IPI - Editorial

IPI 

International Pharmaceutical Industry Spring 2009 

The 2008 Revised Declaration of Helsinki 

and Proposed Solutions for Research 

Ethics in Globalised Clinical Trials 

Medical Imaging and 

Electronic Data Capture 

in Clinical Trials: the 

Future Paradigm 

Drug Counterfeits 

Subject of an Experts 

Discussion at the 

European Parliament 

Managing your info 

flow with LIMS 

www.ipimedia.com



International Pharmaceutical Industry 

Contents 

EDITOR: 

Dr Patricia Lobo MSC, PhD 

E-mail: patricia.lobo@aol.com 

DIRECTORS: 

Martin Wright 

Mark A Barker 

PUBLISHER: 

Clive Baigent 

EDITORIAL ASSISTANT: 

Linda Stewart 

E-mail: linda@ipimedia.com 

BUSINESS DEVELOPMENT: 

Anthony Stewart, Marie Powell 

DESIGN DIRECTOR: 

Ricky Elizabeth 

CIRCULATION MANAGER: 

Dorothy Brooks 

E-mail: Dorothy@ipimedia.com 

FINANCE DEPARTMENT: 

Martin@ipimedia.com 

RESEARCH & CIRCULATION: 

Gramatikov-Vilian@ipimedia.com 

COVER PHOTOS: In-House productions 

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without prior written permission of the Publishers. 

The next issue of IPI will be published in summer 

2009 and quarterly thereafter. 

issn no International pharmaceutical industry 

ISSN 1755-4578 

The opinions and views expressed by the authors 

in this magazine are not necessarily those of the 

Editor or the Publisher. Please note that although 

care is taken in preparation of this publication, the 

Editor and the Publisher are not responsible for 

opinions, views and inaccuracies in the articles. 

Great care is taken with regards to artwork 

supplied, the publisher cannot be held responsible 

for any loss or damage incurred. This publication 

is protected by copyright. 

2009 PHARMA PUBLICATIONS 

6 EDITORS LETTER 

REGULATORY AND MARKETPLACE 

8 America’s Pharmaceutical Research Companies: 

Improving Patient and Practitioner Knowledge about 

Prescription Medicines 

When it comes to providing patients with excellent healthcare, 

there is one essential ingredient that everyone in the healthcare 

delivery chain can subscribe to: informed, knowledgeable 

patients, active in their own treatment, make the best patients. 

Billy Tauzin President and CEO of the Pharmaceutical Research 

and Manufacturers of America (PhRMA) Explains - one sure 

way to improve the quality and utility of healthcare across the 

board is to empower patients with information and help them to 

be true partners in their own care. 

12 The 2008 Revised Declaration of Helsinki and Proposed 

Solutions for Research Ethics in Globalised Clinical Trials 

In October 2008 the World Medical Association (WMA) once 

again revised the Declaration of Helsinki (DoH), this time at its 

General Assembly Meeting in Seoul, South Korea. While the 

WMA insisted that this revision would be largely for editorial 

purposes, the result is a significantly altered 'Ethical Principles 

for Medical Research Involving Human Subjects’, the current 

subtitle of the DoH. Francis Crawley of GCP Alliance discusses 

the changes and its implications. 

16 e-Networking in the Drug Discovery Industry 

The complexities of modern drug discovery often require 

cooperation between many different participants, sometimes 

located in different continents. This is particularly true in an 

outsourcing environment, where clinical trials, manufacturing 

and even preclinical research become globalised. Demands for 

effective communication between companies, laboratories and 

individuals have therefore increased enormously. Fortuitously, or 

possibly causatively, these demands coincide with the supply of 

internet-based networking tools that make geographical 

boundaries and time zones irrelevant. Dr. David Bailey and 

Edward Zanders of Biovillage Ltd discuss why e-Networking is 

expanding rapidly and is here to stay. 

DRUG DISCOVERY, DEVELOPMENT & DELIVERY 

20 Strategies for the formulation of poorly soluble 

compounds and polymorph drugs based on 

polyelectrolyte carriers 

The main challenge in the administration of poorly soluble 

drugs is to design oral formulations displaying a relevant 

bioavailability and to develop injectable systems for the 

parenteral application with minimized toxicity and high drug 

loading. The LBL-Technology ® offers a strategy for enhancing 

the kinetic of dissolution of BCS class II drugs based on the 

presentation of the drug in the form of nanoparticles stabilized 

with layers of polyelectrolyte complexes. Dr. Maria Gonzales - 

Ferreiro of Capsulation Pharma explains. 

IPI 1


Contents 

CLINICAL RESEARCH 

23 Clinical Research Education & training: opportunties and issues 

The demand for the clinical research professionals is rising globally 

and clinical trials are being outsourced from several countries, 

including rapidly growing emerging markets like India and China. 

As a result, human resource managers have a challenge in front of 

them to find out or develop the right quality of manpower. Kamal 

Sahani of Cliniminds explains why in addition to the hiring 

experienced professionals, they need to consider clinical research 

professionals who have undertaken formal training or education in 

clinical research. 

26 Patient Recruitment and Retention in Clinical Trials 

Patient recruitment and retention is the leading problem drug 

companies’ face in developing their new pipelines. As recruiting 

becomes more diverse and complex, pharmaceutical companies 

are striving to discover new innovative ways to facilitate recruitment 

and keep patients enrolled in the clinical trial. With more and more 

clinical trials being done on a global level, it is imperative to have 

an understanding of both government regulations and social 

protocol that accompany these new markets. Dr. Rajam Jaishanker 

of Quest Labs analyses how, speeding up clinical trials is one 

opportunity to cut costs, improve efficiency and bring new drugs to 

market faster. 

30 Medical Imaging and Electronic Data Capture in Clinical 

Trials: the Future Paradigm 

All clinical trial data are ultimately digital. The pathway to this 

digital database is not always as connected as one might expect in 

this technological age. The backbone of clinical trials is now 

Electronic Data Capture (EDC), and this is not yet synchronous with 

the other major aspects of data collection, such as medical 

imaging. Dr. Collin Miller of Bio Imaging explores the combination 

of medical imaging with EDC and provides the future paradigm for 

the triallist in the digital age. 

34 Providing regulatory submissions in electronic format – US 

and EMEA actions 

The United States Food and Drug Administration (FDA) is taking 

concrete steps to require the submission of all types of regulatory 

communication in electronic format. Regulatory authorities globally 

are all moving to require electronic submission of regulatory 

communication. The reasons are many but the public safety 

responsibilities of the regulators require significantly faster access 

to content than can be supported by paper format. Antoinette 

Azevedo shows how great strides have been made by the 

regulatory authorities in the US and EMEA to prepare their 

technical infrastructures for eCTD. 

2 IPI 

LABS 

38 Managing your info flow with LIMS 

Providing the backbone of a clinical trials organisation, a 

Laboratory Information Management System (LIMS) impacts on all 

departments, machinery and personnel. In today's market no 

clinical laboratory or CRO could operate without the support of a 

well integrated LIMS package. And as the technology gets even 

more sophisticated, so do the opportunities for the pharmaceutical 

industry. Sam Singh of ACM Pivotal explores the evolution of 

Laboratory Information Management Systems (LIMS) from the point 

of view of a global clinical trials organisation.


Contents 

IT LOGISTICS 

42 E-freight – Solutions for tough times 

The SWISS approach towards saving the environment and manage 

cargo consignments in electronic form. 

In the complex world of international air freight, where profitability is 

measured by minutes saved, kilograms shipped and litres of fuel 

burned, the Swiss penchant for precision and reliability is a 

valuable asset. Bernd Maresch of Swiss WorldCargo explains why 

it has indeed given the airline a steady foundation that has seen 

profits grow, even as the industry as a whole continues to tighten 

its belt. 

48 Risk Management in Clinical Trial Shipping 

Every time clinical trial supplies or the samples which are 

generated during the lifetime of a trial are transported then an 

element of control is taken from your hands. In order to minimise 

the lack of control, Sue Lee of World Courier discusses what kind 

of risks shipments face when they are actually in transit and when 

they get to the site, so that an assessment can be made of those 

risks, and contingency planning can be used to reduce them as 

much as is feasible in a time- and cost-efficient manner. 


MANUFACTURING & PACKAGING 

52 Greater flexibility in pharma packaging by reducing lot sizes 

and increasing machine running times 

In numerous pharma companies, the following problem is being 

posed: shrinking lot sizes are constantly worsening the ratio of 

packaging system set-up time to running time. The contribution 

below brings into question the current customary 1:1 linking of a 

blister machine, inline printing system and cartoning machine and 

looks at the feasibility and possibilities of partially decoupled 

packaging processes. Dr. Ralph Blum of MediSeal GmbH shows 

when packaging small production lots, partially decoupling lines 

and linking the individual line segments with a logistics module 

leads to a significantly better utilisation of capacity and distinctly 

shorter throughput times. 

56 Drug Counterfeits – Subject of an Experts Discussion at the 

European Parliament. 

The European Parliament and chairman of the Life Science Circle 

invited experts and stakeholders to discuss the threats of drug 

counterfeits in Europe. The venue, which took place at the 

European Parliament in Brussels on December 9th 2008, 

highlighted the increasing concerns about fake medicines 

penetrating the supply chain and the urgency for measures to 

prevent a possibly catastrophic loss of confidence in medicines 

with all the negative consequences on health conditions of 

individuals and on public health. Tassilo Korab of HCPC Europe 

analyses the outcome and proposed solutions. 

60 Pharmaceutical piracy 

Tracking and Tracing and Anti-Counterfeiting 

In 2010, counterfeit drug sales are estimated to reach 75 billion US- 

Dollars globally, an increase of more than 90 percent from 2005. This 

figure is highly alarming. But most alarmingly, we must realise that this 

is no long-term prediction anymore. Nicole Golomb of Simons 

Security Systems GmbH (3S) explains why, the pharmaceutical 

industry, politics, organisations and associations not only need to 

get plans going for an effective protection of medical products 

– a prompt implementation is also necessary as soon as possible.


Editor’s letter 

IPI – The global forum for Life 

Science in 2009 and beyond… 

I’m delighted to join the team at 

International Pharmaceutical Industry (IPI) 

published by Pharma Publications 

(PharmaPubs). IPI offers you a single 

source platform of communication among 

the professional business community of 

the life science industry. 

The current situation… 

On the face of it, while the global economy 

appears to be mired in a deepening crisis 

driven firstly by a lack of credit, followed by a 

banking crisis, collapsing residential and 

commercial properties markets, a sharp 

reversal in the demand for oil and 

commodities, dire predictions of an extended 

recession or even a depression and a general 

lack of investment confidence, the outlook, 

with interest rates at near record lows, heralds 

a period of deflation. 

In the last quarter of 2008, financial markets 

showed extreme volatility marked by a sharp 

fall in market capitalisation across most 

industrial sectors in anticipation of a 

prolonged global recession. The risk of falling 

interest in the face of unsustainable price 

increases threatened stagflation – a stagnant 

economy coupled with hyperinflation. Was 

there any justification to be just a tad more 

optimistic? 

By early December 2008, markets had 

already fallen to their lowest level of the year 

as stock prices dipped even lower than the 

previous low point of 31st March 2008. 

However, among 350 stock prices that make 

up the Financial Times Stock Exchange (FTSE 

350) index, only pharmaceuticals and non-life 

insurance have consistently bucked the 

downtrend. Could this be an indication that 

after several years when the pharmaceutical 

sector had been shunned by investors, 

confidence has begun to return to this 

defensive sector? Investor perception of risk 

might also translate into better returns from 

companies active in the non-life insurance 

sector where returns are more favourable. 

The Axeman Cometh – choppers to the 

rescue… 

I’m off to India next week and I have packed 

The Axeman Cometh by John Farris to read 

once again on the plane. Just as in the early 

2000s, 2008 has been a year of bear market 

conditions, with little signs of economic 

recovery. It goes without saying that the 

human population needs food and 

medicines regardless of the economic 

climate. However, the healthcare business 

may not be recession-proof. David Brennan, 

CEO of AstraZeneca, speaking at a 

Financial Times conference in London, 

warned that recession will be “deep and 

long”, indeed impacting healthcare, 

including the pharmaceutical industry. With 

drug patent expiries, and a shortage of new 

blockbuster drugs to fill the void, we can 

expect a further round of cutbacks, layoffs 

and other restructuring efforts aimed at costcontainment 

and improved efficiency within 

the industry. In the meantime, government 

initiatives aimed at stimulating the economy, 

with talk of “quantitative easing” on top of 

rapidly falling interest rates in an effort to 

stimulate the economy, amount to little more 

than printing lots of cheap money to shower 

the population from a fleet of helicopters 

circulating overhead. This could work if 

there was anything worthwhile to spend it on 

after manufacturing has been savaged. 

To recap - in 2008, Merck cut 8,400 jobs, but 

we saw major cuts at Abbott, AstraZeneca, 

Schering-Plough, UCB Pharma, Wyeth and 

at many smaller drug companies as well. In 

February 2009, we hear unconfirmed reports 

in the Daily Telegraph and Observer that 

GSK is preparing to lay off between 6,000 

and 10,000 workers. While no 

announcements have been made yet, the 

cuts are likely to hit two segments in 

particular – sales reps and R&D. What lies 

behind pharma layoffs is well-known – like 

so many of its rivals, GSK is facing patent 

expirations in the coming years, which 

means increased competition from generic 

drug-makers. The company has already cut 

1,800 pharma reps and 1,200 R&D workers, 

and shut down two plants that produce 

several drugs that are going off patent. The 

French GSK National Works council was 

informed of massive redundancies (848) in 

France – 37 people will face redundancy at 

the R&D centre in Les Ulis, 13 will leave the 

company at the Notre Dame de Bondeville 

plant and 798 people will leave the Evreux 

(Normandy) production plant by 2012. This 

new round of layoffs is part of CEO Andrew 

Witty's ongoing efforts to reorganise and 

diversify GSK to prepare for tough years 

ahead. Witty wants GSK to rely less on 

blockbuster drugs and more on a broad 

range of smaller drugs, which would protect 

the company from repeating the patent-loss 

scramble in the future. 

Mergers and acquisitions, consolidation … 

We have heard about the mega-merger of 

Pfizer and Wyeth. When any two megacompanies 

get together, something has to 

go – who will stand to lose most? There’s 

already one casualty: Crucell, the Dutch 

biotech company producing vaccines. 

Wyeth had been negotiating to buy Crucell, 

and since the merger, Wyeth has bailed out 

of those talks leaving Crucell’s stock to tank. 

Pfizer then announced that it planned to cut 

a further 10 percent of its workforce, or 7,800 

jobs. Analysts predict that the merger will be 

more likely to hit Wyeth staff numbers harder 

than Pfizer. To make the deal profitable, this 

would require deep cuts in the workforce. 

In February, Novartis sold US $5 billion 

worth from a bond sale, stocking the drugmaker’s 

coffers for “financial flexibility”. This 

was followed by Roche raising US $16 billion 

from a bond sale, which was the largest US 

dollar-denominated corporate bond sale 

ever. This may mean that Roche is that 

much closer to a takeover of Genentech. 

Roche’s decision to bypass banks in favour 

6 IPI www.ipimedia.com

of the bond markets says a couple other 

things, too: that the Swiss pharma wasn't 

confident that the troubled banking system 

could come through to finance the US $42 

billion buyout – but it is confident of 

eventually sealing a deal with Genentech. 

Otherwise, why risk paying high interest on 

billions in bonds? On 24th February, 

Bernadette Tansey reported in the San 

Francisco Chronicle that the unanimous, 

three-member committee forming 

Genetech’s Board formally advised non- 

Roche investors, who hold about 44 percent 

of Genentech shares, to refuse Roche's offer 

to take the prospering biotechnology 

company through the hostile takeover bid 

that Roche launched on 9th February - the 

Genentech committee had told Roche it 

would consider a sale at US $112 a share. 

Genentech argues that its chest of cancer 

drugs and potential new medicines offer 

investors the prospect of significant future 

growth as an independent company. But its 

value would be even greater as an 

acquisition for Roche, which already draws a 

substantial share of its revenues from its 

right to market Genentech's blockbuster 

cancer drugs outside the United States. By 

acquiring full control of Genentech, Roche 

would not only gain the US revenues for 

those drugs, but would also avoid having to 

renegotiate its right to sell the medicines 

abroad when that option expires in 2015. 

More recently there have been reports by the 

Wall Street Journal that GSK is in the early 

stages of discussions to acquire Piramal 

Healthcare for around US $1.5 billion, 

although these reports have been denied by 

the Chairman of Piramal, Mr Ajay Piramal. 

GSK already has a big presence in India with 

a sales force as large as that of Piramal; 

although they may not require that kind of a 

field force, in terms of products this would 

increase market share. Also, GSK may not 

require Piramal’s contract manufacturing 

facilities so there may well be some 

divestment. However, there are lots of 

question marks and as of now Mr Ajay 

Piramal has clearly denied the reports and 

has said that the news is totally unfounded 

–so one will need to wait and watch. 

All change - musical chairs… 

Deirdre Connelly, Eli Lilly’s President, has 

jumped ship to join GSK as President of its 

North American Pharmaceuticals. From a 

sales rep in 1983 to executive director of HR, 

then leading the entire US operation of Lilly’s 

US affiliate, she joined GSK reporting 

directly to Andrew Witty. Connelly replaced 

Chris Viehbacher who left to become CEO of 

Sanofi-Aventis. Not to be outdone, soon 

after Glaxo announced Connelly's 

appointment, Lilly tapped Enrique Conterno 

to take her place. Conterno had been Lilly's 

senior vice president of healthcare 

professional markets in the US. 

The future seems bright…… 

According to IMS data, the global pharma 

market is still growing in terms of sales 

revenue and is forecast to hit US $820 billion 

in 2009, while the annual rate of growth may 

be levelling off at about 5 percent. Whilst the 

US is still the largest market, this growth is 

coming from the “pharmamerging” markets 

– the so called BRIC markets of Brazil, 

Russia, India, and China, plus South Korea, 

Turkey and Mexico. Apart from that, 

innovation (for example, innovation in 

oncology, biotech products and specialist 

products) is driving the product level growth 

in 2009 as well as an increase in generics. 

Novo Nordisk increased operating profit by 

38% in 2008 - performance driven by sales of 

modern insulins and gross margin 

improvement. The dividend is to be 

increased by 33%. Lars Rebien Sørensen, 

president and CEO, said: "We are satisfied 

with the solid business results achieved in 

2008 driven by the continued penetration of 

our modern insulins in all key markets. 

Despite the general economic downturn we 

still expect double-digit growth in both sales 

and operating profit for 2009 and we are 

increasing our long-term financial targets." 

Eli Lilly and Daiichi Sankyo have won 

European approval for their blood thinner 

Prasugrel, one of the most closely watched 

therapies in late-stage development. 

Regulators gave a green light to use the 

medicine on patients who had stents put in to 

clear arteries near the heart. The Wall Street 

Journal's health blog was quick to note that 

this is just one of many examples where 

Europe has led the US when it comes to new 

approvals. The drug will be called Efient in 

Europe, where it will go up against the 

blockbuster Plavix, which is marketed by 

Bristol-Myers Squibb and Sanofi-Aventis. 

Analysts are expecting the FDA to follow up 

with approval in the US following an expert 

panel's unanimous recommendation. 

Having long been regarded as an 

unattractive market, vaccines have reemerged 

as a successful growth driver for 

Big Pharma. The launch and rapid uptake of 

novel, high-price products such as Wyeth's 

Prevnar or Merck & Co's Gardasil, along with 

the emergence of novel vaccine 

technologies and favourable legislation, have 

brought vaccines back into the main focus of 

pharmaceutical and biotech companies. 

Schering-Plough will provide the World 

Health Organization (WHO) with access to 

pandemic influenza vaccine manufacturing 

technology in developing countries. The 

WHO may also give sub-licenses to firms 

operating in various developing countries. 

The agreement, which was signed by 

Nobilon, the company’s human vaccine 

business unit, grants the organisation a nonexclusive 

license to develop, register, 

manufacture, use, and sell seasonal and 

pandemic live, attenuated, influenza 

vaccines (LAIV), produced on embryonated 

chicken eggs. Egg-based LAIV technology 

is specifically considered attractive for this 

purpose, because the manufacturing 

technology process is easier to transfer, 

capital investment is lower, and yields are 

higher as compared to inactivated influenza 

vaccines, according to Schering-Plough. 

