authorisations-and-registrations/manufacture-and-import-of-medicines-

and-intermediates

A manufacturer must hold a wholesale dealer’s authorisation if it wholesale deals med-

icines that are not manufactured at an address approved on the MIA, or if the manu-

facturer chooses to wholesale their own manufactured medicines from other addresses

than those authorised on the MIA (e.g. separate storage addresses).

FINLAND

Name list of authorized wholesale license holders in Finland (for more detailed requests,

contact qdefect@mea.)

• http://www.mea./valvonta/laaketehtaat_ja_-tukkukaupat/toimiluvat/

kotimaiset_laaketukkukaupat

FRANCE

List of authorised pharmaceutical companies in France, including notably wholesalers,

importers and exporters.

• http://agence-prd.ansm.sante.fr/php/etapharm/index.php

ICELAND

List of Information about Icelandic companies with a valid WDL:

• http://www.lyfjastofnun.is/Eftirlit/Lyfjaheildsolur_og_dreing/Listi_yr_

lyfjaheildsolur/

All authorized wholesalers are also registered in the EudraGMDP database.

ITALY

Permalink to the updated page:

• http://www.dati.salute.gov.it/dataset/distributori_farmaci.jsp

Download link (refences: D – Depositario = warehousing service shipping/distributing

medicines on behalf of manufacturers; P – Produttore = manufacturer; G – Grossista =

wholesaler):

• http://www.dati.salute.gov.it/imgs/C_17_dataset_4_download_

itemDownload0_upFile.CSV

MALTA

A webpage listing various pharmaceutical activities licensed/certied/registered after

establishing that the relevant GxP requirements and provisions of the Medicines Act are

achieved. This webpage lists various headings for facilities with a: GMP certicate, man-

ufacturer’s licence, wholesale dealer’s licence, plus registered brokers and API importers

and distributors. Clicking on the individual listed heading opens a document with the

relevant listed entities under that heading.

• http://www.medicinesauthority.gov.mt/licensed-pharmaceutical-activities

ROMANIA

The list of authorized Romanian wholesalers can be found at the following link:

• http://www.anm.ro/anmdm/_/Lista%20depozite.pdf

The suspended wholesalers are marked in red.

SPAIN

The list of authorized Spanish wholesalers can be found at the following link:

• https://labofar.aemps.es/labofar/registro/entidadesDistribucion/consulta.

do?metodo=detalleBusqueda

By clicking in the name of the company, in blue, it is possible to access to more detail

data. Some of these details are still missing pending of the update of the authorisations

to the new format but all the authorised companies are listed. Also it is indicated wheth-

er the wholesale dealer’s licence is temporarily suspended.

SWITZERLAND

Link to the authorized wholesalers in Switzerland:

• https://www.swissmedic.ch/bewilligungen/00155/00241/00253/index.

html?lang=en

THE NETHERLANDS

There are currently 229 wholesale dealers listed on EudraGMDP under WDA - Nederland.

There may be more wholesalers with a license that are not yet transferred to EudraGM-

DP, and for those you could search the list of licensed manufacturers and wholesalers at

• http://www.farmatec.nl/geneesmiddelen/vergunningen/farmacie/

Lijstvergunninghouders.aspx

This is a pdf list that you could search for the name or address of the wholesaler. WDA is

indicated by the letter G in the column “Registernummer” (number in the register).

UNITED KINGDOM

List of UK MHRA licensed wholesalers:

• http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/

Manufacturersandwholesaledealerslicences/index.htm

VIII.

Q&A

At the beginning of the use of the “fakeshare” web tools, AIFA gathered questions from

all interested MS authorities, and prepared an ad hoc Q&A document, that was present-

ed during the second “fakeshare” webinar, and shared through the restricted web area,

in order to create common consensus on some issues related to the case: the following

list of Q&A is an excerpt from that document, with the exclusion of the questions related

to practicalities or to aspect that are now out of date.

Q. Can medicinal products, that are related to the illegal wholesalers outside Italy, be

dened as falsied?