Keep them rolling… 

Our thanks go to all the authors of the 

interesting and informative articles in this 

issue of IPI. In future issues, we plan to 

review the drug discovery market, drug 

delivery technologies, new developments in 

biotech, outsourced manufacturing and 

clinical research developments. Enjoy this 

issue and we look forward to your comments 

and articles. 

Patricia Lobo, MSc, PhD 

As an independent management Consultant 

for Life Science Business Solutions (LSBS), I 

am honoured to be invited by Pharma 

Publications to be the Editor of International 

Pharmaceutical Industry (IPI). 

I have worked in the pharma sector for 

over 30 years after graduating in Chemistry, 

Microbiology and Biochemistry and gaining 

an external PhD in Biochemical 

Pharmacology and a business training 

course. My industrial career in the UK led 

from the QC department of a generics CMO 

to the R&D department of GD Searle (now 

Pfizer), followed by working as a CRA with 

Stiefel Laboratories, as Senior Clinical 

Research Scientist with Farmitalia Carlo Erba 

(now Pfizer), Oncology Business Unit 

Manager with Schering Plough, and for 

nearly 17 years as a Management Consultant 

for Technomark and RSA Consulting Ltd. 

There I have supported international Life 

Science clients with assignments in 

manufacturing, clinical research, 

development and marketing, providing 

specialised advice in drug development, 

outsourcing, clinical research or 

manufacturing, due diligence, strategic 

planning and marketing, including advice to 

corporate finance and equity organisations 

on M&As, JVs, alliances and investment. I 

have published over 20 scientific articles, 

organised a major conference and exhibition 

in London, set up a database of Contract 

Manufacturers, 

Email: patricia.lobo@aol.com 



America’s Pharmaceutical Research 

Companies: Improving Patient and 

Practitioner Knowledge about 

Prescription Medicines 

When it comes to providing patients with 

excellent healthcare, there is one essential 

ingredient that everyone in the healthcare 

delivery chain can subscribe to: informed, 

knowledgeable patients, active in their own 

treatment, make the best patients. Such 

patients are better able to understand their 

condition, the treatment and medical 

options proposed by healthcare 

practitioners, and are also better able to 

commit themselves to following through on 

treatments and making lifestyle and other 

changes that may be necessary to become 

healthy and stay healthy. In short, one sure 

way to improve the quality and utility of 

healthcare across the board is to empower 

patients with information and help them to 

be true partners in their own care. 

Fortunately, we live in an era when more 

information about disease, medicines and 

treatment options is available to both 

patients and medical practitioners than ever 

before. As a result, patients can be better 

advocates for their own care, and healthcare 

professionals can be more knowledgeable 

both about a patient’s conditions and also 

the latest, best treatment options. 

At the same time, however, the sheer 

volume of information now available – for 

example, via the internet – also poses a 

challenge to patients and healthcare 

professionals alike. While patients and 

healthcare professionals need more 

information about health, disease and 

available treatments, they also need that 

information to be accurate and reliable for it 

to be truly useful. Ideally, then, patients and 

healthcare practitioners need to be able to 

quickly and effectively sort through multiple 

and sometimes contradictory – though 

seemingly credible – sources of information 

in order to find answers both on diseases 

and their effects as well as the best 

treatment options. That is a daunting task for 

healthy healthcare consumers, and one that 

is all the more difficult when the consumer is 

also a patient confronting a serious 

condition or disease. 

As the makers of innovative medicines, 

America’s pharmaceutical research 

companies understand that patients and 

practitioners need reliable information so 

that they can make good healthcare 

decisions. Patients and practitioners must 

be able to work together to help ensure that 

patients get the right treatment for the right 

condition at the right time. Knowledge – 

about a disease and treatment options – is 

the key to ensure this critical formulation 

comes together for each patient. 

Clearly, medicines are playing an 

increasingly important role in healthcare. 

The right medicine to the right patient at the 

right time can not only help a patient avoid a 

disease or treat a disease, it can also help 

minimise other health issues – from costly 

hospitalisations and surgeries to the 

“Patients and practitioners 

must be able to work 

together to help ensure 

that patients get the right 

treatment for the right 

condition at the right time” 

unintended health consequences of a failure 

to seek treatment. The cost of avoidable and 

treatable chronic diseases to both patients’ 

health and to the economy, for instance, 

exemplifies how important it is for patients to 

consult and engage practitioners and for 

practitioners to have broad knowledge 

about both disease and treatment options. 

Pharmaceutical advertising and 

marketing can and must play an important 

part in the provision of critical information to 

both patients and practitioners. America’s 

pharmaceutical research companies 

recognise both this important function of 

their marketing but also their obligation to 

help meet the information needs of patients 

and practitioners. This awareness has 

resulted in a growing commitment by 

America’s pharmaceutical research 

companies to improve the quality of their 

marketing efforts and also to enhance their 

interactions with healthcare practitioners by 

focusing on professionalism and 

transparency. 

In an effort to better meet the information 

and knowledge needs of both patients and 

practitioners, the Pharmaceutical Research 

and Manufacturers of America (PhRMA) and 

its member companies have embarked on a 

number of industry-driven initiatives 

designed specifically to improve the 

information available about the medicine 

they make and its appropriate uses. 

For example, in July 2005, PhRMA’s 

Board of Directors unanimously approved 

Guiding Principles on the Direct to 

Consumer Advertisements About 

Prescription Medicines. These guiding 

principles grew out of an increasing 

awareness of public concern over the quality 

of information provided in pharmaceutical 

direct-to-consumer advertising (DTC). The 

resulting principles (for more information 

visit: http://www.phrma.org/dtc) encourage 

the communication of accurate and fairly 

balanced information about medicines and 

help ensure that DTC advertising remains an 

important and powerful tool to help educate 

patients while at the same time addressing 

many of the concerns expressed about DTC 

advertising in recent years. 

These principles also come from an 

understanding – bolstered by many surveys 

and studies – demonstrating that patients 

knowledgeable about both potential 

diseases and possible treatments are more 

likely to ask their physician’s advice and be 

more active in protecting and improving their 

own health. The principles affirm that DTC 

advertisements are created to help inform 

and empower consumers and to make them 

aware of new medicines and their benefits 

as well as risks. Additionally, marketing 

should be designed to promote increased 

communication between doctors and 


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E-Mail: contact@ipr-ee.com 

www.ipr-ee.com


patients about existing conditions as well as 

other potential health issues. Further, the 

principles recognise that marketing and 

advertising can play an important role in 

helping to de-stigmatise a disease or 

condition and prompt patients to seek 

needed treatment. 

The principles, among other goals, 

encourage America’s pharmaceutical 

research companies to: 

• Spend appropriate time educating 

healthcare professionals about a new 

medicine before it is advertised to 

patients; 

• Include information about help for the 

uninsured and the under-insured in its 

commutations, where feasible; 

• Respect the seriousness of health 

conditions being advertised in DTC 

advertisements; and, critically, 

• Provide risk and safety information in DTC 

advertisements that is designed to 

achieve a balanced presentation of both 

risks and benefits associated with a 

medication. 

In addition to their DTC advertising initiative, 

PhRMA and its member companies have 

also recently focused on efforts to improve 

the interactions between healthcare 

professionals and the representatives of 

pharmaceutical research manufacturers. In 

July 2008, PhRMA introduced its revised 

voluntary code governing these 

relationships(http://www.phrma.org/news_ro 

om/press_releases/phrma_code_reinforces 

_commitment_to_responsible_interactions_ 

with_healthcare_professionals/). 

The code specifically seeks to help 

ensure that healthcare professionals have 

access to the latest, most accurate 

information available regarding prescription 

medicines, while making interactions 

between physicians and company 

representatives more professional and 

transparent. 

Specifically, the code promotes 

communications that: 

• Inform healthcare professionals about the 

benefits and risks of biopharmaceutical 

medicines to help advance appropriate 

patient use; 

• Provide scientific and educational 

information; 

• Support medical research and education; 

and, 

• Provide feedback and advice about 

medicines and how they are being used 

by both manufacturers and healthcare 

professionals. 

The code also contains provisions that 

address provision of educational grants and 

continuing medical education by 

pharmaceutical research companies. 

Importantly, these voluntary initiatives by 

pharmaceutical research manufacturers are 

the result of PhRMA member companies 

recognising the importance to both patients 

and healthcare professionals of accurate 

and balanced information about medicines. 

The initiatives are also the result of 

pharmaceutical research companies 

listening to and addressing many of the 

concerns of both patients and practitioners 

about the content and quality of industry 

marketing practices. In the end, however, 

what is most important is that patients and 

practitioners have access to the best 

information about diseases, medicines and 

available treatment options so that they can 

work together to protect and improve a 

patient’s health and, in many instances, 

pharmaceutical research companies are in 

the best position to provide credible, needed 

information about the risks and benefits of 

the medicines they make ■ 

Billy Tauzin was named president and chief 

executive officer of the Pharmaceutical 

Research and Manufacturers of America 

(PhRMA) in January 2005 and immediately 

took up two of the most important causes of 

his career. Billy Tauzin began his public 

service career in the Louisiana State 

Legislature where he served in a variety of 

distinguished posts such as Chairman of 

the House Natural Resources Committee 

and Chief Administration Floor Leader. He 

was chosen twice as one of Louisiana’s ‘Ten 

Best Legislators’. 

Email: info@phrma.org 

10 IPI


The 2008 Revised Declaration of Helsinki 

and Proposed Solutions for Research 

Ethics in Globalised Clinical Trials 

In October 2008 the World Medical 

Association (WMA) once again revised the 

Declaration of Helsinki (DoH), this time at 

its General Assembly Meeting in Seoul, 

South Korea. While the WMA insisted that 

this revision would be largely for editorial 

purposes, the result is a significantly altered 

'Ethical Principles for Medical Research 

Involving Human Subjects’, the current 

subtitle of the DoH. The revision contains 

both ‘editorial’ changes, including a revised 

use of wording in places and the integration 

of ‘explanatory notes’ into the main text, as 

well as the addition of new ‘principles’ and a 

greater emphasis on the primacy of the DoH 

Revised Ethical Principles 

Significant revisions appear throughout the 

2008 DoH. The following listing groups the 

principle revisions according to the thinking 

within the WMA that informed the revision. 

1. An emphasis on the individual research 

participant (‘subject’) whose wellbeing 

‘must take precedence over all other 

interests' (paragraph 8) and (when 

competent) must ‘freely agree (consent) – 

without exception – to the 

research’(paragraph 22). 

2. Greater emphasis on transparency in 

clinical research, including (a) specified 

information to be included in the protocol: 

‘information regarding funding, sponsors, 

institutional affiliations, other potential 

conflicts of interest, incentives for subjects 

and provisions for treating and/or 

compensating subjects who are harmed 

as a consequence of participation in the 

research study' (paragraph 14) and (b) 

specific information and methods for 

delivering patient information / informed 

consent (paragraph 24), and (c) a 

requirement to register publically ‘every 

clinical trial’. 

3. A restatement of the WMA position on the 

use of control arms in medical research, 

specifically indicating two exceptions 

where the use of placebos is allowed: (a) 

above other national and international 

ethical and legal requirements. The WMA 

was clearly aiming at a text to strongly 

impact both the international research ethics 

discussion and real-time practical 

requirements for medical research, 

including (if not, primarily) clinical trials. 

More recently, on 19 February 2009, the 

New England Journal of Medicine published 

an article entitled 'Ethical and Scientific 

Implications of the Globalization of Clinical 

Research’ in which a group of clinical 

triallists from the Duke University School of 

Medicine and the University of North 

‘where no current proven intervention 

exists’ and (b) 'where for compelling and 

scientifically sound methodological 

reasons’ in which research participants will 

not be exposed ‘to any risk of serious or 

irreversible harm’ (paragraph 32). 

4. A stronger position on what research 

participants are ‘entitled' to at the end of 

studies: (a) ‘to be informed of the outcome 

of the study' and (b) ‘to share any benefits 

that result from [the study]’ (paragraph 

33). The specific entitlement to ‘post-study 

access by study subjects to interventions 

identified as beneficial in the study or 

access to other appropriate care or 

benefits’ needs to be stated in the protocol 

(paragraph 14). 

5. A new concern with the role of ‘community’ 

along with ‘populations’ (introduced in 

2000) insisting that research must be 

‘responsive to the health needs and 

priorities of this [wherein the research 

takes place] population or community, and 

if there is a reasonable likelihood that this 

population or community stands to benefit 

from the results of the research’ 

(paragraph 17). Importantly, paragraph 22 

makes it clear that the individual’s interests 

and decisions take precedence over those 

of the community. 

Carolina School of Medicine produced a 

commentary raising the question: ‘To what 

extent should people in developing 

countries be enrolled in clinical trials?’ The 

article by US clinical researchers challenges 

the ethical and scientific value of clinical 

trials in places such as Central and South 

America, Eastern Europe, Southeast Asia, 

the Middle East, Africa, China, and India. 

Although they (Glickman et al.) reference the 

current 2008 version of the DoH, they 

indirectly quote the now debunked 2000- 

2004 version in an overall argument that 

says greater clarity of ethical principles is 

needed, greater quality control regarding 

clinical trial data and its geographic 

relevance needs to be implemented, and 

more government oversight is required. 

Since the recent and, oftentimes, heated 

discussion on revising the DoH began at the 

WMA General Assembly in Hamburg in 

November 1997, the WMA has repeatedly 

emphasised its wish that in revising the DoH 


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the needs of research participants and 

researchers in ‘developing countries’ are 

being strengthened in relation to the 

perhaps real or perceived threats coming 

from places like the United States and the 

European Union, particularly with regard to 

commercially sponsored clinical trials. At the 

same time, as recently reported in this 

journal, leaders in the research ethics 

communities in these countries did not 

always feel that the WMA consultation 

process or resulting text well represented 

their values and concerns. Still there remain 

strong parallels between the concerns with 

the globalisation of clinical trials as 

expressed by the WMA, as well as by 

groups such as Glickman and others. In 

general, this is a concern that the 

motivations of greed, profit, and downright 

indifference to others does (and will 

continue to) allow for clinical trials that are in 

the interest of the powerful at the expense of 

the weak. 

Instead of refurbishing its own 'ethical 

principles' or adopting new ethical principles 

from others, as the WMA does in the DoH, 

Glickman and others have identified a 

number of issues with clinical trials in 

‘developing countries’ and proposed 

‘solutions’. Many of the issues overlap those 

addressed by the WMA in the DoH, 

including research participant selection, 

clinical trial transparency, the role of ethics 

committees/IRBs, commercial interests, and 

confidentiality. Glickman and others also 

include the issues of regulatory oversight, 

investigator training, a lack of 

pharmacogenomic information, and 

payments to research participants. For 

Glickman these issues present problems 

that need to be addressed, even resolved, if 

the current trend of increased clinical trial 

data from outside the US can justify the 

ethical and scientific confidence in the data 

gathered in clinical trials and used to claim 

new health benefits by pharmaceutical and 

device products. Glickman’s group 

proposes several concrete steps to be taken 

in order to provide more confidence in 

clinical trials carried on outside the bastions 

of ‘developed countries’. 

Solutions to the Globalisation of Clinical 

Trials 

Listed here in paraphrase are selected 

solutions to the ethical and scientific issues 

raised by clinical trials in developing 

countries, as proposed by Glickman and 

others recently in the New England Journal 

of Medicine: 

1. targeted enrolment of trial populations 

based on geographic region and a 

market match for the intended product; 

2. the publication of ‘all clinical trial data’ 

ensuring the rights of investigators 

globally to publish independently of 

sponsors; 

3. develop a formal mechanism that allows 

for ‘sharing regulatory oversight’ of 



clinical trials globally and a public registry 

of ethics committees / IRBs globally; 

4. create training programmes for 

investigators in clinical research and 

ethics; 

5. use the US FDA Voluntary Genomic Data 

Submissions programme globally across 

other regulatory agencies; 

6. increase the use of centralised ethical 

review procedures; 

7. adopt standard contract language and 

confidentiality agreements for clinical 

trials. 

Glickman concludes the article indicating 

that a single listing of fixes to the challenges 

of ethics and science in today’s international 

clinical trials market place is unlikely to bring 

satisfaction in and of itself: ‘Long-term 

solutions to problems arising from the 

globalization of clinical research will require 

input from stakeholders in academia, 

industry, and regulatory agencies around 

the world.’ The authors, however, appear to 

still want to limit the discussion to those with 

the money, power, and/or authority: they fail 

to recognise the contribution that 

representatives from ethics 

committees/IRBs and, perhaps most 

importantly, representatives of patient and 

consumer organisations can make to the 

efficiency, as well as the ethical and 

scientific understanding, of clinical research. 

Without input from a broader stakeholder 

group, the engagement in globalised clinical 

trials is highly unlikely to get either the 

principles or the solutions, let alone the 

practices, right. At this time when more is 

being called for, even more is needed. 

Indeed the structure of the international 

discussion, alongside how and to what 

extent contributions may be made to that 

discussion, is a major issue that haunts the 

WMA in defending its revised DoH. The 

process for the present revision of the DoH 

began in May 2007 with the establishment of 

a Working Group composed of 

representatives from the national medical 

associations of Brazil, Germany, Japan, 

South Africa, and Sweden. From the outset, 

the primary purpose of this revision process 

was termed 'editorial': the WMA was largely 

interested in integrating the Notes of 

Clarification to paragraphs 29 and 30 of the 

2000 version that were added in 2002 and 

2004. Major issues were not immediately in 

the remit of the Working Party, and it was 

explicitly barred from addressing the 

fundamental structure and arrangement of 

the text. The WMA felt that the Notes of 

Clarification were not clearly understood in 

relation to the texts they were intended to 

clarify. 

The WMA also proposed to use this 

opportunity to clarify other issues in Helsinki 

and to address specific issues that recently 

appeared to be of importance and in need 

of global clarification. Just why certain 

issues were chosen for inclusion (for 

example, the registration of clinical trials) 

and others were set aside (for example, 

research on healthy volunteers) has not 

been publicly disclosed by the WMA, 

though it may be that there was a certain felt 

political advantage within the organisation to 

adapt recommendations from other 

organisations. Between May 2007 and 

September 2008, the WMA invited two 

rounds of comments on the DoH and 

hosted three workshops to discuss the 

issues and proposed changes. No public 

reports of the comments received nor of the 

workshops were prepared and, although 

there have been calls for transparency with 

regard to the WMA process for revising 

Helsinki, the WMA has decided not to make 

public the comments received or reports of 

the workshops. While the pharmaceutical 

industry seems to have been well integrated 

into the process through the participation of 

the International Federation of 

Pharmaceutical Manufacturers and 

Associations (IFPMA) as well as the 

participation of individual companies, there 

does not appear to have been a structured 

discussion with representatives from such 

groups as ethics committees or patient 

organisations. 

Glickman and others have also run up 

against similar obstacles in proposing 

solutions to problems in globalised clinical 

research. Although they call for a broader 

discussion on the problems they see as being 

brought about by the globalisation of clinical 

trials, their proposed solutions are limited to a 

group of researchers all living and working 

within a 100 kilometre radius inside the posh 

American south. As they look eastward past 

Washington, DC and Brussels, there is a 

tendency to characterise the larger part of the 

world (of clinical trials) outside the US and the 

EU as ‘developing countries’. It appears all too 

easy not to look westward in one's own 

backyard of Appalachia and the vulnerable 

characteristics of many of the research 

participants that populate the clinical trials in 

Durham and Chapel Hill, North Carolina. It is 

perhaps too simple to believe that their clinical 

trial cohorts are socially better off than cohorts 

in Moscow, Mumbai, Singapore, Shanghai, or 

Buenos Aires. If the participants in this 

discussion are not attentive and listening, 

there is the clear and present danger of 

mistaking national and cultural identity for 

some superior position on the ladder of ethical 

and scientific justification. At the very least 

proposals for solutions to the challenges of 

international clinical trials require international 

authorship, and more than a reference listing 

of 62 references with only a single one drawn 

from a so-called developing country, China. 

It is now an accepted fact that clinical trials 

are no longer primarily confined to the ICH 

region that provided the background to the 

1996 E-6 Good Clinical Practice Guideline. 

The United States, Japan, and the European 

Union (even having more than doubled in 

size) no longer have any special claim to 

hosting clinical trials. This flattening of the 

clinical trials marketplace does lead to a 

rethinking of the key issues in research ethics, 

as well as the methodological and quality 

characteristics of clinical trial data on which we 

base scientific and public health decisions. 

Glickman and others are right to assert: ‘The 

future of the pharmaceutical and device 

industries is predicated on addressing these 

issues.’ This future will depend, as the WMA 

has seen, on a reappraisal of the ethical 

principles that underlie clinical research as 

well as on an attempt to collectively seek 

solutions, as Glickman and others indicate, to 

contemporary ethical and scientific issues in 

clinical trials. More importantly, however, the 

future of these industries, both academic and 

commercial, will require us to revise our 

practices to meet the new realities which 

present themselves in science, culture, and 

ethics ■ 

Francis P. Crawley 

is the Executive 

Director of the Good 

Clinical Practice 

Alliance – Europe 

(GCPA) in Brussels, 

Belgium and a World 

Health Organization 

(WHO) Expert in ethics. He is the co-founder 

of the Strategic Initiative for Developing 

Capacity in Ethical Review (SIDCER). He is 

a past member of the UNAIDS Ethical 

Review Committee and currently Chairs the 

Ethical Review Committee at the 

International Network for Cancer Treatment 

and Research (INCTR). He has played a 

pivotal role in developing European and 

international guidance in ethics and 

regulation for health research. 

Email: fpc@gcpalliance.org 



e-Networking in the 

Drug Discovery Industry 

The complexities of modern drug 

discovery often require cooperation 

between many different participants, 

sometimes located in different continents. 

This is particularly true in an outsourcing 

environment, where clinical trials, 

manufacturing and even preclinical 

research become globalised. Demands for 

effective communication between 

companies, laboratories and individuals 

have therefore increased enormously. 

Fortuitously, or possibly causatively, these 

demands coincide with the supply of 

internet-based networking tools that make 

geographical boundaries and time zones 

irrelevant. e-Networking is expanding 

rapidly and is here to stay. 

Background 

The pharmaceutical industry is beginning to 

reinvent itself as commercial pressures 

make the old FIPCo (fully integrated 

pharmaceutical company) model 

increasingly unsupportable. For example, 

patent expiries on best selling medicines 

over the period 2007 to 2012 will cost the top 

50 companies $115 billion in lost revenues 

(the patent cliff) (1). It is no longer possible 

for companies to replace these lost sales 

revenues by remaining isolated, so 

partnership models are being developed to 

create the fully integrated pharmaceutical 

network (FIPNet). This involves sharing 

financial risk with partners, as well as 

outsourcing many research and 

development functions that were once kept 

firmly in-house. Large western 

pharmaceutical companies are increasingly 

turning to high-growth economies such as 

China and India for support, from discovery 

research (e.g. medicinal chemistry and 

biotechnology) all the way through to 

manufacturing. 

This globalisation process has been 

greatly facilitated by the internet, through 

improved person-to-person communication 

(email), as well as through information 

portals which provide access to regulatory 

guidelines, research literature etc. Next 

generation web-based tools which use Web 

2.0 technology make information flow a truly 

two-way process by using blogs, wikis and 

social/business networking sites. 

To be successful in drug development, 

such tools must increase the interchange of 

ideas between scientists, clinicians and 

business people. To be effective, they must 

help to increase the rate of discovery, 

development and marketing of new 

medicines. 

We have recently reviewed developments 

in scientific networking from the perspective 

of the drug discovery scientist (2, 3). In the 

current article, we extend these observations 

to cover the broader drug development and 

“Next generation webbased 

tools which use 

Web 2.0 technology 

make information flow 

a truly two-way process 

by using blogs, wikis 

and social/business 

networking sites” 

marketing arena. We conclude that social 

and business networking technologies 

increasingly provide a serious, credible and 

essential resource for the pharmaceutical 

and biotechnology industries. 

e-Networking and Web 2.0 

Improvements in networking and 

communication technologies have given rise 

to new concepts, particularly that of Web 

2.0. Web 1.0 is the well-established internet 

of static web pages and downloadable 

content (“pull” technology). Web 2.0, 

however, allows direct user control (“push” 

technology) of content on remote web 

pages. The Web 2.0 concept involves 

“harnessing the collective intelligence” of a 

community (4). This does not imply a major 

change of technology, but is more about 

“teaching the old web new tricks” (5). These 

“new tricks” include blogs, wikis, 

folksonomies, RSS feeds and mashups. 

Blogs (web logs) contain regularly 

updated personal commentary, descriptions 

of events, diary entries etc that are hosted by 

individuals or organisations on their 

websites. Blogs are very powerful 

networking tools, since others may 

contribute interactively in the form of online 

conversations. Sometimes the content is 

delivered as audio in the form of podcasts, 

or video (vlogging). 

Wikis (Hawaiian for “fast”) are information 

resources that can be edited by the online 

community. The most famous example is 

Wikipedia (http://en.wikipedia.org/), an 

online encyclopaedia that is continually 

evolving as content is added, removed or 

modified. 

Folksonomies (folk taxonomies) consist 

of search terms provided by the online 

community to search the web according to 

individual preferences. This feature 

distinguishes folksomonies from the more 

controlled vocabularies used by search 

engines to find information on the internet. 

RSS feeds (Real Simple Syndication) are 

a form of aggregator that automatically pulls 

together updated information, such as news 

headlines or recent publications, and 

delivers the content directly to users as a 

single display on the web page. 

Mashups are applications that combine 

data from more than one source into a 

feature such as a generalised world map 

overlaid with specific information. An 

example of this is the community map for the 

Drug Design Resource, described in detail 

elsewhere (2, 3). These technologies are 

evolving rapidly and can be found within an 

increasing number of internet networking 

sites. 

Social networking 

Most internet users are aware of social 

networking sites such as Facebook, 

MySpace and Bebo. Because they are used 


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mostly for social interactions among young 

people, there are obvious limitations to their 

utility in professional interactions among 

drug industry personnel. However, there is 

some activity in the drug development area 

as we have described in a previous article 

(2). Whatever the topic under discussion, 

they give their members access to specific 

networks regardless of professional status, 

and allow members to make new contacts 

almost instantaneously. 

Traditional means of networking, such as 

telephoning, sending emails or attending 

conferences are often much less efficient. 

Interestingly, the social network model has 

been adopted by a specialist medical 

imaging organisation (High Frequency 

Clinical & Preclinical Imaging Community) to 

support their Annual Convention 

(http://www.aium2009.org). Individual 

groups have been set up along the 

Facebook model for different specialisations 

(e.g. sonography or thyroid imaging). We 

expect to see this more widely adopted by 

the wider community. 

Lastly comes Twitter (www.twitter.com). 

This site hosts one-sentence 

thoughts/comments/links on any subject 

that can be followed by those with the 

inclination to do so. This internet version of 

text messaging has been used by 

organisations as well as individuals, and 

there is a surprising amount of material 

related to drug discovery. It remains to be 

seen whether this will be a passing fad, or 

something genuinely useful for near realtime 

alerts for news on science and 

business. 

Business networking 

Most business networking is conducted 

face-to-face at meetings and conferences, 

although cost issues have encouraged the 

uptake of video conferencing. The internet 

itself has also been used as a 

videoconferencing tool. For example, 

companies like WebEx 

(http://www.webex.com/) provide video and 

text links in a variety of configurations that 

allow sophisticated networking to anyone 

with a broadband connection. More value is 

being extracted from conferences by their 

organisers through podcasts and web 

seminars (webinars) that provide material for 

those unable to attend. 

Business networking sites are flourishing, 

particularly because of the dynamic job 

market and the increasing competition for 

business. Sites like LinkedIn, Ryze and Xing 

provide a more structured environment for 

the establishment of personal networks. We 

have discovered from our own experience 

with the Group facility within LinkedIn that 

these sites provide powerful networking 

platforms for collaboration (see 

http://www.linkedin.com/groups?home=&gi 

d=151138&trk=anet_ug_hm and 

http://www.linkedin.com/groups?gid=13309 

1&trk=hb_side_g) 

Drug discovery and development networks 

A broad group of disciplines, covering 

science, medicine, engineering and the law, 

are required to bring drugs from the 

laboratory to the marketplace. Expert 

communities centred on these disciplines 

can share valuable information and 

experience on topics of mutual interest. The 

following examples give a flavour of the 

potential applications in drug development: 

1) Pooling expertise on drug safety 

The Drug Safety Executive Council (DSEC) 

(http://www.drugsafetycouncil.org/index.cfm 

) in the USA is a network of over 1500 drug 

safety personnel in pharmaceutical 

companies. Each company is in a 

competitive marketplace, but decided to 

pool information on technologies to test 

drug safety because of the trust established 

through a networking infrastructure driven by 

the web. This benefits all companies without 

compromising proprietary information. 

2) Exchange of clinical information 

Pfizer announced a strategic partnership 

with Sermo (www.sermo.com) in 2007 as an 

early example of social networking by a large 

pharmaceutical company to further its 

business objectives. This direct online 

discussion with physicians is a significant 

departure from the normal exchange of 

medical information about the company’s 

products, be they formal conferences or 

sales visits to surgeries. 

3) Drug discovery for the developing world 

There is a well-known mismatch between the 

need for novel drugs to treat diseases 

endemic in the developing world and the 

willingness of the pharmaceutical industry to 

divert resources away from “western” 

diseases. This situation is beginning to 

change through partnerships between major 

drug companies, academia and small 

companies in the developing world. The 

internet provides an ideal tool for developing 

networks between these disparate 

organisations. One example is a 

coordination strategy for lead discovery for 

malaria, tuberculosis (TB), African sleeping 

sickness, Leishmaniasis and Chagas 

disease (6, 7). Here, the use of resources is 

highly coordinated within innovation 

networks or virtual drug discovery networks. 

A similar concept is provided by an Indian 

initiative “Open Source Drug Discovery” 



(http://www.osdd.net/what_is_osdd.htm), 

and also for TB. 

4) In silico drug design 

Alongside several other resources, 

Biovillage has established the specialist in 

silico drug design networking site - The Drug 

Design Resource (DDR) – employing 

traditional information resources enhanced 

by Web 2.0 technologies. The latter includes 

RSS feeds of the latest drug design literature 

as well as map-based mashups of the 

community. This resource is currently being 

expanded to provide both additional content 

and added connectivity (see below). 

The evolution of membership-driven 

content at The Drug Design Resource 

As a first step in producing an integrated 

suite of resources in the drug design area, 

we have linked a series of Web 2.0 platforms 

together, as shown in Figure 1. Staple 

information sources derived from peerreviewed 

journal articles, published books 

and conference reports are assembled 

through the curated DDR website 

(http://www.drugdesignresource.com/). The 

Resource is also linked directly to 

spontaneous blogsites, including the FBDD 

blogspot at www.practicalfragments. 

blogspot.com and the SBDD blogspot at 

http://blogs.informa.com/sbdd), both of 

which provide conduits for immediate 

feedback from the community. At the same 

time, the DDR is dynamically linked to 

individual entries in the professional 

networking site LinkedIn, providing an up-todate, 

curated ensemble of individual contacts 

and additional, person-centric information. 

Such an architecture provides immediate 

Fig. 1 

Expanding connectivity within the 

drug design community through 

various e-networking modalities 

Curation 

Journals 

Curation 

Blog 

Leaders in 

e-Drug Design 

DDR 

LinkedIn 

access to a wide variety of valuable 

information, ranging from the individual to 

the corporate. It can also bridge research 

taking place on different continents and 

within different disciplines, providing a 

unique platform for the exploration of 

relevant discovery information. It is also 

cumulative, with scientific content evolving in 

parallel with individual contributions. 

More importantly, it provides a ‘voice’ for 

its membership, in the first instance the 

development of a project networking facility 

(for more information see the Drug Design 

Directory at www.drugdesignresource.com). 

Conclusions 

Scientific communication and networking 

underpin the globalisation of the 

pharmaceutical industry, a trend which is 

being facilitated through the introduction of 

new web-based tools (Web 2.0). In this 

article, we have discussed some of the 

approaches to scientific networking that are 

relevant to drug development. The common 

theme is interactive participation, whether by 

signing up to a social or professional online 

network, contributing to a blog or discussion 

board, or creating/editing a Wiki. 

It has always been recognised that 

personal interaction is vital for seeding and 

developing scientific ideas. Web 2.0 

technologies simply expand the number of 

people that can participate in these 

conversations. What were once monologs 

from static Web 1.0 technology have now 

become ‘polylogs’. These are changing 

rapidly as their utility in essential 

professional activities – such as job hunting, 

opinion seeking, data sharing and 

collaboration – becomes evident ■ 

Facebook 

Peer Review 

Books 

Peer Review 

Dr David Bailey is a 

Cambridge-based 

entrepreneur. Cofounder 

of IOTA 

Pharmaceuticals Ltd 

and BioVillage Ltd, he 

was previously the 

founding CEO of two 

Cambridge-based start-ups, De Novo 

Pharmaceuticals Ltd and Purely Proteins Ltd. 

Dr Bailey headed up the Molecular Sciences 

Department at Pfizer in Sandwich for 8 years, 

before becoming Vice President at the 

Californian biotech company Incyte 

Genomics. He is a Board Director of the 

Babraham Institute in Cambridge and 

consultant entrepreneur for the University of 

Greenwich in London. 

Email: david.bailey@biovillage.co.uk 

Dr Ed Zanders has an 

extensive research 

background in 

biochemistry and 

immunology through 

over thirty years’ 

experience in 

academia and industry. 

He spent 16 years at 

Glaxo in the UK and Switzerland where he was 

a Senior Research Manager with responsibility 

for drug discovery programmes in 

inflammatory diseases. He later joined De 

Novo Pharmaceuticals Ltd and Purely Proteins 

Ltd in VP positions. In addition to co-founding 

BioVillage Ltd, he has also established a 

pharmaceutical training company, 

ScienceInform Ltd. 

Email: ed.zanders@biovillage.co.uk 

References 

1. Editorial Nature Rev Drug Disc 8: 3-7 2009 

2. Bailey DS and Zanders ED, Drug Discovery 

in the Era of Facebook – New Tools for 

Scientific Networking, Drug Discovery 

Today, 13:863-8 2008 

3. Bailey D and Zanders E, e-Networking and 

Drug Discovery. Innovations in 

Pharmaceutical Technology, October 2008 

4 . 

http://www.oreillynet.com/pub/a/oreilly/tim/ne 

ws/2005/09/30/what-is-web-20.html 

5. Sagotsky JA et al. Life Sciences and the 

web: a new era for collaboration. Molecular 

Systems Biology 4:201 1-10 2008 

6. Solomon N and Hudson A, Innovative lead 

discovery strategies for tropical diseases. Nature 

Reviews Drug Discovery 5: 941-955 2006 

7. Hopkins AL, Witty MJ and Nwaka S, Mission 

Possible. Nature 449: 166-169 2007 



Strategies for the formulation of poorly 

soluble compounds and polymorph 

drugs based on polyelectrolyte carriers 

The main challenge in the administration of 

poorly soluble drugs is to design oral 

formulations displaying a relevant 

bioavailability and to develop injectable 

systems for the parenteral application with 

minimised toxicity and high drug loading. 

The LBL-Technology® offers a strategy for 

enhancing the kinetic of dissolution of BCS 

class II drugs based on the presentation of 

the drug in the form of nanoparticles 

stabilised with layers of polyelectrolyte 

complexes (Fig. 1). 

In this way, nanosuspensions of drug 

substances with impaired water solubility 

can be produced displaying a particle size 

distribution in the nanometre range, 

modified surface charge and high drug 

concentrations (Fig. 2). These drug delivery 

systems are especially attractive for their low 

aggregation in further galenic steps in the 

development of solid dosage forms and for 

their fast dissolution profiles. 

There is a broad range of polycationic 

and polyanionic pharmaceutical excipients 

which build complexes by means of their 

electrostatic interaction. Polyelectrolyte 

complexes are amorphous carriers, which, 

depending on the production method and 

composition, present different rheological 

and plastic behaviours, mechanical 

properties and degrees of porosity (Fig. 3). 

These polyelectrolyte matrices are optimal 

scaffolds for the precipitation of polymorph 

drugs in the most preferred amorphous 

state (Fig. 4). These compositions, besides 

stabilising the drug in the amorphous state, 

also have the additional role of being 

appropriate filler excipients for solid dosage 

form development. Polyelectrolyte 

complexes loaded with drugs can be 

produced in the form of sponge-like 

supramolecular structures presenting an 

amorphous nature and with improved 

rheological properties, stability, solubility and 

later bioavailability. 

Fig. 1 

CLSM (confocal laser scanning microscopy) of a nanosuspension of a BCS class II 

drug stabilised with polyelectrolyte layer (left); detailed representation of the particle 

surface (right) 

Fig. 3 

Polarised microscopy 

of a sponge-like 

polyelectrolyte 

complex. 

Maria Gonzalez Ferreiro, MSc Pharmacy, 

PhD Pharmaceutical Technology (Freie 

Universität Berlin, Germany) is Head of 

Pharmaceutical Development at Capsulution 

Pharma AG in Berlin. 

Email: m.ferreiro@capsulution.com 

Fig. 2 

Particle size distribution 

of a nanosuspension 

formulated via LBL- 

Technology® 

Fig. 4 

X-ray powder diffraction 

(XRPD) of a control 

polymorph drug in the 

crystalline state (grey), a 

drug-free sponge-like 

polyelectrolyte carrier 

control (black) and 

different formulations 

thereof displaying the 

drug stabilised in the 

most preferred 

amorphous state (red, 

blue, green). 


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Does your CRO pay 

enough attention 

to detail? 

Experience plays a crucial role in the field of Clinical Research. 

That is why after 10 years we have become the best in the business and 

have earned your valuable trust. 

Through 10 years of dedicated research in more than 70 

Phase II – IV Clinical Studies and 3 FDA and 1 EMEA inspections, we have 

developed an impeccable track record across fifteen countries in Greece, 

Turkey and the MENA (Middle East & North Africa) region. 

Our attention to detail has helped us to excel in: 

• Feasibility Studies 

• Investigator selection 

• Regulatory submissions 

• Trial management and monitoring 

• Project Management 

Because 

Expertise 

comes with 

Experience 

MEK Consulting, Berytech Technological Pole, Mar Roukos, 1107 2240 

Mkalles Lebanon, Tel: +961 (4) 531 372 Fax: +961 (4) 539 087 

Email: enquiry@mekconsulting.com www.mekconsulting.com 

Consulting 

Contract Research Organisation


Clinical research education 

& training: opportunties 

and issues 

Background 

Clinical trials were initiated around 1537, but 

came to the limelight when James Lind in 

1747 first introduced control groups in a 

study of scurvy. He later went on to become 

the father of clinical trials. Clinical trials 

started flourishing from 1800’s, and the 

focus of studies used to be on study design. 

From 1863 onwards scientists started using 

placebos. Randomised studies were 

initiated in 1923, and from 1945 the focus 

moved to ethical aspects of clinical trials. 

However, a lot has changed in the clinical 

research scenario since then. Today, clinical 

trials are conducted through a regulated 

approach following certain guidelines laid 

down by the International Conference on 

Harmonization (ICH), which is spearheaded 

by the USA, Europe and Japan. 

Clinical research constitutes a large 

sector of the healthcare industry and 

employs a significant percentage of the 

healthcare workforce. The biomedical 

research industry spends an estimated 

US$38 billion worldwide annually. Out of this, 

the global CRO market size is US$15 billion, 

growing at 16% per annum. 

The growing demand for clinical trial 

professionals has led to an increasing 

number of institutions offering academic 

programmes in clinical research. According 

to a 2001 CenterWatch survey, the US has 

slightly more than 200,000 clinical research 

professionals. There are 60,000 trials 

following the Food and Drug 

Administration’s guidance for GCPs and 

more than 40,000 GCP-trained investigators, 

but the number of investigators is 

decreasing even as the number of trials 

increases. According to some reports there 

are over 1000 global competitors in the CRO 

segment offering various services, and it is 

estimated that over 40,000 subjects 

participate in global clinical trials every year. 