AIFA (ITALY). We consider these medicines as “supplied with fake documentation” (e.g.

invoices stating that they were supplied by non authorized/non active wholesalers), and

consequently FALSIFIED. See Dir. 2001/83, as amended by Dir. 2011/62. TITLE I, Deni-

tions, Art. 1.

33.Falsiedmedicinalproduct:

Anymedicinalproductwithafalserepresentationof:

(a) itsidentity,includingitspackagingandlabelling,itsnameoritscompositionasregardsany

oftheingredientsincludingexcipientsandthestrengthofthoseingredients;

(b) itssource,includingitsmanufacturer,itscountryofmanufacturing,itscountryoforiginorits

marketingauthorisationholder;or

(c) itshistory,includingtherecordsanddocumentsrelatingtothedistributionchannelsused.

Thisdenitiondoesnotincludeunintentionalqualitydefectsandiswithoutprejudiceto

infringementsofintellectualpropertyrights.

Q. Where in the European legislation can I nd the right paragraphs to force the Par-

allel distributors/Wholesalers to give us the requested information?

POINT FOR DISCUSSION. Dir. 2001/83, TITLE IV considers together “Manufacture and im-

portation”; TITLE XI (“Supervision and sanctions”), art. 111, states that

1g.Inspectionsshallbecarriedoutbyofcialsrepresentingthecompetentauthoritywhoshallbe

empoweredto(…)

(c) examineanydocumentsrelatingtotheobjectoftheinspection,subjecttotheprovisionsin

forceintheMemberStateson21May1975placingrestrictionsonthesepowerswithregardto

thedescriptionofthemanufacturingmethod;

(d) inspectthepremises,records,documentsandpharmacovigilancesystemmasterleofthe

marketingauthorisationholderoranyrmsemployedbythemarketingauthorisationholder

toperformtheactivitiesdescribedinTitleIX.

With respect to wholesalers, there are clear provisions under Art. 80:

Holdersofthedistributionauthorizationmustfullthefollowingminimumrequirements:(…)

(e) theymustkeeprecordseitherintheformofpurchase/salesinvoicesoroncomputer,or

inanyotherform,givingforanytransactioninmedicinalproductsreceived,dispatchedor

brokeredatleastthefollowinginformation:

• date,

• nameofthemedicinalproduct,

• quantityreceived,suppliedorbrokered,

• nameandaddressofthesupplierorconsignee,asappropriate,

• batchnumberofthemedicinalproductsatleastforproductsbearingthesafetyfeatures

referredtoinpoint(o)ofArticle54;

(f) theymustkeeptherecordsreferredtounder(e)availabletothecompetentauthorities,for

inspectionpurposes,foraperiodofveyears;

Q. What do we do if the Parallel distributors/Wholesalers refuse to give information

or refuse to do a recall and send their lawyers against us?

AIFA (ITALY). Lack of compliance with Directive 2001/83 would be a major infringement

with respect to any authorization.

Q. What measures are planned for the suspected Italian wholesalers, will there be a

withdrawal of licences?

Q. Are the above mentioned Italian operators declared GDP non-compliant? If so, has

this been entered into Eudra GMDP?

AIFA (ITALY). The ones who bought from “non authorized wholesalers” (i.e. the ones in

Latvia etc.) will undergo sanctions from the competent authorities (i.e. local Authorities).

Article80Holdersofthedistributionauthorizationmustfullthefollowingminimum

requirements:

(a) theymustmakethepremises,installationsandequipmentreferredtoinArticle79(a)

accessibleatalltimestothepersonsresponsibleforinspectingthem;

(b) theymustobtaintheirsuppliesofmedicinalproductsonlyfrompersonswhoarethemselves

inpossessionofthedistributionauthorizationorwhoareexemptfromobtainingsuch

authorizationunderthetermsofArticle77(3);

(…)

(ca)theymustverifythatthemedicinalproductsreceivedarenotfalsiedbycheckingthe

safetyfeaturesontheouterpackaging,inaccordancewiththerequirementslaiddowninthe

delegatedactsreferredtoinArticle54a(2);

(d) theymusthaveanemergencyplanwhichensureseffectiveimplementationofanyrecall

fromthemarketorderedbythecompetentauthoritiesorcarriedoutincooperationwiththe

manufacturerormarketingauthorizationholderforthemedicinalproductconcerned;