Recruitment is a major stumbling block in 

the drug development process, and 

increasing staff costs mean that more and 

more studies will be outsourced to the 

emerging markets. Sponsors are looking at 

emerging markets to leverage the high cost 

of trials in the US and Europe, and to reduce 

time to market. 

Need for Education & Training 

The demand for clinical research 

professionals is rising globally and clinical 

trials are being outsourced from several 

countries, including rapidly growing 

emerging markets like India and China. As a 

result, human resource managers have a 

challenge in front of them to find out or 

develop the right quality of manpower. In 

addition to hiring experienced professionals, 

they need to consider clinical research 

professionals who have undertaken formal 

training or education in clinical research. 

In the developed markets target 

audiences for clinical research education 

and training are often those persons who are 

currently active in clinical research. However, 

in the emerging markets the target 

audiences of such training programmes are 

graduates and postgraduates in medicine, 

science, pharmacy and other related 

subjects without experience in clinical 

research. This new strategy of training fresh 

graduates has been adopted to build 

capacity, and develop a new well-trained 

clinical research workforce in the emerging 

markets. 

Clinical research managers / 

coordinators are an important part of the 

clinical trial process. In order to be a 

successful clinical trial professional the 

person would need to have formal training in 

clinical research or previous work 

experience in clinical trials, and a working 

knowledge of the clinical research industry. 

Programme Content 

A good clinical research training programme 

must provide knowledge of GCP (good 

clinical practices), and the Code of Federal 

Regulations or regulations of other 

countries, viz. EMEA, MHRA, Schedule Y of 

India, Anvisa of Brazil, TGA Australia, Health 

Canada and several other countries like 

China and Russia. It is important that the 

training of clinical research managers and 

coordinators emphasises the history of 

research regulation, guidelines and forms, 

codes of federal regulations, phases of 

clinical research, IEC / IRBs and submission 

requirements, informed consent process, 

protocol review and evaluation, project 

management, budget preparation and 

negotiation, regulatory submissions, 

adverse events, study drug accountability, 

and setting up one’s research site. 

It takes a lot of responsibility and 

experience to be a clinical research 

professional. It is important for the clinical 

research professionals to understand ethical 

issues involved in human research, follow 

regulations stringently, work effectively with 

other stakeholders like IEC/IRB, create and 

conduct informed consent, manage study 

data, manage adverse events, understand 

the community/research interface, collect 

high quality data, identify funding sources 

and prepare grant proposals, and fulfil 

reporting obligations. 

Clinical research professionals must 

learn the drug development process; 

understand global clinical research 

regulations, the informed consent process 

and the relevant regulations; help coordinate 

sponsor site visits; manage clinical trial 

protocol; and identify ethical issues in 

clinical research and their impact on the 

development of good clinical practices. 

Participating in audits is important for a 

clinical research coordinator because 

without the training, a clinical coordinator 

would not be able to perform or face the 

audit to high quality standards for an 

inspection. It is important to maintain a safe 

and quality environment in clinical settings to 

ensure the individuals participating in the 

clinical trials, and the future consumers, will 

be safe. 

Until about the early part of 2000, a 

science or pharmacy graduate could easily 

get a job as a clinical research coordinator 

www.ipimedia.com 


Does your CRO pay 

enough attention 

to detail? 

Experience plays a crucial role in the field of Clinical Research. 

That is why after 10 years we have become the best in the business and 

have earned your valuable trust. 

Through 10 years of dedicated research in more than 70 

Phase II – IV Clinical Studies and 3 FDA and 1 EMEA inspections, we have 

developed an impeccable track record across fifteen countries in Greece, 

Turkey and the MENA (Middle East & North Africa) region. 

Our attention to detail has helped us to excel in: 

• Feasibility Studies 

• Investigator selection 

• Regulatory submissions 

• Trial management and monitoring 

• Project Management 

Because 

Expertise 

comes with 

Experience 

MEK Consulting, Berytech Technological Pole, Mar Roukos, 1107 2240 

Mkalles Lebanon, Tel: +961 (4) 531 372 Fax: +961 (4) 539 087 

Email: enquiry@mekconsulting.com www.mekconsulting.com 

Consulting 

Contract Research Organisation


programmes and graduate & postgraduate 

degrees. Most of these programmes vary 

from country to country, and there is no 

standardisation of the course curriculum. 

There is a need for short-term specialised 

programmes. Although university 

programmes offer long-term programmes 

on clinical research, there is a great need for 

short duration specialised programmes on 

subjects like pharmacovigilance, drug 

safety, biostatistics, quality assurance in 

clinical research, bioequivalence & 

bioavailability, subject recruitment & 

retention, regulatory issues and several 

other such topics. These programmes 

provide more practical training to the 

students in the workshop environment. 

Challenges in Clinical Research 

Education & Training in the absence of a 

standardised curriculum there are gaps in 

the training programmes. 

There are several factors which limit the 

implementation of quality clinical research 

education and training programmes. One of 

the critical issues is the quality of training 

facilities. There is a lack of commitment in 

the industry and investigators to train 

budding clinical research professionals. 

Some other issues are the allocation of 

training budgets by companies. Most 

companies consider training and education 

to staff as an incentive rather than an 

investment to improve the quality of clinical 

trials conducted by them. 

Another issue which impacts training is the 

high cost of the large number of programmes. 

Most of the programmes offered have 

prohibitive costs, hence most students and 

even working professionals cannot afford 

these programmes. 

There are several other challenges which 

need to be addressed to implement the quality 

programmes, viz. who should be trained, who 

should provide training, course design, 

programme delivery mechanisms, cost, role of 

the industry, accreditation, what role 

professional associations could play in setting 

the benchmarks, whether there is a need for 

formal university programmes or whether 

certification / diploma programmes are able to 

address the needs of the industry. Several 

such questions are unanswered today. 

Like other professional education 

programmes, e.g. management education, 

there is a great need for the educational and 

training institutions to arrive at a common 

forum together and device a strategy to 

address the above challenges ■ 

Kamal Shahani 

received his Masters 

in Business 

Administration from 

FORE School of 

Management in New 

Delhi and also holds 

Degree in Commerce 

and Post Graduation in International 

Business. He has over 20 years experience 

in the Indian healthcare and clinical research 

industry on the senior management positions 

and has set up and managed large 

healthcare and clinical research projects. 

Kamal at present provides specialised 

market research, business & consulting 

services and India entry strategy services, 

including regulatory support services to the 

clinical research companies from North 

America. He is also an Honorary Advisor to 

the leading clinical research education and 

training companies in India. 

Email: info@cliniminds.com 



Patient recruitment and 

retention in clinical trials 

Patient recruitment and retention is the 

leading problem drug companies face in 

developing their new pipelines. As recruiting 

becomes more diverse and complex, 

pharmaceutical companies are striving to 

discover new innovative ways to facilitate 

recruitment and keep patients enrolled in the 

clinical trial. With more and more clinical 

trials being done on a global level, it is 

imperative to have an understanding of both 

government regulations and social protocol 

that accompany these new markets. 

Patient recruitment and retention remains 

one of the most significant challenges faced 

by the pharmaceutical industry today, and 

accounts for hundreds of millions of Euros 

being spent due to delays in the clinical 

development process. Speeding up clinical 

trials is one opportunity to cut costs, improve 

efficiency and bring new drugs to market 

faster. 

Operational delays in clinical trials reduce 

patent exclusivity time and shorten the most 

commercially productive phase of a 

product’s life cycle. The primary source of 

such delays is the recruitment and retention 

of patients who fit the trials’ requirements. 

More and more drugs on trial have been 

designed to attack very specific biological 

targets. This necessitates the need to 

identify, recruit and retain patients who fit an 

increasingly narrow medical profile. 

Therefore, pharmaceutical companies and 

clinical research organisations are seeking 

new ways to optimise recruiting operations 

and gain a competitive edge. Patient 

Recruitment and Retention in Clinical Trials is 

a new report from Business Insights that 

provides a comprehensive review of patient 

recruiting strategies, focusing on successful 

approaches and emerging trends from 

across the globe. Use this report in patient 

and physician recruitment and to identify 

successful strategies to combat the clinical 

trials productivity crisis. 

The principles of successful patient 

enrolment involve the blending of sitefocused 

support strategies with a clear value 

proposition delivered with personal 

communication expertise. Building a 

relationship of understanding with the 

investigative site team and the participant is 

the ultimate goal. 

Recruitment Survey 

Site surveys indicate that CROs know less 

than sponsors about recruitment and 

retention. CROs have little internal expertise in 

recruitment strategy, budgets and timelines. 

The surveys also demonstrate that sites want 

specific tools: they do not want paid media 

campaigns or call centres, but rather they 

want at least an hour of recruitment training at 

the study launch meeting, and they want a 

point of contact to resolve their challenges 

with enrolment and retention. 

Subject Recruitment 

Subject recruitment is critical to the success 

of clinical research, both for scientific return 

and financial viability. Research studies that 

fail to meet recruitment goals provide 

minimal scientific return and may have a 

negative financial impact on the institution. 

There is substantial up-front institutional 

investment in the initiation of each of these 

protocols (institutional review board [IRB] 

review, contract negotiations, 

administration). Inadequate recruiting may 

increase study costs, delay time to 

completion, and possibly invalidate a trial 

due to insufficient study power. Thus, even 

modest improvements in the subject 

recruitment process may pay large 

dividends in accelerating the bench-tobedside 

cycle of new drug therapies or 

medical devices. 

Extramural Recruitment Efforts: 

• Providing clinicians with multi-language 

flyers that are easy to read and IRBapproved 

• Providing clinicians with brochures that 

are available on the internet and for office 

distribution 

• Providing sample letters to clinicians and 

introducing them to this trial 

• Providing educational opportunities to 

clinicians and nurses introducing them to 

this trial 

• Providing information to pathologists 

regarding this trial including how they may 

contact physicians with a potential study 

subject 

• Announcements in newsletters and 

websites available to participants 

• Presentations at participant meetings 

Intramural Recruitment Efforts: 

• Providing IRB-approved, multi-language 

flyers and brochures to the offices of PIs 

and associates for distribution 

• Providing laminated charts with 

inclusion/exclusion criteria for PIs, 

colleagues, study coordinators and 

nurses 

• Reviewing medical records in order to 

identify potential subjects 

• Encouraging primary physicians to inform 

potential subjects about the study 

• Encouraging PI to maintain open 

communication with associates in order to 

capture potential new subjects 

Steering Committee Efforts: 

• Collecting data on failed screens 

• Continual evaluation of barriers to 

recruitment 

The Principal Investigator’s Toolbox: 

1 Flyer for potential subjects 

2 Brochure for physicians to display in office 

3 Letter to referring investigators 

4 Letter to area physcian 

5 Laminated chart with inclusion/exclusion 

criteria 

6 Primer on subject recruitment 

7 Primer on consent process 

8 Primer on subject retention 

9 Subject handbook 

Primer on Subject Recruitment 

• Avoid approaching potential subjects until 

trust and rapport has been built 


www.ipimedia.com


• Appropriate introductions to a potential 

subject must be done if PI is not the 

primary physician This is necessary to 

build trust in the PI and to reassure the 

subject that the primary physician 

supports enrolment and study plan 

• Assure subject and family that continuity 

of care is not contingent upon 

participation 

• Fully explain compensation for travel, 

parking, meals, etc while attending study 

visits 

• Explain opportunity to receive some 

primary care under the auspices of the 

study, with potential of medical costs 

• Explain opportunity to receive closer 

medical attention and exposure to newer 

medications 

• Highlight opportunity to contribute to the 

advancement of medical knowledge 

Primer on Consent Process 

• Consent and assent should be available in 

primary language of the subject 

• Ideally the PI and study coordinator should 

be present 

• Allow enough time to speak with the 

subjects 

• Have both parents present if a minor is the 

subject 

• Go over all items in the consent and 

assent forms with as much explanation as 

possible 

• Allow time for questions in each section 

• Provide a copy of forms to take home for 

discussion and thought 

• Provide a realistic assessment of time, 

procedures, length of trial, benefits and risks 

involved in participating in the study 

• Emphasise that voluntary withdrawal from 

the trial at any time will not affect relationship 

with physician 

• Provide copies of signed forms to subject 

Extramural Centre Recruitment Efforts 

Include: 

• Announcements in journals, newsletters, 

websites 

• Presentations at medical meetings 

Steering Committee Centre Recruitment 

Efforts Include: 

• Reimbursement analysis with modification 

as needed and supported 

• Training support 

Clinical Cores Centre Recruitment Efforts 

Include: 

• Training support 

• On-site support as needed 

• Help with IRB submission 

Developing and Implementing an Effective 

Recruitment Strategy 

• Improve patient motivation, creating and 

communicating the study’s value 

proposition to patients 

• Providing positive reinforcement at every 

visit 

• Acquiring and utilising educational/ 

support study materials for patients and 

their families 

• Comparing incentives, what patients say 

they need and what an ethics committee 

will allow 

• Improving listening skills for site staff 

The Impact of Protocol Design on Patient 

Recruitment 

• Designing with the patient in mind 

• The quantitative and qualitative data 

required to accelerate patient recruitment 

• Analysis of clinical trial durations in 

accordance with therapeutic areas 

• Screening systems for recruitment 

• Chief investigator and responsibilities 

• Impact of changing inclusion and 



exclusion criteria 

• Extrapolating data from past trials to 

forecast future ones 

Current Changes in Regulatory Affairs 

• A legislative update in recruitment for 

clinical trials 

• Manufacturers’ and wholesale dealers’ 

licences 

• Clinical trials authorisations 

• Surviving inspections of premises and 

procedures 

Patient Recruitment at Investigator Hub Sites 

• Identifying a hub site 

• Confronting the issues for pharma 

• Existing potential solutions 

• Cost issues 

• Hub sites advantages 

Patient Retention 

Recent reports have indicated that the 

Health Insurance Portability and 

Accountability Act (HIPAA) that came into 

effect in 2003 has adversely affected clinical 

trial conduct and patient retention by 

imposing significant time and cost burdens 

and by impeding clinical trial recruiting and 

patient retention, which in turn has deterred 

patient search efforts – locating patients lost 

to follow-up. This commentary will serve as 

the third of a series that will discuss 

strategies to enhance patient retention and 

finding patients lost to follow-up based on 

evolving interpretations of the HIPAA 

regulations. 

Challenges of Patient Retention 

When conducting a clinical study on a 

treatment or intervention, it is imperative to 

retain patients throughout the entire study 

duration and for a follow-up period, which 

can be months or even a decade for 

longitudinal studies. Patient retention for 

study duration and follow-up represents a 

major challenge and we must address this 

issue to avoid potentially devastating 

consequences to the clinical trial industry. 

In fact, estimates reported in 2003, before 

the impact of HIPAA, indicate that 85% of 

trials do not finish on schedule, 60% to 80% 

of clinical trials do not meet their 

chronological endpoints because of 

challenges in recruitment, and 30% of trial 

sites fail to recruit even a single participant. 

Additionally, disappointing statistics show 

that 26% of patients drop out after providing 

consent, and greater than 94% of studies 

are delayed due to failed enrolment / patient 

retention (including patients lost to followup). 

The situation is worsening in large part 

due to HIPAA regulations. In fact, from 1997 

to 2003, the percentage of studies 

completed on time decreased from 18% to 

6%.3,4 The costly consequences of trial 

delay are so staggering that each day of 

delay can equate to $220k, and a two-month 

delay can equate to $70 million potential 

product sales due to postponed launch. 

Strategies to Enhance Patient Retention 

We can enhance retention of participants 

by utilising appointment reminders, with the 

caveat that this process must be cognisant 

of participant privacy. Under HIPAA, 

postcard reminders are discouraged due to 

the possibility of a patient’s medical 

diagnosis being inferred by anyone seeing 

the postcard (by virtue of a study logo or 

clinic’s name). Therefore, if utilizing mail 

reminders, enclose in an envelope without a 

return address that includes the affiliated 

study group (e.g., the Diabetes Research 

Group). Additionally, a mail reminder should 

not resemble a medical bill as patients may 

delay opening. 

Utilising a mail reminder several days in 

advance, followed by a telephone reminder 

24 to 48 hours prior to a follow-up 

appointment is an effective strategy for 

patient retention. Utilising this method 

ensures that the patient’s protected health 

information (PHI) is not revealed. 

Reimbursement of patients is also a wellknown 

strategy for effective patient retention. 

However, the processes of reimbursement 

must be consistent with participant privacy. 

Patients can also be reimbursed with gift 

cards, books of stamps, and other monetary 

equivalents. 

Lastly, a critical element of patient 

retention strategies are plans that include 

patient search initiatives to locate those lost 

to follow-up quickly and efficiently, so they 

return to the study in a timely manner. It has 

been shown that if patients lost to follow-up 

are contacted expeditiously they will return 

to the study, either during the ongoing phase 

or for follow-up evaluations. 

Aiding patient retention through site 

selection and Management 

• Finding the best locations to suit your 

needs 

• Strategies to evaluate site and resource 

requirements 

• Accounting for patients’ needs and 

privileges in site selection 

• Medical monitoring and reporting of any 

serious adverse effects 

Retention of Patients in Clinical Trials 

• Creating and communicating the study’s 

value proposition to patients 

• Providing positive reinforcement at every 

visit 

• Acquiring and utilising 

educational/support study materials for 

patients and their families 

• Comparing incentives, what patients say 

they need and what an ethics committee 

will allow 

• Improving listening skills for site staff 

Key findings of the report 

Almost half of all trial delays are caused by 

patient recruitment problems. These delays 

cost makers of specialty products more than 

$500,000 in lost sales and they result in 

losses of over $8m for blockbusters. 

The internet is an important tool to recruit 

both patients and physicians, but remains 

under-utilised throughout the US, Europe 

and Japan. 

Clinical research continues to migrate from 

the US and Western Europe to cheaper 

offshore locations. Virtually all of the leading 

CROs and many pharmaceutical companies 

including Pfizer, Roche, GlaxoSmithKline 

and Novartis now have an established 

presence in India, China and Eastern 

Europe. 

In March 2007, the European Medicines 

Agency (EMEA) adopted a draft guideline on 

requirements for first in-man clinical trials for 

potential high-risk medicinal products, which 

could further tighten patient recruiting ■ 

Dr. Rajam Jaishankar 

has conducted a 

number of updates, 

workshops with 

evidence-based 

medicine as the 

theme, in the field of 

reproductive medicine 

in all most metros in India. She is the founder 

member of the Tamilnadu Pharmaceutical 

Welfare Trust and the former member of the 

Infertility subcommittee of the Association of 

obstetrics and Gynaecology. She is 

associated with the “Indian Fertility Society” 

(IFS), the National Association of 

Reproductive and Child Health of India 

(NARCHI), the Federation of Obstetrician and 

Gynaecological Societies of India (FOGSI) 

and the European Society of Human 

Reproduction and Embryology (ESHRE). 

Email: admin@questlifesciences.com 



Medical Imaging and Electronic 

Data Capture in Clinical Trials: 

the Future Paradigm 

All clinical trial data are ultimately digital. The 

pathway to this digital database is not always 

as connected as one might expect in this 

technological age. The backbone of clinical 

trials is now Electronic Data Capture (EDC), 

and this is not yet synchronous with the other 

major aspects of data collection, such as 

medical imaging. With the need for more 

streamlined processes, this paper explores 

the combination of medical imaging with 

EDC and provides the future paradigm for 

the triallist in the digital age. This will not only 

ensure an earlier final database lock, which is 

a key milestone, but during the trial data 

quality control (QC), and specifically image 

data QC, and evaluation can be performed in 

a more contemporaneous fashion with 

immediate feedback to those managing the 

study and the local investigator site. The 

ultimate goal is to unify all the essential data 

in a standardised format to expedite 

submissions and to increase the quality of 

those submissions. 

Introduction 

The use of medical imaging in clinical trials 

has seen an exponential growth in the last 

decade due to increased use of technology 

and improved computing power (1). This use 

continues to grow, particularly in early stage 

development when the latest techniques can 

aid in the early go/no-go decisions in new 

pharmaceutical/biotech 

product 

development. Examples of new techniques 

which are starting to be more commonly used 

in Phase I and II are listed in Table 1. For 

completeness, the more common 

applications that are used in Phase III are 

listed in Table 2, although the techniques are 

not exclusive to the phases listed. 

The need for an imaging core lab (ICL) 

has been described elsewhere (2) and is 

now a standard part of the team of the 

vendors in clinical trials (3). The days of 

leaving the image interpretation and analysis 

to the local investigator site have long gone 

due to the loss of data, reduced precision 

and lack of standardisation. The local 

investigators’ radiological department’s 

work is optimised for image acquisition and 

image interpretation for patient 

management, but not for the safety and 

efficacy reads. 

Along with the increased use of medical 

imaging in clinical trials, electronic data 

capture (EDC) has progressed significantly, 

so that in 2008 more than 50% of all trials 

used some form of EDC (4). The obvious 

question is raised about how to integrate the 

medical imaging and EDC into one system 

or process. This challenge is being 

addressed on many fronts. Historically the 

two processes have been managed 

“The information 

delivered by AG 

Mednet and others is 

not yet integrated with 

EDC systems, therefore 

the investigator site 

can provide 

information via the 

EDC system to the 

core lab about the 

incoming images” 

independently, and the ICLs have been 

totally separate entities from the EDC 

companies. The reason for this is twofold: 1. 

medical imaging is memory-, storage-, and 

transport-heavy, with some image files 

exceeding 10MegaBytes (MB) in size, and 2. 

the requirements in the radiology 

department are such that they either do not 

have access to the EDC system or the 

technologists do not have the knowledge to 

transfer the images to a system that takes 

them outside their institutional firewall. 

Convergence of the two processes is now 

starting to take place, although complete 

integration is highly unlikely for the 

immediate future due to the challenges 

mentioned. However we can anticipate 

some immediate developments and 

envision the full integration paradigm with 

the corresponding advances and 

improvements. 

This paper will discuss the concept of 

maximising the value of combining EDC 

and medical imaging, the utilisation of the 

synchronicity and working with ICLs and an 

EDC vendor with the current technology. A 

brief exploration of the mid-term future 

potential will also be entertained. 

Medical Imaging and Electronic Data 

Capture 

In most hospitals or clinics, medical images 

are available in a digital format, and even 

plain X-rays are obtained using digital X-ray 

although there are still some centres 

supplying plain film X-rays. The more 

technically savvy investigational sites will 

have the ability to submit the images to the 

imaging core lab via new technology 

processes such as those developed by AG 

Mednet (5). Not only are the images being 

sent electronically, but the data transmission 

information is sent and the images are 

anonymised. While this does not seem 

unreasonable in the current environment, 

there are still logistical and technical issues 

with some investigator sites, even beyond 

the issue of those sites still using film. 

Furthermore, the initial cost of setting this 

service up will be more than remaining with 

the well tried and tested method of sending 

the images via courier. 

Interestingly, using overnight courier 

services versus an electronic method only 

gains a few hours in the time of receipt of the 

images at the ICL, since many sites send 

their images at the end of the business day, 

regardless of which methodology is used. 

Therefore for the direct electronic transfer 

method the images will arrive at the end of 

the ICL’s working day and so will start being 

processed on the following work day. If the 

images are sent by courier they are routinely 

delivered by 10 or 11 am the following 


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morning to the ICL, providing a net increase 

of time of delivery of less than four hours 

compared to the direct digital delivery 

system. However, there are additional 

advantages and disadvantages that have to 

be carefully considered with both methods; 

these are summarised in Table 3. 

The information delivered by AG Mednet 

and others is not yet integrated with EDC 

systems, therefore the investigator site can 

provide information via the EDC system to 

the core lab about the incoming images. 

Also, many EDC systems are tied in with 

interactive voice response systems (IVRS). If 

these are set up correctly, the ICL can 

receive notification at patient screening or 

randomisation, alerting them to the fact that 

there are screening images inbound, and 

they can be ready for the required rapid turnaround 

for eligibility of this data. 

Medical imaging endpoints are used 

primarily for efficacy, but are being used 

more for safety evaluation, e.g. bone density 

assessment in trials, like the ATAC study for 

breast cancer (6) or isotretinoin in acne (7). 

Medical imaging is also used as part of the 

eligibility criteria. The tie into EDC therefore 

becomes more critical, and the need for the 

ICL team and the EC team to discuss the 

trial data flow is important. It will no longer 

be acceptable to have these two groups 

working independently, since with the 

optimal logic built into the EDC, the imaging 

will take on a bigger role. EDC will capture 

the results of the patient management and 

safety reporting with adverse events. The 

results of the safety reads and possibly the 

efficacy reads will need to be entered to 

provide the comprehensive picture. EDC 

programming is not just a matter of entering 

the questions from the CRF but building a 

complete logic sequence to the data 

capture. If this is provided as a combined 

team, the correct logic sequence can be 

applied, ensuring that the principal 

investigators (PI) and study site coordinators 

can be “steered” through the process to 

ensure there is no missing data. 

➜ 

Table 1. Novel Imaging Techniques used in Phase I/II Studies 

Molecular imaging techniques: 

Positron Emission Tomography (PET) 

Novel PET tracers, 

Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), 

Magnetic Resonance Spectroscopy (MRS), 

functional MRI (fMRI) 

Finite Element Analysis (FEA) 

Active Shape Modelling (ASM) 

Hip Structural Analysis 

Table 2. Imaging Techniques more Commonly Used in Phase III Studies. 

X-ray 

Plain film 

Digital X-ray (DXR) 

Angiography 

Computerised Tomography (CT) 

Magnetic Resonance Imaging (MRI) 

Ultrasound 

Echocardiography 

Doppler Ultrasound 

Intima Media Thickness (IMT) 

Dual Energy X-Ray Absorptiometry (DXA) or bone densitometry 

Single Photon Emission Computerised Tomography (SPECT) 

Fundus photography 

Optical Coherence Tomography (OCT) for retinal imaging 

Table 3. The advantages and disadvantages of courier v direct electronic 

image transfer 

* Some older techniques require a “black box” to be installed and linked 

into the PACS system. This has been found to be unworkable at the site. 



Furthermore the logic should prevent 

incorrect data being entered. The author 

has experienced this first-hand in a complex 

osteoporosis study where with some round 

table discussions, the logic and 

performance of the EDC was enhanced and 

reduced the data entry at the site, while 

capturing the same information. 

The blinded reads that are conducted by 

the ICLs are, in most instances the two 

central radiologists (or readers, since they 

can also be rheumatologists, cardiologists 

etc) reading the images in isolation of all the 

data, with a third to adjudicate any 

differences (8). However, in oncology the 

readers need to know if the patient has had 

a resection or radiation therapy, depending 

on the study. This information should be 

available in real time to them via the EDC 

system. Many oncology reads often go on 

to a so-called “global assessment”. This is 

the process where a central oncologist will 

review the images with one radiologist and a 

set of clinical data that has been determined 

a priori. This provides a trial overview of the 

data and ensures there is complete 

congruity of the images and clinical data. 

Obviously the use of the EDC system makes 

this process much more seamless and the 

global assessment can potentially be 

captured in the EDC system. Historically 

these kinds of global assessments have 

been rate-limiting to the end of the study: the 

clinical data had to come into the data 

management department of the sponsor or 

the contract research organisation (CRO) 

and, once cleaned, shipped to the ICL for 

integrating into the read system. Only then 

could the final global read be conducted, 

often weeks or months after the last patient, 

last visit (LPLV) time point. With an integrated 

EDC system this process can be moved up 

to occur within days of LPLV and not slow 

down the data integration and database lock. 

Another aspect that has been gaining 

ground is the development of Adaptive 

Clinical Trials. These can only work if EDC is 

being used. In some of the more complex 

versions even the imaging may change 

depending on the arm or the inclusion 

criteria. This requires a very close 

relationship between the EDC vendor and 

ICL in the setup stages to ensure everything 

is captured in the correct sequence. 

As more imaging is used in Phase II, the 

cost-effectiveness of using the right EDC 

vendor to work with the ICL becomes 

increasingly important. Pressure on the 

pharmaceutical industry to develop process 

improvements at all levels has dramatically 

increased. Phase II studies are probably the 

last area to feel the pressure to compress 

timelines. EDC has formerly been seen as 

this cumbersome technology that requires 

months of programming and therefore not 

suitable to the Phase I/II environment. This 

is no longer the case and within an eight 

week lead time, EDC and imaging can be 

set up in an expeditious manner to provide 

clean and rapid data with the right partners. 

The Future 

As we conceptualise the future, combining a 

robust EDC platform with even some of the 

basic medical imaging technologies that are 

now being deployed will allow the image 

management to be built into the EDC 

component. The images can then be 

reviewed by the ICL and can be sent to the 

blinded read all within the same software 

platform. All the reads are then captured in 

the same EDC software platform. 

As we look into the future not only does 

this EDC synchronicity provide an elegant 

one-stop shop solution but it provides image 

data handling in the same environment as 

the other electronic data. Furthermore with 

proper planning and programming, the 

monitors and sponsor can have all this 

information in dashboard format providing 

advanced monitoring tools. 

Conclusions 

In the next 36 months or so, we can 

anticipate that medical images will be 

transferred electronically to the core lab as 

a de facto standard, and the courier will be 

relegated to the smaller investigator sites, 

new sites, or those sending X-rays. We 

can anticipate that those EDC vendors 

who are forward-thinking and linked in with 

ICLs will exploit the relationship and 

further improve the logic and questions in 

the EDC process. There will be a much 

closer tie-in with the IVRS and notifications 

to the ICL will result in a more rapid followup 

and knowledge of the incoming 

images. This will further reduce the losses 

of images that occur in clinical trials. 

The ultimate goal is to unify all the 

essential data in a standardised format, to 

expedite submissions, and to increase the 

quality of those submissions. With the 

advent of the e-clinical space, over time, 

medical imaging will become a 

specialised extension of this rapidly 

growing technology, rather than a standalone 

facet ■ 

Dr. Collin Miller SVP 

Medical Affairs at Bio- 

Imaging, heads up the 

scientific over-sight 

within the company & 

provides consulting on 

trials in the muscularskeletal 

arena. He has 

a gained a Fellowship of the ICR (UK) and 

has attained the UK recognition of a 

Chartered Scientist. Dr. Miller has written and 

co-authored over 40 scientific publications 

and is co-editor of the books “Clinical Trials in 

Osteoporosis,” and “Clinical Trials in 

Osteoarthritis and Rheumatoid Arthritis,” 

published by Springer Ltd. 

Email: admin@questlifesciences.com 

References 

1. Reiber H, van Kuijk C, Schwarz, L. 

Medical Imaging and its use in clinical 

trials. European Pharmaceutical 

Contractor Autumn 2005.p80-84 

2. Miller CG, Noever K. “Taking care of your 

subject’s image: The role of Medical 

Imaging Core Laboratories” Good Clinical 

Practice Journal 2003, 10 (9) p 21-24 

3. Miller CG. Medical Imaging Core 

Laboratories. Applied Clinical Trials 

October 2005 

4. April 2007, Health Industry Insights 

#HI206351 

5. www.bioimaging.com/overview/agmednet 

6. Eastell R, Adams JE, Coleman RE et al. 

Effect of anastrozole on bone mineral 

density : 5 year results from the anastrzole, 

tamoxifen, alone or in combination trila 

18233230. J Clin Oncol. 2008, Mar 

1;26(7) 1051-7 

7. DiGiovanna JJ, Langman CB, Tschen EH 

et al. Effect of a single course of 

isotretinoin therapy on bone mineral 

density in adolescent patients with severe, 

recalcitrant, nodular acne. Journal 

American Academy of Dermatology 2004, 

Volume 51, No 5. p709-717 

8. Miller CG, Noever K. Reading Medical 

Images in oncology clinical trials. 

European Pharmaceutical Contractor 2004 

Summer, p 95-100 




Providing regulatory submissions 

in electronic format – US and 

EMEA actions 

The United States Food and Drug 

Administration (FDA) is taking concrete 

steps to require the submission of all types 

of regulatory communication in electronic 

format. Regulatory authorities globally are 

all moving to require electronic submission 

of regulatory communication. The reasons 

are many but the public safety 

responsibilities of the regulators require 

significantly faster access to content than 

can be supported by paper format. 

The cost of preparing the content to be 

reviewable in electronic format forms the 

bulk of the time and human resources 

needed to prepare electronic submissions. 

Failing to prepare the electronic content in 

compliant format can result in the regulatory 

authority refusing to conduct the review until 

the lack of compliance is corrected – this 

could have a profound impact on a 

company’s viability if a competitor drug is 

approved while the first sponsor is 

correcting non-compliant content. 

Compliance of electronic documents can 

be easily and inexpensively achieved 

through the proper use of Microsoft Word to 

author documents, combined with the use of 

templates with electronic submission 

compliance features built into the template 

design. 

1 HISTORY OF ELECTRONIC 

SUBMISSION REQUIREMENTS 

1.1 US FDA 

• FDA Centers for Drug Evaluation and 

Research (CDER) and Biologic Evaluation 

and Research (CBER) have required 

submission of electronic case report 

tabulations (CRTs) and case report forms 

(CRFs) in electronic format for new drug 

and new biologic license applications 

(NDAs and BLAs) since 1999 , . 

• FDA CDER has required package inserts 

to be submitted in electronic Structured 

Product Labeling (SPL) format since 

October 1, 2005 . 

• FDA CDER has required electronic 

submissions to be presented in the 

electronic Common Technical Document 

(eCTD) format since January 1, 2008 . 

• FDA is requiring the content of the Drug 

Establishment and Drug Registration 

forms to be submitted in electronic format 

beginning June 1, 2009 . 

• FDA has published the proposed rule that 

retired previous electronic submission 

formats, and set the stage to require all 

submissions be in electronic format using 

the eCTD organisation structure and 

electronic navigation aids . 

1.2 EMEA 

The electronic submission juggernaut is 

not limited to the US market: 

• The European Medicines Evaluation 

Agency has announced a timeline which 

requires all agencies participating in the 

centralised procedure for marketing 

authorisation applications (MAA) to begin 

submitting in electronic format on January 

1, 2009 , and in the eCTD format on 

January 10, 2010. 

Finally, there is an international effort 

underway with involvement by regulatory 

authorities and industry to define the next 

generation of bi-directional communication 

of regulatory submission content in a 

messaging format called Regulated Product 

Submission that is intended to address 

electronic submission requirements for all 

products regulated by FDA – drugs, 

biologics, devices, veterinary medicine, food 

additives, and cosmetics. 

2 TECHNICAL REQUIREMENTS 

Since 1999, the fundamental building block 

of electronic submissions has been the 

Adobe Acrobat Portable Document Format 

(PDF). However, this is not ordinary run-ofthe-mill 

PDFs created by scanning or 

printing to Adobe PDF. All regulatory 

authorities who accept electronic 

submissions have very strict requirements 

for the format and electronic navigation aids 

within PDF files, Regulatory authorities 

globally have refused to review electronic 

submissions whose PDF files lacked 

required navigation aids. 

All of these requirements can be met by 

implementing MS Word templates and 

configuring PDF conversion to support 

these requirements. PDF conversion can be 

done via PDFMaker, a plug-in to the 

Microsoft Office suite that is automatically 

implemented when the Microsoft Office 

applications are installed first, and Adobe 

Acrobat Standard or Professional are 

installed second. These properties can also 

be assured by correct configuration of 

Acrobat Distiller. Further, companies with 

MasterControl electronic document 

management systems (EDMS) configured 

for life sciences applications frequently have 

a PDF rendition server or generator in the 

EDMS suite that can be configured to 

support the requirements that are identified 

below. 

FDA has published guidance that 

describes the requirements for PDF files for 

eCTD submissions, Portable Document 

Format Specifications, version 2.0, dated 

2008-0604,www.fda.gov/cder/ 

regulatory/ersr/ PDF_specification_v2.pdf. 

Other regulatory authorities have published 

requirements that are virtually identical to 

the guidance supplied by FDA. 

2.1 Fundamental PDF Requirements 

One of the strongest directives from the 

regulatory authorities’ requirements is that 

PDF files conform to predefined page sizes, 

have adequate margins on all sides and 

have adequate font sizes for legibility. 

These translate into the following 

specifications: 

• US letter page size for the FDA 

• A4 page size for rest of the world 

• Margins of at least one inch on all four 

borders, with larger margins on the 

binding edge in the event that paper 

volumes will be required 

• Times New Roman or Arial font, with the 

body text in 12 point and tables no smaller 

than 10 point 

34 IPI www.ipimedia.com


2.2 PDF File Format and Display 

Requirements 

PDF files should be in File Format 1.4 and be 

set to open to Fast Web View. These 

properties can be configured in the 

PDFMaker or PDF rendition process, but 

can be added to PDF files after the fact by 

using the PDF Optimizer function of Acrobat 

Standard or Professional. 

PDF files should automatically open to 

the page orientation of legibility. If 

PDFMaker, Distiller or a rendition engine is 

used to convert from MS Office to PDF 

format, this property can be automatically 

applied to the individual pages. However, if 

the PDF is created from scanned images, 

this requires the pages to be 

individually inspected and the page 

rotation property adjusted for pages 

that display incorrectly. 

2.3 PDF Files Created by 

Scanning 

Scanning is to be avoided unless 

there is no other choice. Scan 

documents of sufficient quality should 

be made searchable via Optical 

Character Recognition (OCR), which 

has been validated for accuracy of the 

recognition (for example that 1 has not 

been translated as l or i, or 0 has not 

been translated as O or o). 

If scanning must be done, the FDA 

guidance provides specifications that 

include: 

• Recommended resolution for 

different types of content 

• Compression algorithms for black & 

white, grayscale and colour 

• Image colour matching to assure 

fidelity of the depiction of colour 

for screen and print output 

formats 

2.4 Navigation via Hyperlinks 

and Bookmarks 

One of the most critical requirements to 

facilitate review is that PDF files contain 

“Compliance of 

electronic documents 

can be easily and 

inexpensively achieved 

through the proper use 

of Microsoft Word to 

author documents, 

combined with the use 

of templates with 

electronic submission 

compliance features 

built into the template 

design” 

hyperlinks and bookmarks to aid review in 

navigating within a file and between files. 

Examples of hyperlinks include: 

• From table of contents, list of figures, list of 

tables, list of appendices, to the content of 

the document 

• To supporting annotations, related 

sections, references, appendices, tables, 

or figures not located on the same page 

as the narrative text 

Bookmarks should match the table of 

contents hierarchy and depth, so that the 

document can be navigated via either the 

table of contents or the bookmarks. 

All bookmarks and hyperlinks should 

have relative file paths; that is not refer to 

server names, drive letters, or any 

company-specific network 

components. 

All bookmarks and hyperlinks 

should have the magnification 

property of Inherit Zoom, so that the 

reviewer’s view preferences are 

preserved when navigating via 

bookmarks and hyperlinks. 

Hyperlinks should be designated via 

thick blue lines or by blue text. If 

documents are created from an 

intelligent source – such as the MS 

Office applications – the blue text 

property can be applied at the time the 

documents are authored, and the PDF 

conversion process carries this property 

to the PDF file. However, if documents 

are scanned, hyperlinks can be 

represented only by thin blue lines. 

2.5 Page Numbering 

Individual PDF files in an eCTD should 

be page numbered beginning at page 

one, so that the PDF file and the 

document page number are the same. 

2.6 Conclusions on Preparing 

Compliant PDF Files for eCTD 

All of the PDF file properties described in 

the FDA guidance document can be 

assured by: 



• Using MS Word templates designed for 

eCTD compliance 

• Styling the document using Heading 1 

through 9 and Captions 

• Using MS Word properly – building tables 

of contents, tables of figures and tables, 

inserting hyperlinks or cross-references 

when referring to related content 

• Configuring PDFMaker, Distiller or PDF 

rendering engines to create compliant 

output 

• Be aware of the recommended 

configurations of resolution and colour 

when scanning documents 

These requirements apply not just to internal 

authors and regulatory operations staff, but 

should be made part of standard 

deliverables from contract writers, contract 

research organisations, and other outside 

suppliers. 