(e) theymustkeeprecordseitherintheformofpurchase/salesinvoicesoroncomputer,or

inanyotherform,givingforanytransactioninmedicinalproductsreceived,dispatchedor

brokeredatleastthefollowinginformation:

• date,

• nameofthemedicinalproduct,

• quantityreceived,suppliedorbrokered,

• nameandaddressofthesupplierorconsignee,asappropriate,

• batchnumberofthemedicinalproductsatleastforproductsbearingthesafetyfeatures

referredtoinpoint(o)ofArticle54;

(f) theymustkeeptherecordsreferredtounder(e)availabletothecompetentauthorities,for

inspectionpurposes,foraperiodofveyears;

(g) theymustcomplywiththeprinciplesandguidelinesofgooddistributionpracticefor

medicinalproductsaslaiddowninArticle84;

In particular, the Italian implementation of Dir. 2001/83 indicate the art. 80 requirements

as “essential” for granting the wholesale authorization; this aspect will be covered even

before the trial, and (if relevant) the update of the EUDRA GDMP system will be consid-

ered.

Q. Is it true that in Italy hospitals have no licence as wholesalers?

AIFA (ITALY). Yes.

Q. Are Italian labelled medicinal products that are hospital only in Italy to be classi-

ed as falsied if they are in the legitimate supply chain elsewhere in EU/EEA?

Q. Is it illegal for an Italian wholesaler to export hospital only medicines to other

EU-countries?

AIFA (ITALY). No: Italian wholesalers may legally export also hospital only medicines.

Q. Is there a list of Italian medicinal products that are hospital only?

AIFA (ITALY). Yes: it is published and updated regularly by AIFA, it is available on the

web. http://www.agenziafarmaco.gov.it/it/content/tabelle-farmaci-di-classe-e-

h-al-15052014 (Excel le: http://www.agenziafarmaco.gov.it/sites/default/les/

Classe_H_per_Principio_Attivo_15.05.2014. xls)

Q. If Italian medicinal products that are hospital only are found in the legitimate sup-

ply chain in EU/EEA, what action should be taken, i.e. company to quarantine, Na-

tional Competent Authorities to seize, company to return to marketing authorization

holder, etc?

AIFA (ITALY). We should rene the question: since it is possible that hospital only drugs

are legally exported, we should focus on ILLEGAL products. If Italian medicinal products

that are hospital only and are conrmed as “falsied”, e.g. paired to fake documentation

with respect to the origin are found in the legitimate supply, the rules for falsied med-

icines should be applied.

Q. For the stolen cold chain medicines is there any evidence that the cold chain has

been maintained, i.e. by data-logger records that cover the relevant periods of time?

AIFA (ITALY). No direct evidence. With respect to the medicines under investigation, as

far as we know, up to now none reported EMA complaints/pharmacovigilance data/etc.

clearly related to cold chain issues; the criminals were using a certain degree of care

in handling things, apparently, since they were working on a “long term business”; and

they wanted to avoid incidents. The “Herceptin incident” starting the case seems to be

an indication of the “enlargement of the platform” – i.e. the central coordination unit of

the criminal organization started using “non specialized burglars” for “supplying” the

network, which was the cause for the incident. We know Police is studying the camera

recordings of recent thefts, in order to identify “people carrying portable refrigerators”.

Q. Can you conrm that the tampering/adulteration of Herceptin is a one-off incident

and, in principal, is not related to the theft of medicines?

Q. How many of the involved medicinal products are at the moment conrmed to be

manipulated? (I think it is only Herceptin!?)

AIFA (ITALY). The only manipulation we found up to today is the Herceptin one. We have a

series of indications supporting the interpretation of the manipulation as a “bad quality

supplier tampering”: the very low incidence of the case, the bad quality of manipulation,

the presence of water in all tampered vials, support this interpretation of the incident.

We suppose that someone working in the targeted hospital took the medicines, some

empty vials and some labels, and tried to arrange some “extra vials” to be added to the

supply.