Correct preparation of PDF files for eCTD 

submissions ensures that the review starts 

on time and enables the review to be 

conducted with the support of the electronic 

navigation aids that are so critical to the 

review experience. 

3 FDA ELECTRONIC SUBMISSION 

GATEWAY 

FDA has implemented the Electronic 

Submission Gateway (FDA ESG) to enable 

sponsors to send information electronically 

to the FDA. It has been implemented using 

a software application certified to comply 

with secure messaging standards . The FDA 

Centers accepting submission via the ESG 

are listed in Table 1, along with the 

submission types that may be submitted via 

the ESG. 

FDA has made usage of the ESG 

inexpensive, requiring only digital certificates 

at the cost of US$20 per user per year, and 

an easy-to-follow process for registering for 

a test account and performing three test 

transmissions in order to qualify for a 

production account. 

EMEA and other health authorities 

around the world who accept electronic 

submissions have not implemented a similar 

capability for electronic transmission of 

regulatory communication, except for 

adverse event reports in the European 

Union. 

4 CONCLUSION 

Great strides have been made by the 

regulatory authorities in the US and EMEA to 

prepare their technical infrastructures for 

eCTD. Further announcements and 

clarification of intent to mandate electronic 

submissions are expected in 2008, with 

regular updates planned for this journal ■ 

Antoinette Azevedo founded e-Submissions 

Solutions.com (a California corporation) to 

advise all sizes of 

biotechnology and 

pharmaceutical 

companies on the use 

of technology to 

manage regulatory 

documents and 

publish electronic 

submissions. Her experience ranges from 

developing strategies for document 

management and electronic publishing, to 

implementation of fully-validated systems, 

and production of paper and electronic 

submissions accepted for review by 

regulatory authorities worldwide. 

Email: AAzevedo@e-Submissions 

Solutions.com 

References 

1 Guidance for Industry: Providing 

Regulatory Submission in Electronic 

Format—NDA, U.S. Department of Health 

and Human Services, Food and Drug 

Administration, Center for Drug Evaluation 

and Research (CDER), January 1999. 


Regulatory Submission in Electronic 

Format—General Considerations, U.S. 

Department of Health and Human 

Services, Food and Drug Administration, 

Center for Drug Evaluation and Research 

(CDER), Center for Biologic Evaluation and 

Research (CBER), January 1999. 


Regulatory Submissions in Electronic 

Format —Content of Labeling, Food and 

Drug Administration, Center for Drug 

Evaluation and Research (CDER), Center 

for Biologic Evaluation and Research 

(CBER), April 2005. 



Format —Human Pharmaceutical Product 

Applications and Related Submissions 

Using the eCTD Specifications, Center for 

Drug Evaluation and Research (CDER), 

Center for Biologic Evaluation and 

Research (CBER), April 2006. 



Format — Drug Establishment and Drug 

Listing, U.S. Department of Health and 

Human Services, Food and Drug 

Administration, Office of the Commissioner, 

July 2008. 

6 Guidance on Providing Regulatory 

Submissions in Electronic Format: 

Withdrawal of Guidances, [Docket Nos. 

1999D-0054, 2001D-0475, and 2003D- 

0364] (formerly Docket Nos. 99D-0054, 

01D-0475, and 03D-0364, respectively) 

U.S. Department of Health and Human 

Services, Food and Drug Administration, 

7 EMEA Implementation of Electronic-Only 

Submission and eCTD Submission: 

Practical Guidelines Relating to Non-eCTD 

Electronic Submissions, London, 1 

November 2008, EMEA/633919/2008 v1.0. 


Submission and Mandatory eCTD 

Submissions in the Centralised Procedure: 

Statement of Intent, London, December 

2008, EMEA/572459/2008. 

9 Regulated Product Submission, U.S. 

National Institutes of Health, National 

Cancer Institute, www. 

gforge.nci.nih.gov/plugins/wiki/index.php? 

Regulated%20Product%20Submission&id 

=234&type=g 

10 Portable Document Format 

Specifications, U.S. Department of Health 

and Human Services, Food and Drug 

Administration, Center for Drug Evaluation 

and Research (CDER), Center for Biologic 

Evaluation and Research (CBER), version 

2.0, 2008-06-04. 


Submission and eCTD Submission: 

Questions and Answers Relating to 

Practical and Technical Aspects of the 

Implementation, London, December 

2008, EMEA/596881/2007, v0.5. 

12 FDA Electronic Submission Gateway (ESG), 

http://www.fda.gov/esg/, FDA Industry 

Systems Website Staff, May 1, 2008. 

13 FDA Electronic Submissions Gateway, 

Submission Types Supported by the FDA 

ESG,www.fda.gov/esg/userguide/WebHel 

p/AS2_Routing_IDs.htm#figure7http://ww 

w.fda.gov/esg/, FDA Industry Systems 

Website Staff, May 1, 2008. 

14 FDA Electronic Submissions Gateway, 

Submission 

Statistics, 

http://www.fda.gov/esg/submission_stats 

.htm , FDA Industry Systems Website 

Staff, May 1, 2008. 



Managing your flow with LIMS 

The evolution of Laboratory Information 

Management Systems (LIMS) from the point 

of view of a global clinical trials organisation 

Providing the backbone of a clinical trials 

organisation, a Laboratory Information 

Management System (LIMS) impacts on all 

departments, machinery and personnel. In 

today’s market no clinical laboratory or 

CRO could operate without the support of 

a well integrated LIMS package. And as the 

technology gets even more sophisticated, 

so do the opportunities for the 

pharmaceutical industry. 

LIMS exist to track clinical trial collection 

kits, manage and track specimens, manage 

laboratory testing workflows and quality 

performance, create laboratory reports and 

manage study-specific databases. 

Exclusive to hospitals in the early 1980’s, 

LIMS were originally used to manage patient 

samples and data on site. The systems 

began to evolve and were identified by 

clinical trials organisations as an effective 

way of managing the processes in 

commercial laboratories dedicated to drug 

development studies. A number of IT 

providers recognised the business 

opportunities available and began to mould 

the existing systems to suit the needs of 

clients working throughout the 

pharmaceutical sectors. 

By the 1990s most clinical laboratories 

had installed some form of LIMS system and 

in 1998, the FDA put into place regulation 21 

CFR part 11 to keep a tight grip on quality 

throughout the trials process. The regulation 

governs the scope and application of 

electronic records and signatures within the 

industry, with reference to validation, audit 

trails, record retention and record copying. 

As the regulations changed, so did the 

users’ need for more functionality – mainly 

driven by the pharmaceutical companies. 

Within a clinical trials organisation, 

laboratory staff wanted the LIMS to 

incorporate quality control and trends 

emerging from the studies with significant 

changes from pre-study samples and tools 

were created to perform these tasks. 

Project managers also recognised the 

benefits of integration into the LIMS 

package. As client demands increased, the 

project management functionality developed 

to provide the capability to interrogate the 


www.ipimedia.com


data once it was captured. To this end, the 

search engines evolved, front end reports 

were added and the overall user interface 

began to change by developing monitoring 

and reporting systems. 

The globalisation of the clinical trials 

industry has played a big part in the 

development of LIMS. The increase in multisite 

studies has forced the need for a 

centralised database of patient and product 

data which is fully compliant, secure, and 

accessible. 

The LIMS reports need to be available to 

all relevant personnel, sometimes on a 

global scale, including all the internal 

clinicians and project managers and 

externally to the doctors, monitors and 

sponsors. This is usually delivered through a 

front end system which allows different users 

varying levels of access depending on the 

need. For example, data may be blinded to 

a doctor carrying out the dosing on a 

diabetes study where 50 per cent of the 

patients are on the placebo. More 

sophisticated LIMS should also provide you 

with the capability to deliver the report in a 

number of ways – from hard copies, single 

or cumulative reports to remote data access 

systems. 

One of the more recent developments in 

LIMS is the traceability of samples 

throughout the clinical trials process from 

despatch by the investigator, arrival at the 

lab, through the testing procedure, right to 

freezer storage and disposal. Client 

requirements have to be met for full sample 

auditable history reports for every sample 

received in the laboratory listing for example 

sample freeze/thaw cycles or storage 

temperatures. 

Whilst a LIMS database cancels out the 

need for manual data input, it doesn’t take 

away the need for trained personnel to 

manage the processes of distribution, 

sample storage and other manual laboratory 

work. However, it does provide you with the 

capability to process more samples, 

forecast the timings of studies, monitor 

patient safety and work more effectively 

throughout the lab procedures. 

The system also allows you to measure 

the output capabilities of the laboratory, 

project the workload and any backlog, and 

forecast the number of personnel needed to 

perform the work. The LIMS database will 

also record trends and help forecast the type 

of work in the months ahead, for example, 

seasonal studies on winter viral infections. 

Once the scope of the study has been set up 

on the LIMS, accurate projections of 

workload can be calculated, subject to 

timely patient recruitment! 

There are relatively few IT companies 

which offer LIMS packages across the UK 

and Europe. Those that do have often 

“advanced security, data 

integrity, and audit trail 

capabilities should 

meet the stringent 

requirements of 

pharmaceutical 

clients” 

worked closely with their clients over the 

past decade to evolve their system and 

deliver the ever increasing list of functions 

and benefits. Other clinical trials companies 

and CRO’s have chosen to develop their 

own systems on site, responding directly 

and exclusively to the requests made by 

their sponsors and in-house team. The 

majority of service providers have released 

multiple versions of their LIMS package, 

improved, updated and in line with any new 

regulations. 

For a clinical trials organisation looking for a 

good LIMS package, the essential 

requirements are as follows: 

• Compliance with regulations – an obvious 

one perhaps, but with the FDA regulations 

constantly evolving, a LIMS provider must 

be wholly up to date on the changes and 

additions to regulation 21 CFR Part 11; 

• Easy to use – the best LIMS packages are 

those that are web-based, offering 

flexibility to work from laptops at different 

workstations around the laboratory. On 

another point, your personnel are trained 

as scientists, not IT experts, therefore the 

time it takes to train the staff on the system 

should be minimal; 

• Flexibility – a package that can be easily 

adapted, both by the IT provider and the 

user, allows an organisation to respond to 

its clients needs more effectively and add 

functionality as the business grows; 

• Security – a system’s advanced security, 

data integrity, and audit trail capabilities 

should meet the stringent requirements of 



pharmaceutical clients. LIMS must also 

provide a robust back up system to 

support a laboratory’s disaster recovery 

strategy; 

• Compatibility – the system must integrate 

with a lab’s different analysers 

For a pharmaceutical company working with 

a clinical trial organisation, the most 

important elements of LIMS are as follows: 

• Compliance with regulations; 

• Flexibility – the capability to see your study 

in any format you require; 

• Timely – to have real-time results which 

allow you to review/amend the study as 

needed; 

• Integrity – for the LIMS to provide you with 

accurate and secure data which can be 

monitored and shared globally; 

• A critical monitor of patient safety data 

• Adaptability – the willingness of the clinical 

trials organisation to work with its LIMS 

provider to adapt the system the suit your 

requirements. 

So where can the technology take the 

industry in the future? It is likely to be a case 

of evolution, not revolution and 

developments will come in line with any 

amendment of the FDA regulations. 

As the technology improves, so will the 

functionality of LIMS and their ability to 

integrate with other systems. Already we’re 

seeing an advancement in doctors’ case 

reporting with the majority of them now using 

electronic CRFs. Clinical trials organisations 

are now required to send their patient report 

for inclusion in these CRFs, creating a much 

more conclusive reporting system. 

The improvements to LIMS will also be 

led by sponsors’ needs. As the end user, 

pharmaceutical companies are likely to 

request more sophisticated reporting 

systems which provide quicker and more 

accessible results particularly with regard to 

patient safety. 

In the future, interim reporting is likely to 

become more mainstream, giving the 

sponsor the opportunity to review the study 

“LIMS must also provide 

a robust back up 

system to support a 

laboratory’s disaster 

recovery strategy” 

at any stage in order to amend the dosage, 

recruit more patients or simply monitor 

progress. Another request raised by a 

number of sponsors is the ability to link the 

storage information to the end data 

including the freezer temperature and 

disposal requirements. 

With the ever increasing use of EDC 

(Electronic Capture Systems) within the 

clinical trials industry, all LIMS databases 

should be upgraded to provide functionality 

to directly communicate with these systems. 

Away from the laboratory, improvements 

will need to be made to the invoicing 

procedures using LIMS. Integration of 

financial information is already being 

developed to include project management 

fees, analytical costs, courier services, 

sample storage and electronic data transfer 

all of which require ongoing investment. 

As a business and management tool, 

LIMS is integral to any clinical trials 

organisation and the investment required is 

fairly minimal compared to the obvious 

benefits it provides. 

In summary, the efficient running of a 

commercial laboratory has become 

dependent on LIMS technology and, with an 

emphasis on responding to clients needs, 

the opportunities for the future are endless ■ 

Sam Singh is Director of Information Services 

and a founder member of Pivotal 

Laboratories, now ACM-Pivotal. Sam has 

worked in central laboratories for nearly 15 

years and has considerable experience in 

handling laboratory data as it is being 

generated. He has spent several years within 

the healthcare sector, developing LIMS. He 

has extensive ‘hands-on’ experience in 

managing laboratory data within a central 

laboratory environment, including producing 

Data Management Reports, data cleaning 

and performing database structure and 

integrity checks. As a SAS programmer, as 

well as a MUMPS programmer, he has 

particular expertise in programming 

laboratory data formats for electronic transfer 

to a huge variety of sponsor database 

systems. 

Email: s.singh@acm-pivotal.uk.com 



E-freight – Solutions for tough times 

The SWISS approach towards saving 

the environment and manage cargo 

consignments in electronic form 

In the complex world of international air 

freight, where profitability is measured by 

minutes saved, kilograms shipped and 

litres of fuel burned, the Swiss penchant for 

precision and reliability is a valuable asset. 

For Swiss WorldCargo, it has indeed given 

the airline a steady foundation that has 

seen profits grow, even as the industry as a 

whole continues to tighten its belt. 

A new leap has been made in managing 

air cargo and unsurprisingly, IATA has 

chosen Swiss WorldCargo to pioneer this 

process. “No paper, thanks!” will be the 

motto of Switzerland’s quality cargo carrier 

from the beginning of next year, as it will 

record and handle cargo consignments in 

electronic form. The new approach is not 

only good news for the environment; it will 

simplify processes, enhance transport 

quality and save money, too. 

“We are honoured to be chosen by IATA 

to trial e-freight in a practical working 

environment and help this new facility 

achieve its worldwide breakthrough as 

swiftly as possible,” says Markus Loeffler, 

Senior Manager e-freight at Swiss 

WorldCargo. “We see our selection as a 


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‘paperless pioneer’ by the airline sector’s 

umbrella organisation as a clear 

confirmation that Swiss WorldCargo is one 

of our industry’s most innovative cargo 

service providers. But we also view it as an 

incentive and a commitment to further refine 

this forward-looking cargo handling 

approach.” 

IATA’s overall aim is to ensure that air 

cargo consignments are handled 

electronically as extensively as possible by 

the end of 2010. This will save a vast amount 

of paper – an annual volume that would fill 

39 Boeing 747-400 freighters, the 

association has calculated. It should also 

save the partners in the logistics chain 

worldwide a total of USD 1.2 billion a year – 

provided all these partners are electronically 

linked up and are prepared to make the 

switch to the paperless handling approach. 

The new e-freight facility will initially be 

introduced at Zurich Airport – again on 

IATA’s initiative. In practical terms, this 

means that not only Swiss WorldCargo but 

all the parties involved in the local logistics 

chain will exchange their consignment 

details online. The corresponding portal will 

thus include links to Zurich’s forwarders, 

handling agents and distribution agencies, 

and to the Swiss customs authorities. 

SWISS doing well in tough times 

“2008 has been very challenging,” says 

Oliver Evans, Chief Cargo Officer for Swiss 

International Air Lines, who recently passed 

through Bangkok. “However, through 

“I think e-freight will 

snowball once it hits 

Asia, and then it can’t 

be stopped. All the 

knowledge and skills 

that we learn as we’re 

going along will 

accumulate, and will be 

available to whoever 

joins the initiative” 

various hedging strategies that were 

developed by Lufthansa Cargo (Swiss 

WorldCargo’s parent company), we 

managed to minimize the damage and 

focus on areas that remained profitable. We 

were also forced to introduce surcharges, 

which helped us recover some costs. 

Although not ideal, these strategies together 

allowed us to stay on course.” 

Indeed, despite capacity growing by 20% 

last year, SWISS reports a constant 84 

percent system-wide load factor. “To us, this 

is a proof that our strategy is robust, and 

something that we should continue to 

nurture.” 

While Swiss WorldCargo has managed to 

maintain its very high performance of 

previous years, its competitors have not. 

Swiss WorldCargo’s third Customer 

Satisfaction survey held in 2008, further 

emphasises that it has a competitive 

advantage against its business rivals. The 

objective of the study, which included 1702 

interviews in 9 languages and in 35 

countries, and 3 weeks of phone calls 24/7 

was to measure three levels of customer 

satisfaction: 

• Overall satisfaction and loyalty 

• Main service elements in the air cargo 

process chain 

• Sub-elements that gave additional 

information and insight to the key 

elements. 

Industry Evolution 

Starting at a time when Swiss International 



Air Lines was emerging from the ashes of 

Swissair, and with the industry still reeling 

from 9/11, Mr Evans has seen firsthand the 

small details which can pay off in spades 

further down the road. 

For instance, one of the areas which has 

refused to buckle to economic or industry 

pressure is special cargo, a relatively small 

but significant part of the total market. 

“Special cargo shipments grew quite a lot in 

2007, but this year has seen the overall trend 

slow a bit,” he says. “However, the very 

nature of specialty shipments is what keeps 

them profitable. The smaller a market is and 

the more acute the needs of our customers 

are, the more urgent the shipments become. 

Our track record in this specialized area has 

ensured that it plays a large role in the 

success of our company.” 

In addition to focusing on the fine details, 

Mr Evans is also heavily involved in the move 

to e-freight. “I think elimination of paperwork 

is one of the last frontiers of efficiency in the 

industry – sometimes we use over 20 

documents for one shipment, which is a 

practice ripe for irregularities and confusion. 

Not only can we save on the environmental 

and hard costs of using all that paper, but we 

can also save on the cost of irregularities 

rising from the fact that everyone has a piece 

of the information, but not the whole picture.” 

Due to their relatively small market share, 

Switzerland was not chosen for the first wave 

of pilots but was picked to be a member for 

the second stage. “We feel that the SWISS 

community is a very special one, with 

advanced technology and a tight-knit 

forwarding community, and we really felt that 

we belonged in the pilot program,” says Mr 

Evans. The company is in the final stages of 

testing, and expects to initiate live shipments 

before the IATA cargo symposium in 

Bangkok in 2009. 

Going Hi-Tech 

As proof of their commitment to high-tech 

industry solutions, in early 2008 SWISS 

became one of the first airlines to give up 

their 30-year old ‘legacy’ IT platform in 

favour of a sleek new system that was 

designed specifically for them. The move 

was the biggest investment the company 

had made since its inception in 2002. 

“Our old computer system did the job, 

but it only did the job, so we needed to 

upgrade. We finally settled on Mercator, the 

IT arm of Emirates Group, because they had 

a team in place that would customize the 

system for us and help get us up to speed, 

which was essential. Having a good product 

is only half the story – if you don’t know how 

to implement it, you still have a problem.” 

The biggest challenge that e-freight will 

face is industry-wide integration. “It must be 

an attractive global initiative,” says Mr 

Evans. “Before that can happen, every bank, 

“despite capacity 

growing by 20% last 

year, SWISS reports a 

constant 84 percent 

system-wide load 

factor” 

shipper, forwarder, handling company, 

airline, and customs authority must be ready. 

We need to bring some enthusiasm to the 

table so that after a few successful pilots, 

everyone will say ‘I want a piece of that!’” 

But, as mentioned previously, industry 

support won’t be enough if you can’t 

integrate the new system properly. Many in 

the Asian logistics industry are familiar with 

the ‘if it isn’t broke, don’t fix it’ mentality, but 

Mr Evans doesn’t think this will be a 

problem. 

“Thais are keen learners, as our team in 

Thailand had demonstrated by their love of 

their jobs. If you have a passion for 

something, you do it. I think e-freight will 

snowball once it hits Asia, and then it can’t 

be stopped. All the knowledge and skills that 

we learn as we’re going along will 

accumulate, and will be available to whoever 

joins the initiative. Of course, some people 

won’t be ready, and they’ll be left behind, but 

those who are prepared will reap the 

benefits.” 

Mr Evans thinks that Thailand will fare 

well with the inevitable change. “Thailand is 

one of the key Asian economies and offers a 

lot of promise for tomorrow, with good longterm 

business prospects. Our team here is 

very good and is driving growth in this 

market. 

Troubles Bring Opportunities 

“Looking into 2009, we’re cautious but 

optimistic. We believe we have the right size 

of fleet, and the right number of destinations. 

We will be replacing some of our A330-200s 

with A330-300s for more fuel efficiency, but 

besides that, we’ll keep doing what we’ve 

been doing.” Plans are also in place to 

increase frequencies into Bangkok and offer 

daily service, but these won’t be 

implemented until further down the road. 

“I’ve studied the facts and figures, but I 

am an optimist by nature,” says Mr Evans. 

“The world is globalizing, and you will 

inevitably see crises pop up from time to 

time. People become overconfident, make 

risky investments, and then a wobble 

becomes a crisis. But I believe the crisis 

we’re seeing now is healthy; it’s a painful 

correction of the overconfidence that got us 

here. At SWISS, we say that we need to be 

prepared to weather the storm, and the only 

thing you learn from history is that out of a 

storm come a lot of opportunities. You just 

have to be ready for them.” 

About Swiss WorldCargo 

Swiss WorldCargo is the airfreight division of 

Swiss International Air Lines Ltd. With a 

worldwide network serving more than 150 

destinations in more than 80 countries and a 

broad spectrum of services, Swiss 

WorldCargo earns genuine added-value for 

its customers and makes a substantial 

contribution to the earnings of SWISS ■ 

Bernd Maresch is the 

Director Marketing 

Strategy & PR; at 

Swiss WorldCargo 

and Liaison Manager 

Lufthansa Cargo and 

partner. Having 

received his Master of 

Business Administration and Social Sciences 

from FriedrichAlexander University of 

Erlangen/Nuremberg, Bernd has acquired a 

wealth of experience within the Air Cargo 

industry. He started his career at Crossair AG 

and then climbed through the ladders at 

SwissCargo. His vision and foresight has 

enabled Swiss WorldCargo to reach the 

pinnacle within the Pharmaceutical and Life 

Sciences industry. 

Email: bernd.maresch@swiss.com 



Risk Management in 

Clinical Trial Shipping 

Every time clinical trial supplies or the 

samples which are generated during the 

lifetime of a trial are transported then an 

element of control is taken from your 

hands. In order to minimise the lack of 

control, this article will discuss what kind of 

risks shipments face when they are 

actually in transit and when they get to the 

site, so that an assessment can be made of 

those risks, and contingency planning can 

be used to reduce them as much as is 

feasible in a time- and cost-efficient 

manner. 

Contingency planning is an important 

procedure to protect your assets. The 

process begins with a risk assessment 

analysis and focus is on incidents which 

appear more probable and are likely to 

impact upon key elements of the transport 

chain. Risk factors vary by country and 

region, so this approach may be required to 

be done both globally and locally. From the 

evaluation of risk, likelihood and impact, you 

can consider what controls can be 

implemented and then define the roles and 

responsibilities in an incident response. 

Although not all incidents can be avoided or 

controlled, this approach to risk evaluation 

helps to protect patient safety, company 

liability, protocol validation, intellectual 

property and study timelines. 

What are the consequences if a 

consignment is lost or destroyed? First of all 

there is a delay in supply to the site. There 

may not be any replacement product. Some 

clinical trials material goes through years of 

manufacturing, and may go through 20 

different processes in order to get it to a 

point where it can actually be delivered to 

the site. Arranging a new supply may require 

taking excess material from another site, or 

from another study. If the study is for a 

seasonal disease, something like 

pneumonia or influenza, the start of the 

disease season may be missed, losing a 

potential 12 months. Patients are removed 

from trials, losing data, which means delays 

in licence application. That can have very 

serious financial implications, but may also 

affect the share price and reputation of the 

sponsor. If a subject is enrolled on a study 

with a big pharmaceutical company and the 

company then fails to deliver the drug to 

them, then what is the patient’s impression 

going to be? 

There are a number of commonalities 

which will be detrimental to shipments. 

Because of limited stability data on 

investigational product temperature 

excursions represent major problems. 

Mapping of routes assesses the average 

temperatures experienced over time, rather 

than assuming or hoping what is likely to 

happen. Whilst the climate and individual 

weather issues are things which no-one can 

“Traditionally shipments 

are made at the start of 

the week, so that they 

will be delivered before 

the weekend almost 

everywhere” 

control, choosing not to ship in extreme 

conditions can be prudent. 

When shipments must be sent, then 

using additional protection such as heated 

active containers or thermal blankets can 

lessen the likelihood of excursions. In the 

event of shipping extremely temperaturesensitive 

shipments, the thermal challenge 

can come from other cargo. Dry ice boxes in 

the same area of the hold, or stacked inside 

a Unit Load Device, may result in chilling of 

a carefully selected thermal box, and this 

should be mitigated by using good quality 

boxes and on occasion thermal wrapping. 

The internal configuration of the product 

can dramatically affect control of 

temperature. Tiny patient packs consisting 

of a very small vial with a lot of air around 

them make temperature control extremely 

difficult, due to a lack of thermal mass. It is 

possible to increase the amount of thermal 


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IPI 49 

IPI


mass using phase change material, or water 

gel packs, in the product box with the 

material. 

Whatever stability data is available can 

assist in choosing appropriate packaging. 

If, for example, the worst thing that can 

possibly happen is that the material freezes, 

then a package should be selected that is 

less likely to freeze and more likely to keep 

the internal temperature at the high end of 

the temperature range. 

Once the consignment arrives in a far-off 

country, with airline employees who do not 

speak any English but can recognise the 

numbers 2-8 on the outside of a shipment, 

then the materials can be killed with 

kindness by being placed into the fridge. 

Part-thawed gel packs can bring the 

temperature down below freezing. Careful 

labelling is required to reduce the likelihood 

of this happening. There are pharmaceutical 

companies which no longer put the name of 

the company on the outside of their box just 

in case somebody sees a pharmaceutical 

company’s name and puts it straight in the 

fridge. It may be more appropriate that all 

the information about keeping it cold or 

keeping ambient temperature goes onto the 

airline paperwork instead, which should be 

arranged with your transport provider. 

Regulatory changes can have a 

substantial effect on shipment timelines. For 

example, last year unannounced changes to 

the export regulations in Russia interrupted 

supply chains for shipping patient samples 

for around two weeks. Having flexible 

options in place to hold shipments in frozen 

or refrigerated temperatures may be a 

worthwhile backup, but may be prohibitively 

expensive to have on hand just in case. 

Changes to regulations are not confined to 

Russia, or the Far East. Regularly changes 

are introduced with no notice at all by the 

USA and by South American countries. The 

lack of warning can result in shipments 

being held for weeks at a time whilst new 

import permits are applied for, or changes 

made to documents which may then need 

couriering to customs or to the regulatory 

authorities, during which time temperature 

will need to be maintained. A system for gel 

pack replenishment or for storing boxes in 

the airline fridge (once they are outside the 

validation period for the boxes if they contain 

frozen refrigerant) should be considered, 

and this may be offered by your transport 

provider. 

Interruption of air carrier handling is the 

one of the most common incidents. Air 

cargo disruptions can be caused by many 

different factors such as weather delays, 

equipment problems, regulatory changes, or 

civil unrest. Controls vary by region and by 

the available transportation infrastructure in 

“If the study is for a 

seasonal disease, 

something like 

pneumonia or 

influenza, the start of 

the disease season 

may be missed, losing 

a potential 12 months” 

a given country, but when such events occur, 

it may be useful to have arrangements in 

place to utilise other methods of transport 

including road and rail services. You need to 

choose a reputable courier or freight 

forwarder to take responsibility for your 

package. 

Communication is critical in responding 

to an event. Critical role players need to be 

informed when service interruptions and 

supply delays occur, and escalation policies 

and information conduits should be in place 

well before any event occurs. Being aware 

of regulatory problems, air traffic control 

strikes, inclement weather, public holidays, 

civil unrest, interruptions in critical supplies 

such as dry ice, or any incident that could 

disrupt shipment timelines, is vital. 

After all the work done to transport a 

shipment safely and within the necessary 

temperature parameters, there is a very 

significant possibility that the investigator 

site will take the consignment into their 

facility and then fail to store it correctly. This 

usually happens because the site personnel 

who have been trained are not there, for 

example because it is their day off or they 

are on holiday. Traditionally shipments are 

made at the start of the week, so that they 

will be delivered before the weekend almost 

everywhere. Many shippers are now 

calculating shipping date from when the site 

can take delivery, rather than forwards. If the 

site says “We want it on Thursday morning 

because that’s when the research nurse is 

in,” then the date is calculated backwards 

from that time, which may mean shipping it 

on Tuesday afternoon. Shipments may be 

sent on a Friday so that they are at the front 

of the queue for customs clearance on 

Monday morning in Jakarta, or Philadelphia, 

remaining inside the validation time for the 

shippers. 

Pre-empting potential problems at the 

site requires a very clearly agreed chain of 

custody. Training just the primary 

investigator on how to deal with the drug is 

rarely successful, because the majority of 

the time a research nurse, or the practice 

manager, will receive the material. Training 

multiple people will vastly improve the 

likelihood of a successful delivery with no 

temperature excursions. 

Whilst the process of packaging, 

shipping and sending clinical trials material 

may at first sight appear very simple, it is 

clear from this limited overview that there are 

numerous factors which might contribute to 

the failure of a consignment to reach the 

destination in ‘perfect health’ ■ 

Sue Lee – World 

Courier (UK) Ltd. has 

a background in 

Microbiology and has 

worked for World 

Courier for 17 years. 

As Manager BioPharm 

Systems, Research 

and Development she oversees the logistics 

for multinational clinical trials. Sue provides 

consultation and technical expertise to 

shippers, sponsors, labs and World Courier 

working groups on training, BioPharm 

shipping, and dangerous goods. 

She is a qualified DGSA for road and rail and 

IATA trained for shipping Dangerous Goods 

including Radioactives, and is a member of 

the Institute of Freight Professionals (Grad.) 

Email: Sue.lee@worldcourier.co.uk 



Greater flexibility in pharma packaging 

by reducing lot sizes and increasing 

machine running times 

In numerous pharma companies, the 

following problem is being posed: 

shrinking lot sizes are constantly 

worsening the ratio of packaging 

system set-up time to running time. The 

contribution below brings into question 

the current customary 1:1 linking of a 

blister machine, inline printing system 

and cartoning machine and looks at the 

feasibility and possibilities of partially 

decoupled packaging processes. 

1. Introduction 

Falling lot sizes are increasingly presenting 

the pharma packaging industry with a 

challenge. The ratio of set-up time to 

running time is constantly worsening, with 

the result that in many cases line efficiency 

is below 30%. The conversion, cleaning and 

clearing process is being consistently 

tightened up, but the improvements which 

are achieved are not in themselves sufficient 

to solve the structural problem of shrinking 

lot sizes. With today’s standard 1:1 

combination in the pharma industry of a 

blister machine, an inline printing system 

and a cartoning machine, every partial 

conversion - not to mention every fault - 

shuts down the entire packaging line. 

The following analysis questions this 1:1 

combination and examines a variant 

involving partially decoupled processes, in 

which the blistering, cartoning and printing 

stages can be carried out independently 

of each other - possibly only on a 

temporary basis. 

The possibility of bundling together 

generally small packaging lots on the blister 

machine and finishing them in a 

subsequent, decoupled secondary 

packaging process is termed ‘Late Stage 

Customisation’ (LSC); this is a concept 

which has been developed by the Körber 

Medipak Group, with the aim of enabling 

machine running times to be increased 

despite shrinking lot sizes (figure 1). 

The BIB-BOB module is designed to be 

mobile, so it can be linked quickly and easily 

to different blister machines or cartoning 

systems. The blister can be printed with 

customer-specific or country-specific 

information either by a printing system on 

the blister machine, which can be 

configured quickly, or at a later time, as it 

returns from the bulk magazine. 

In order to determine the possible 

increase in efficiency from 

partially decoupled line combinations, 

MediSeal, together with the Institut 

für Konstruktionstechnik und 

Anlagengestaltung (IKA) in Dresden, has 

developed a simulation program which 

allows the throughput time and the line 

efficiency of a typical European pharma 

packaging operation to be mapped. The 

program allows a direct comparison of the 

efficiency of “classic” line configurations 

and partially decoupled packaging 

processes. 

2. Simulation of a pharma company with 

different line configurations 

Fig. 1: Below 

The Körber Medipak Group’s concept for 

increasing machine running times 

despite falling lot sizes in pharma 

packaging. 

One essential feature for temporary 

storage of blisters is a logistics module - 

known as a BIB-BOB 1 (figure 2), which 

a) automatically removes blisters from a 

packaging line or thermoformer, stacks 

them in an orderly fashion in a 

magazine, and, b) at a later point in time 

feeds them back from the magazine into 

a cartoning system. 

Fig. 2: Right 

The BIB-BOB module - a logistics unit 

for removing or feeding blisters in bulk. 


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In the example described, a pharma 

packaging company supplies a product to 

30 European countries. The packaging lot 

sizes vary between 200 and 60,000 trade 

packs; the language, the number of tablets 

per blister or the number of stacks per 

carton may vary from batch to batch. 

Dosaging of the active substance in the 

tablet must remain constant in this simple 

analysis. Depending on the type of 

conversion, 60 to 120 minutes were built in 

for the corresponding conversion and 

cleaning times. Downtime and idle time 

were included - depending on the line - on 

the basis of 5 to 12% of production running 

time. 

For planned production of 1.6 million 

blisters (approximately 455,000 trade 

packs), the pharma packaging company 

has two one-track lines of mid-range 

performance available - each equipped with 

a digital printing system. The nominal output 

of the thermoformer (e.g. a CP400), for two 

different cutter formats, is 180 and 320 

blisters per minute respectively; for the 

cartoner (e.g. a P3000), the figure is up to 

300 trade packs per minute. 

The two lines are identical and process 

300 packaging orders one after the other in 

the pre-specified production sequence. 

Under the conditions outlined, the 

packaging company with the two lines 

would need 161 hours in total to produce 

the 1.6 million blisters (approximately 

455,000 trade packs). 

The chosen line configuration is 

described below as “classic”, i.e. the blister 

machine, printer and cartoner are 

permanently connected to each other in a 

1:1 ratio (CLC ) 2 . 

3. Late Stage Customisation 

In order to (theoretically) process the prespecified 

production sequence again, the 

pharma packaging company makes the 

following changes to its plant: 

a) Line No. 2 is split up: the P3000 

cartoner is replaced by a smaller model 

(e.g. a P1600) with a nominal output of max. 

160 trade packs per minute. Both the CP400 

thermoformer and the P1600 are connected 

to a BIB-BOB system. The blisters produced 

on this CP400 are stacked using BIB mode 

in carton magazines (Line 2a); they are then 

automatically unloaded - at a later time - into 

the P1600 (Line 2b). If necessary, a blister 

printing system can be placed upstream of 

the P1600. 

Line No. 1 remains unchanged, i.e. the 

blisters produced are transferred directly to 

the P3000 cartoner. 

b) In contrast with the previously identical 

distribution of production orders over the 

two lines, lots for countries with a demand 

for larger numbers of items are now shifted 

to Line No. 1, whilst smaller lots (up to a few 

thousand trade packs) are moved onto sublines 

2a/b. A manual packaging station was 

also set up for the smallest lots (less than 

150 trade packs), as in this case even the 

quick-conversion P1600 (Line 2b) would not 

be economical. 

Fig. 3 

The two different line 

configurations, CLC 

(a) and LSC (b) 

compared: in the LSC 

configuration, line 2 

was split in to two 

sub-processes 2a 

and 2b, each with a 

BIB-BOB unit, and 

cartoning output was 

reduced. A manual 

packing station was 

also added for very 

small lots (Line 3). 

Fig. 4 

Cumulative production 

quantity of the two line 

configurations over time. 



4. Comparison of production output on 

the classic CLC configuration and the 

modified LSC line configuration 

4.1 Comparison of throughput times 

Figure 4 shows the cumulative blister 

production of the two line configurations 

(green=LSC; red=CLC). It is striking how 

the respective production outputs diverge 

right from the start and the LSC variant 

manages a continuously higher output. The 

specified production volume of 1.6 million 

blisters (approximately 455,000 trade packs) 

is reached after 9650 minutes (about 161 

hours) in the “classic” line configuration 

(CLC), whilst including the LSC variant cuts 

this time to 6650 minutes (about 111 hours). 

Throughput time can thus be reduced by 

about 31%. 

If both line configurations were run for the 

same time, e.g. 9650 minutes, the LSC 

variant would enable 700,000 more blisters - 

i.e. about 44% - to be produced. 

The reason why the differences are so 

considerable can be illustrated by a Gantt 

diagram analysis (fig. 5). 

4.2 Comparison of line utilisation 

sequences 

The simulation distinguishes between and 

documents the different line conditions 

using 4 categories: production (green), 

conversion time (pink), fault (red) and 

waiting time (blue). 

Figure 5 shows a comparative section of 

the product sequence for Line 1, once in 

classic mode (CLC, lower bar sequence) 

and once in LSC mode (upper bar 

sequence). It documents the production 

times and downtimes for each individual 

line. In the case of LSC mode, it is striking 

how Line 1 has significantly more and 

longer production times (green bar) than in 

CLC mode. The reason for this is that in LSC 

mode only the larger lots remain on Line 1, 

so the ratio of production time to conversion 

time is substantially better. 

Figure 6 documents the production 

times and downtimes of each individual line 

over the course of the entire production run. 

The two bars on the left represent the 

classic CLC concept; the following four bars 

show the line configuration modified using 

Fig. 5 

Gantt diagram: 

production 

sequences, 

Line 1. 

Fig. 6 

Documentation of 

the running and idle 

times of all lines, in 

the “classic” CLC 

configuration (L) 

and in “LSC mode” 

(R). 

the LSC approach. According to this, lines 1 

and 2 achieve 38.5 percent overall 

equipment effectiveness (O.E.E.) on 

average, whilst the same line in LSC mode 

achieves an O.E.E. of 64%. Merely removing 

small lots from line 1 enables an increase in 

use of capacity of 22% and 29% (25.5% on 

average) (fig. 6). 

Line 2a (CP400 with BIB-BOB) achieves 

a similarly good use of capacity; its 

production sequence is no longer 

interrupted by faults and size changes on 

the cartoner side (e.g. just changing the 

blister stack height). 

The manual packaging station was 

hardly used in the example, so “waiting 

time” is a predominant factor here. 

5. Summary 

Particularly when packaging small 

production lots, partially decoupling lines 

and linking the individual line segments with 

a logistics (BIB-BOB) module leads to a 

significantly better utilisation of capacity and 

distinctly shorter throughput times. 

Furthermore, as a result of decoupling, faults 

and conversion times only affect the part of 

the line involved. The BIB-BOB module has 

been designed so flexibly that if necessary it 

can dock with existing machinery ■ 

Dr. Ralph Blum is 

Vice President Sales 

and Markting at 

MediSeal GmbH. In 

2003,he joined 

MediSeal, a company 

well known as a 

specialist in the field of 

blister packing and sachet packing 

machines as well as cartoning machines. 

Ralph Blum holds a Masters Degree in 

Physics and a PhD in Management 

Sciences. He joined MediSeal’s parent 

company, Körber AG, in Hamburg in 1999 as 

a member of the group's M&A Team. 

1.Abbreviation of “Blister into a Box - Blister out of 

a Box”. 2.Classic Line Configuration.. 