Q. What are the specic reasons for the Italian companies being on the list of concern?

Q. Does the Italian wholesalers mentioned on the list of operators identied as having

supplied medicines sourced from the illegal operators identied outside of Italy have

a valid WDA in Italy?

AIFA (ITALY). The list we published includes authorized operators, which according to

the medicines traceability data/seized invoices/customs data, were directly or indirectly

“victims” of the fake wholesalers, i.e. they exported medicines “arriving” from the Lat-

vian/Hungarian/ etc. wholesalers - as the documents pretended. Please, note that since

they simply traded medicines from this network, they should simply considered as “un-

der reinforced checks” – the Italian names in the list are not blacklisted.

Q. What is AIFA’s recommendation to member states for any consignments of the

products of its watchlist? Immediate recall or quarantine of all those products of

Italian origin following precautionary principle as there is an illegal supply chain (un-

authorised wholesaling activity)?

Q. Do you have batch numbers for any of the medicines on the list of concern?

Q. Of the 64 products identied by AIFA, is it possible for AIFA to differentiate this list

of medicinal products into those that have a potential legitimate supply route out of

Italy and those which have no potential legitimate supply route out of Italy?

AIFA (ITALY). AIFA (ITALY). The list was considered as a “support for inspections”, a sort

of watchlist, being based on documents issued by fake wholesalers; so, at this stage the

recommendation is to use it for extra verication, not for recalls or seizures. In the ex-

amined documentation we have batch numbers, but since the batch numbers come from

fake invoices, we are performing extra checks, connecting the purchase invoices with the

selling ones. Our plan is to send MS Authorities data and copies of all conrmed invoices/

trades by next week, including conrmed batch numbers; in this way, we will cover also

the EMA point, i.e. the possible “nal destination” of medicines. According to the picture

we are building and to other ongoing investigation we are trying to liaise with, it seems

that some specic medicines (doping substances and Botox, for instance) were destinat-

ed to the national black market, or to the web.

Q. What dates does your information regarding stolen medicines cover? i. e. how long

have the companies been dealing in stolen/falsied medicines?

Q. When did this begin? What would be the recommended exclusion dates for consign-

ments supplied to member states?

AIFA (ITALY). We have industry data for 2013-2014, and all Ministry of Health data from

2012 to 2014. According to our information, the case started at least 3 years ago (i.e.

end of 2011, beginning of 2012). Since we are speaking about products with a very quick

turnover, we performed a risk assessment, deciding to ask the Prosecutor the more re-

cent data; we would then recommend to focus on 2013-2014 purchases, at least for the

moment.

Q. How can you state for a specic medicine (i.e. Mabthera and Avastin) that no legal

export has taken place the last 12 months? Have you decided whether or not to extend

the range of “12 months”? Also it would be helpful to know exactly when “12 months

ago” is - is it April or May 2013, or what is behind this timeframe?

AIFA (ITALY). Italy has a full medicines traceability in place: all medicines packages are

identied with an unique code, so we may check all trades/export/movements of medicines.

You nd some explanation (in Italian) and a picture (easier to understand) here http://www.

salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=1373&area=tracciabilita%20

farmaco&menu=monitoraggio. The “12 months” window means “after April 1, 2013”.

Q. What kind of documentation does an Italian wholesaler need to export medicines

to other EU-countries (special documents?, notication to authorities in Italy? Other?)

AIFA (ITALY). Only authorized wholesalers (authorized at local level; the authorization is

notied to Ministry of Health) may export medicines; they may only export authorized

medicines, obviously. There is an obligation to send all data about the export (i.e. medi-

cine name and number of pieces) to the Traceability Repository.

Q. What enforcement measure is being undertaken against the Italian wholesale

dealers involved? Have we an assurance that this pipeline has now been stopped?

AIFA (ITALY). They were inspected by the Police forces, all their transactions were ex-

amined and doublechecked by AIFA/Ministry of Health, and also the Italian Customs are

verifying their trades. Some of the operators already stopped their activities, and the

Prosecutors and the local authorities are planning direct actions on them. We noted a

strong reduction in thefts after the beginning of investigations, even if we cannot be sure

to have identied all channels – we still have thefts, but we don’t know if they are relat-

ed to a “delay” in stopping the “suppliers”, or to another exporting channel. An update on

the activities performed in Italy is already part of this White Paper.