Drug Counterfeits – Subject of 

an Experts’ Discussion at the 

European Parliament 

Dr. Jorgo Chatzimarkakis, Member of the 

European Parliament and Chairman of the 

Life Science Circle, invited experts and 

stakeholders to discuss the threats of drug 

counterfeits in Europe. The event, which 

took place at the European Parliament in 

Brussels on December 9th 2008, 

highlighted the increasing concerns about 

fake medicines penetrating the supply 

chain and the urgent need for measures to 

prevent a possibly catastrophic loss of 

confidence in medicines with all the 

negative consequences of health 

conditions on individuals and on public 

health. 

While the final report of CEBR 1 to the 

European Commission in 2002 still found 

that: “Public Health is monitored closely 

across the EU by the relevant drug 

administrations and instances of counterfeits 

are thought to be relatively rare”, the experts 

agreed that appropriate action was needed 

to maintain the high level of security and to 

prevent counterfeiters abusing the 

opportunities resulting from new global trade 

arrangements which may decrease 

traceability of pharmaceutical products and 

increase the chances for counterfeiting. 

Tony Björk, Vice-President of the PGEU, 

the Pharmaceutical Group of the European 

Union, the European association 

representing community pharmacists, 

suggested that a precautionary approach 

should be taken and that the pharmacist 

should act as the last line of defence against 

counterfeits. He referred to the benefits of 

the existing distribution system and said that 

mass serialisation with authentication at 

pharmacy level offered a way forward but 

added that issues like data control, work 

flow and cost of the system still needed to 

be addressed. Like most of the other experts 

he pointed out that the distribution of 

medicines via the internet was a cause of 

concern. “We cannot dis-invent the internet” 

he said, “but we must not actively 

encourage internet distribution unless the 

safety issues are resolved”, and he added 

that the right of the member states to limit 

internet sales of prescription medicines must 

be respected. 

Although often accused of being 

one of the possible sources of fake 

medicines, parallel trade can be an 

additional watchdog in the supply 

chain, emphasised Mr Edwin Kohl, 

the President of VAD, the German 

association of pharmaceutical parallel 

distributors. Since parallel 

importers need a 

manufacturing/labelling 

licence to market products, they 

are subject to the same strict rules 

as all manufacturing pharmaceutical 

companies within the EU, and using 

unreliable sources would put their own 

existence at stake. He stressed that imports 

“We cannot dis-invent 

the internet, but we 

must not actively 

encourage internet 

distribution unless the 

safety issues are 

resolved” 

from outside the EU were not parallel trade 

in the European terminology. Mr Kohl raised 

the question of how the counterfeit product 

could enter the wholesale market, and 

provided a solution that offers security 

against counterfeits. He suggested that the 

purchasing wholesaler should request 

information on the purchase from the selling 

wholesaler and the manufacturer of the 

drug, who would provide all data on the 

product excluding the original 

purchasing/selling price. Such a 

procedure would make sure that the 

purchaser obtained 100% certainty about 

the origin of the acquired product and would 

thereby be enabled to exclude fakes from 

the market. 

Monika Dereque-Pois, Director General 

of GIRP, the European Association of 

Pharmaceutical Full-Line Whole-Salers, 

underlined the importance of a well 

functioning mechanism of the supply chain 

on the basis of knowing one’s supplier and 

customer. GIRP and its members 

acknowledge the high responsibility they 

have to guarantee the safe and efficient 

supply of all medicines to all patients. 

Delivering some 100,000 medicines from 

more than 3500 manufacturers throughout 

the whole continent to more than 150,000 

pharmacies, they play a key role when it 

comes to patient safety and protection 

against counterfeits. Mrs Dereque-Pois sees 

the main point of concern in unregulated 

internet and mail order sale of medicines. 

Insufficient control of licences and the lack of 

Good Distribution Practice (GDP) 

➜ 


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compliance of non-full-line wholesalers, as 

well as slow communications about 

detected counterfeits aggravate the 

problem. Because of the complex web of 

actors without clearly defined 

responsibilities, a solid action plan needs to 

be taken forward, she said. GIRP published 

a position paper on the subject which can be 

downloaded from their website. Furthermore 

GIRP put together an “Anti-Counterfeit Task 

Force” of experts from European full-line 

wholesalers, launched the “Safe Supply 

Chain Coalition” and take part in EFPIA’s 

steering committee on “Coding and 

Identification of Pharmaceuticals”. In 

addition GIRP took part in EGA’s (European 

Generic medicines Association) integrity 

pact, an initiative to secure the supply chain 

and to fight counterfeits. 

Equally GIRP took part in the WHO 

IMPACT initiative as well as in the ad-hoc 

group on counterfeit medicines and the 

European Commission’s consultation 

process. Monika Dereque-Pois stressed the 

importance of collaborating with all supply 

chain partners. She made it clear at the 

same time that in addition to legislation, 

transparency and awareness, technological 

solutions were also needed. The 

wholesalers’ “Zero Tolerance Policy” 

towards counterfeits could only be part of an 

holistic approach towards patient safety, 

addressing supply chain integrity, 

collaboration and communication between 

all stakeholders and the verification of 

product throughout the supply chain. Since 

actually there is no common technology to 

automatically capture product information 

nor a homogenous coding system for 

product identification she urged for a 

machine-readable solution which could 

consist of either barcodes, two dimensional 

codes or electronic identification. 

Regardless of the technology, a seamless 

use of harmonised standards throughout the 

supply chain was a prerequisite in the fight 

against fake medicines. Another essential 

element in this fight is the clear 

accountability of all actors in the supply 

chain who need to be covered by valid 

licences. In this context she made reference 

to the high number of licences given out in 

some member states for pharmaceutical 

wholesalers, of which only a small 

proportion is actively being used (Germany: 

16 out of more than 4000; UK: 11 out of 

1700; Denmark: 3 out of more than 500). 

Mrs Dereque-Pois concluded that to 

successfully fight against counterfeit drugs 

required a clear definition of all actors and 

their responsibilities, harmonised licences 

and control mechanisms, centralised 

databases for the verification of the licences 

for all actors and adequate sanctions for 

non-compliance. 

Mr Klaus Gritschneder from the mail 

order pharmacy Europa Apotheek, located 

in Venlo, Netherlands, explained the 

difference between listed internet 

pharmacies and non-authorised web 

pharmacies. VIPPS, the Verified Internet 

Pharmacy Practice Sites (VIPPS) 

programme, developed in the spring of 1999 

by the National Association of Boards of 

Pharmacy in the US in response to public 

concerns over the safety of pharmacy 

practices on the internet could be a way 

forward also for Europe. The National 

Association of Boards of Pharmacy (NABP) 

was established in 1904 to assist state 

licensing boards in developing, 

implementing, and enforcing uniform 

“Regardless of the 

technology, a seamless 

use of harmonised 

standards throughout 

the supply chain was a 

prerequisite in the fight 

against fake 

medicines” 

standards to protect the public health. 

Pharmacy boards from fifty states, the 

District of Columbia, three US territories, 

nine Canadian provinces, and two Australian 

states make up the association 

membership. A coalition of state and federal 

regulatory associations, professional 

associations, and consumer advocacy 

groups provided their expertise in 

developing the criteria which VIPPSaccredited 

pharmacies follow. VIPPS 

pharmacy sites are identified by the VIPPS 

hyperlink seal displayed on their website. By 

clicking on the seal, a visitor is linked to the 

NABP VIPPS site where verified information 

about the pharmacy is maintained by NABP. 

The public is also welcome to access the 

VIPPS site at www.nabp.net to search for a 

VIPPS internet pharmacy which matches 

their needs. The use of such a “Verification 

Stamp” makes the difference evident 

between authorised and unauthorised webbased 

pharmacies. 

Mr Thomas Hoffman of the German 

Packaging Excellence Centre PEC in 

Stuttgart, Dr Peter Golz from VDMA, the 

German association of machine 

manufacturers, and Mr Richard Mertens 

from Uhlmann Visiotec explained the 

technical possibilities of applying a 

consistent coding system from the smallest 

sealable unit (such as an individual blister 

pocket) to the largest transportation unit like 

pallets, enabling the verification of the 

authenticity and origin of a product, even 

after removal from the original sales pack. 

The code, which is most likely to be a data 

matrix in combination with a unique serial 

number, can be applied by online printers in 

different printing technologies, and would 

allow track and trace of the drug throughout 

the distribution chain. 

Regardless of the technical solutions 

used, it seems to be clear that tight 

monitoring of the players in the 

pharmaceutical market, the close 

collaboration of all parties in the 

supply/distribution chain, tracking and 

tracing of the products and appropriate 

sanctions for non-compliance are required 

in order to maintain the safe supply of the 

market with genuine medicines ■ 

Tassilo Korab holds MSc in healthcare 

Management. He started his career as an 

International Sales Manager, and has been in 

the packaging industry for more than 25 

years. Focusing on patient compliance, 

standards and regulations for child resistant 

packaging and the war against counterfeits. 

Co-founder of HCPC Europe, Tassilo Korab is 

the MD of TKM HandelsgmbH, Austria. 

Email: tassilo@korab.at 



Pharmaceutical piracy 

Tracking and Tracing 

and Anti-Counterfeiting 

It is estimated that in 2010, counterfeit drug 

sales will reach 75 billion US dollars 

globally, an increase of more than 90 

percent from 2005. This figure is highly 

alarming. But most worryingly, we must 

realise that this is no long-term prediction 

anymore. The pharmaceutical industry, 

politics, organisations and associations 

not only need to get plans going for an 

effective protection of medical products - a 

prompt implementation is also necessary 

as soon as possible. 

According to the International Medical 

Products Anti-Counterfeiting Taskforce 

(IMPACT) a medical product is counterfeit 

“when there is a false representation in 

relation to its identity, history or source. This 

applies to the product, its container or other 

packaging or labelling information.” 

Pharmaceutical counterfeits often cannot 

be recognised at first, and sometimes not 

even at second, sight – the counterfeit drug, 

its primary and secondary packaging are 

just too true to the original. Besides 

enormous losses for the pharmaceutical 

industry, the immediate danger for 

consumers is more and more prevalent. The 

forecast of global counterfeit drug sales 

reaching 75 billion US dollars next year asks 

for quick action; a demand that is not easily 

met. Pharmaceutical companies are well 

aware of the threat and many have already – 

more or less efficiently – put security 

measures into place to stop counterfeiting of 

their products. Also, political and industrial 

organisations, associations and institutions 

have reacted to the problem by initiating 

projects and publishing drafts and 

proposals for national or international 

guidelines or legislation changes. Yet, up to 

the present, no common solution has been 

found and the fight against counterfeiting 

still seems to be at its very beginning, 

different attempts and experiments often 

leading to no clear results. 

From RFID to SNI 

In the middle of 2006, FDA abandoned its 

original concept to combat counterfeits and 

ensure traceability with Radio Frequency 

Identification (RFID). Recently new 

developments have been introduced at FDA 

in order to establish standards for a unique 

standardised numerical identifier (SNI) for 

prescription drug packaging. The FDA 

Amendments Act of 27th September 2007 

(FDAAA) imposes March 2010 as the 

deadline for developing or adopting an SNI. 

In January 2009 draft guidance was issued 

by FDA, requesting comments and 

questions from the industry. In a first step, 

FDA has defined a package-level SNI that 

consists of the serialised National Drug 

Code (sNDC) and is composed of the 

National Drug Code combined with a unique 

“no common solution 

has been found and 

the fight against 

counterfeiting still 

seems to be at its 

very beginning, 

different attempts 

and experiments 

often leading to 

no clear results” 

8-digit serial number for each individual 

package. This guidance is considered as an 

“initial step to facilitating other measures for 

securing the drug supply chain” and is only 

to be viewed as a recommendation. 

Standards for track and trace, authentication 

and validation are not included, but will be 

dealt with in one of several announced 

guidances and regulations. Californian 

ePedigree, the last remnant of the ambitious 

FDA plans for the US-wide implementation 

of RFID, is an electronic record to trace every 

step taken by a retail package of 

prescription drugs throughout the supply 

chain. The initial proposal envisaged 2009 

as the deadline. This deadline was initially 

delayed until 2011, and now even until 2015, 

to give the involved parties more time to 

prepare for the implementation. 

European Commission on the move 

While the draft guidance of FDA does not yet 

include the topic of traceability, the 

European Commission is engaged in finding 

a method to protect pharmaceutical 

products against counterfeiting and at the 

same time assuring the traceability of these 

products. In March last year, the European 

Commission therefore launched a public 

consultation in preparation of a legal 

proposal to combat counterfeit medicines 

for human use. The Commission observes 

that “there is evidence that Member States 

are starting to consider taking unilateral 

action to address the problem”. For this 

reason, a consensus needs to be found for 

pack-specific tracing and mass serialisation. 

In its consultation, the EC specifies: “Mass 

serialisation is based on a code on the outer 

packaging which ‘individualises’ the pack. 

The code is read with a reading device. 

Currently, various tamper-proof technologies 

to implement such a concept are under 

discussion by the industry.” Datamatrix and 

2D barcoding are considered to be such 

technologies; other devices are not ruled 

out. One of the 123 responses from 

stakeholders to the European Commission's 

public consultation was issued by the 

European Association of Pharmaceutical 

Industries and Associations. EFPIA, 

amongst others, argues that “a risk-based 

approach may no longer be appropriate to 

apply these measures, as counterfeiters are 

now targeting a growing range of medicines 

and will simply move to target any 

weaknesses in the supply chain.” EFPIA is 

decidedly in favour of the proposed ban on 

repackaging because “it provides an open 

door for any illegitimate party to infiltrate the 

legitimate supply chain with potentially 

dangerous products”. One exception should 

be made to the ban on repackaging: “Any 

legislation will have to make provision to 


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ensure that clinical trials and other research 

activities are clearly out of scope of any 

legislation arising out of the Commission’s 

initiative”. 

Initial first layer of security 

The UK's Medicines and Healthcare 

products Regulatory Agency (MHRA), as 

well as other respondents, raises concerns 

over a possible general repackaging ban at 

European level. Such a regulation would 

imply that importers could no longer comply 

with the requirements of supplying products 

placed on the UK market with an English 

leaflet and English labelling of the primary 

and secondary packaging. Many 

stakeholders emphasised the importance of 

cooperation with the American FDA, and of 

following a multi-layer approach, meaning a 

consideration of many different aspects and 

a bundle of methods. The majority of the 

respondents opined that it would be 

“premature, ineffective and even counterproductive” 

to decide on only one specific 

safety feature. Some respondents also 

stressed the necessity of sufficiently long 

implementation times and warned against 

an increase in bureaucracy. Changes in the 

legislation “should not lead to an overhaul of 

the existing legal system”. A stepwise 

approach seems to be most effective. One 

of the most important points in this 

discussion is that no government or 

international institution has yet found a 

mutual consent as far as the technology for 

counterfeiting and/or tracking & tracing is 

concerned. As required by many 

respondents to the European Commission's 

consultation, a choice of different security 

and traceability features should be possible. 

EFPIA brings it to the point when 

emphasising that “while tamper evident 

features and the use of authentication 

technologies present an initial first layer of 

security, it must be noted that these features 

can potentially be copied and alone do not 

constitute an absolute barrier to reduce 

counterfeits”. Traceability devices do not 

necessarily guarantee the authenticity of the 

traceable product. Although very 

sophisticated in their development, RFID 

tags and datamatrix codes are still far from 

being reliable security features. As for many 

anti-counterfeit features, some recent cases 

have repeatedly shown that these security 

measures can be copied almost as quickly 

as they enter the market for the protection of 

pharmaceuticals. What is more, 

counterfeiters are even ahead of the game. 

They apply security features to products 

that, in their original state, have no such 

feature. New implementations of anticounterfeiting 

devices are often not 

communicated to the public for fear of them 

being copied. Counterfeiters profit from this 

lack of communication. 



Vulnerable distribution chain 

The pharmaceutical supply chain may 

consist of twenty or more different steps 

before the drug reaches the patient. The 

production of each active pharmaceutical 

ingredient (API) is the first step of the 

distribution chain which has to combat 

counterfeiting. If not produced at the 

company’s own laboratory, each active 

ingredient will reach the production site 

through a network of suppliers. The different 

chemical substances are then combined to 

a pure drug substance to produce the final 

medicinal product. The European 

Commission confirms the risk of fake APIs: 

“Already the active pharmaceutical 

ingredients entering the manufacturing 

process may be false representations of the 

original API.” Therefore, choosing reliable 

manufacturers is, of course, an important 

prerequisite. The more people in contact 

with the drug, the greater the chance of an 

infiltration of counterfeits. The next step in 

the drug chain includes packing or filling. 

Additionally, secondary packaging and 

patient information leaflets are required 

before the medicinal product can finally be 

delivered to distributors or vendors. This 

rather simplified description of the 

pharmaceutical supply chain already reveals 

numerous steps which allow counterfeit 

drugs or packaging to enter the distribution 

chain, not forgetting the different routes 

travelled by the product to reach its final 

destination. Depending on the number of 

distributors and interim storages as well as 

on the number of countries or even 

continents, the product has to be 

dispatched by air, road or sea. Each mode 

of transport is exposed to the potential risk 

of counterfeiting. Pharmaceutical packaging 

is particularly prone to counterfeiting. The 

need for a technology that not only secures 

the primary and secondary packaging of 

medical products, but also ensures the 

authenticity of the traceability code and the 

information provided within is obvious. 

Colour-coded security 

One example for such combined technology 

is a system based on micro colour code 

technology to ensure a counterfeit-free legal 

supply chain. These micro colour codes with 

a size of 8 to 90 micrometers consist of four 

to eleven different colour-layers. The 

individual user code, which is exclusively 

allocated to and produced for the products 

of a specific brand-owner, is based on the 

combination of different colour-layers and 

their sorting order. A unique industry solution 

on the basis of these colour codes is now 

available for the combined tracing and 

securing of pharmaceutical products and 

constitutes an essential step towards 

improved security for the drug supply chain. 

The product, its primary or secondary 

packaging, its labels and seals can be kept 

secure by means of individualised colour 

codes. For example, secondary packaging 

is marked with a datamatrix code printed on 

a label to be used for tracking purposes. The 

colour code is also applied onto the label, 

thereby authenticating both the traceability 

code and the product. The same applies to 

primary packaging like tubes or blisters. In 

this example, the traceability code is now 

scanned with a 2D scanner and verified in 

worldwide existing databases. The product 

ID is checked and matched to the 

information provided in the database. 

However, even if the data and the 

information in the database coincide, the 

originality of the product is not yet 

guaranteed. If data verification reveals that 

the product has already been scanned, it is 

almost certainly a fake. Here, the authenticity 

of colour-coded products can immediately 

be verified by the use of a simple standard 

microscope. Manufacturers, distributors, 

police and customers are able to clearly 

distinguish between fake or original 

products and traceability codes. High costs 

of legal proceedings are avoided and 

customer trust in the company's products is 

maintained. The complete solution is 

obtainable from one single source and 

allows pharmaceutical companies to 

combine the logistic advantages of 

traceability with counterfeit-resistance and 

easy integration into the production process. 

2010 is approaching fast. And so is the 

predicted rise in counterfeited 

pharmaceutical products. American 

authorities revealed another alarming 

increase in fake pharmaceuticals: in 2008 a 

rise of more than 100 percent in comparison 

to 2007. The seizure of such high amounts 

of counterfeits is partly due to better 

collaboration among federal agencies. But it 

is mainly due to the overall increase in 

pharmaceutical counterfeits entering the 

legal supply chain. Much has already been 

done in order to find a solution to the 

growing problem. Yet even more still remains 

to be done. The different guidance drafts 

and public consultations are only the first 

step in a long discussion, decision and 

implementation process. Many different 

viewpoints and diverse conflicts of interest 

arise from this debate. No matter which 

codes or features pharmaceutical 

companies and national or international 

legislative bodies will opt for in the future, 

micro colour codes will contribute their share 

to the worldwide issue of tracking and 

tracing and anti-counterfeiting ■ 

For further information, please visit 

www.3SGmbH.com. 

Nicole Golomb is 

Marketing and Sales 

Manager for anticounterfeit 

systems at 

3S Simons Security 

Systems GmbH, 

Germany. She is in 

charge of the management of the specific 

customer projects dealing with individual 

applications of the micro colour-code system 

SECUTAG® on branded articles. Additionally, 

Nicole is responsible for the analysis of 

processing technologies in specific industries 

and the product protection system's integration 

in the different sectors 

Email: nicole.golomb@secutag.com 



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