Q. Is there any evidence of supply to the Italian market?

AIFA (ITALY). For the moment, we have no evidence with respect to the already evalu-

ated products (i.e. the hospital ones), which we may conrm as being out of our legal

distribution network. In Italy, parallel import procedures are related to a centrally is-

sued authorization (managed by AIFA), so we already know that no parallel import was

authorized for any of the already evaluated products. As mentioned above, according to

the picture we are building and to other ongoing investigation we are trying to liaise with,

it seems that some specic medicines (doping substances and Botox, for instance) were

destinated to the Italian black market, or to the web (targeting Italian market) ; then, we

will better evaluate this in the follow up investigations we are starting.

Afterword

Review by the HMA

On February 2015, this White Paper was provided to the HMA for evaluation, prior to submit-

ting the paper to the European Commission.

Dr Ian Hudson, MHRA Chief Executive Ocer, commented on the document as reported at p.27

under the heading “Further proposals”.

On May 11-13, 2015, in the occasion of the 80th HMA Meeting held in Ljubljana, Slovenia, copies

of the publication were distributed to the participants. The publication of the White Paper on

the HMA Website under the WGEO page was approved. Submission of the White Paper to the

EC was also approved.

TABLE OF CONTENTS

I THE STORY (SO FAR) 7

I.I Thefts of medicines in Italy 7

I.II The case 9

II CASE MANAGEMENT 15

II.I The verication process 15

II.I.I Validationoftrades

II.I.II Validationofoperators

II.I.III Triggers for new signals

II.I.IV Restoringofthesecurityoftheitaliansupplychain

beyond the Herceptin case

II.II Coordination activities 21

II.II.I Roles of different entities during this case

III KEY LESSON LEARNED 24

IV PROPOSALS 26

IV.I Enforcement coordination 26

IV.I.I Furtherproposals

IV.II Regulatory approach 28

IV.III Preventive measures 29

V RAS AND NUIS 31

VI WGEO DUE DILIGENCE 35

VI.I Introduction 35

VI.II Scope 36

VI.III Questions and Answers 36

VII OFFICIAL WEB RESOURCES 39

VIII Q&A 43

Afterword: Review by the HMA 51

TABLES

• Theft project: Timetable 7

• Identied unauthorized (“bogus”) wholesalers 11

• List of operators which directly bought

medicines from the “bogus wholesalers” 12

• The supply chain models 13

• Products sold mostly to hospitals 18

AIFA will keep in updating all documentation and databases

related to the case, using the same web tools developed in

the FAKESHARE/FAKESHARE II projects framework, already

used during this crisis.

The restricted area of the www.fakeshare.eu website will be

accessible to all registered users from interested institutions

and stakeholders.

Falsification of biotechnology drugs: Current dangers and/or future disasters?

Article

Aug 2018
J PHARMACEUT BIOMED

Oncology drugs in the crosshairs of pharmaceutical crime

Article

Apr 2018
LANCET ONCOL

Oncology drugs clearly have become a target for pharmaceutical crime. In 2016, falsified oncology drugs ranked fifth in the most commonly falsified drug category among the reports received by the Pharmaceutical Security Institute. Although the prevalence of illicit oncology drugs in the legal supply chains appears to be small, these drugs are difficult to detect, particularly in clinical practice. Forthcoming countermeasures to detect illicit drugs in high-income countries include compulsory antitampering devices and product verification technology for a risk-based selection of medicines. Health-care professionals must implement these new procedures into their workflow and remain vigilant about those medicines that are not selected. Although countermeasures should firmly tighten supply chain security, there are concerns about how quickly pharmaceutical crime will adapt to these protections. Because patients and health-care professionals have shown a lenient attitude towards purchasing medicines from unreliable sources, measures against the highly accessible illegal medicine supply chain remain necessary. To improve detectability in clinical practice, reporting of ineffectiveness and unusual drug effects as adverse events or adverse drug reactions is essential.

ResearchGate has not been able to resolve any references for this publication.

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