Europe is under siege - and will have to struggle to defend itself against death, disease and destitution. This alarmist conclusion may come as a surprise to the 400 million citizens of the European Union (EU), who, by and large, live rather comfortable and healthy lives. But those who know better tell us we should be scared - and should be reaching for panic buttons to find a solution.	

The latest initiative from the EU - the creation of a European centre for disease control to protect us from the imaginable and the unimaginable - is moving towards realization. And, the European Parliament gave the proposal a wholehearted welcome in February.	

Its report on the plan highlighted the dangers Europe faces. One in 10 of new HIV/AIDS cases diagnosed in Europe are now drug-resistant strains - twice the level in the US and "just one menace for millions of our citizens," said the Parliament. And, it went on, multidrug-resistant tuberculosis (TB) and methicillin-resistant staphylococcus aureus are also on the increase. There is a growing threat of major disease epidemics throughout the world - the voluntary and forced movements of people, globalization, wars, famines, and environmental and social changes, all contribute to greater opportunities for the spread of disease. The experience of the SARS (severe acute respiratory syndrome) virus has highlighted the danger of complacency. Such dangers "demand effective surveillance and rapid co-ordinated response," the Parliament said.	

But it is not just naturally-occurring dangers that are causing apprehension in the EU. The Parliament's report on the centre for disease control cited another justification - in almost apocalyptic terms: "Over us is the dark shadow of the threat of bioterrorism," it said. As the Parliament's powerful budget committee observed in the run up to the vote: "The recent spread of SARS and the anthrax alerts of late 2001, which were thought to be because of bioterrorism, reinforced the need to provide European citizens with adequate prevention and control structures." So the Parliament concluded that "public health authorities throughout our Union know they must be prepared to respond to very real health threats, crises and emergencies."	

The EU already has in place some co-ordinating mechanisms for disease surveillance among its member states, but they might be described as fences rather than the wall-like structures that are now under consideration. A communicable diseases network has been operating for 5 years, and a number of dedicated surveillance networks have been conducting epidemiological surveillance and an early warning and response system for specific diseases or groups of diseases (including HIV/AIDS, legionellosis and TB).				

But this can be seen only as "an effective first step," said the European Parliament. "Its limitations are acknowledged by the Commission and participants," and it "needs substantial reinforcement to offer a structured, swift, flexible and efficient co-ordinating role in the EU during the longer term."	

The tasks of the planned new centre (to be located in Sweden) will include rapid action in emergencies; harmonization of surveillance methodologies (including better comparability and compatibility of the surveillance data collected in the member states); epidemiological training; and independent scientific advice to relevant EU agencies. The total annual costs in its first year of operation - scheduled to be 2005 - would be approximately €12 million, rising to around €48 million by 2010. This budget is seen by the European Parliament, however, as "tiny and, probably, inadequate."	

In the legal text voted by the Parliament, the new centre is described as a response to a widening EU responsibility. The EU, it says, "is committed as a priority to protect and improve human health by prevention of human disease, in particular communicable diseases, and to counter potential threats to health with a view to ensuring a high level of protection of health of European citizens."				

The EU "should address European citizens' concerns about public health threats" - not just through "preparedness and control measures," but by "prevention of human diseases." And, it stresses, "the danger of deliberate release of agents also requires a coherent EU response." The centre's mission should be to identify, assess and communicate current and emerging threats to human health from communicable diseases. For outbreaks of illness of unknown origin, it should be empowered to act on its own initiative until the source of the outbreak is known. And, "as emerging health threats may have mental as well as physical health consequences, the centre should … gather and analyse data and information on emerging public health threats and developments for the purpose of protecting public health in the European Community by preparedness."	

The centre is intended, according to the legal text, "to maintain scientific excellence at all times through its own expertise and the expertise in the member states, and should foster, develop and steer applied scientific studies." It should also foster the exchange of best practices and experience on vaccination programmes. This, it anticipates, will enhance the visibility and credibility of scientific expertise in the EU. And "where independent scientific expertise is not available from existing dedicated surveillance networks, the centre may set up independent ad hoc scientific panels." It also intends to support EU planning for disease response, strengthening links with clinical and public health sectors, reinforcing the public health laboratory capacity for rapid diagnosis, and co-ordinating training programmes.	

The weaknesses of Fortress Europe - and the perils of holes in its walls - were also the subtext of a health-related meeting of the influential Kangaroo Group in February. Very few associated with this group would be ready to accept the "fortress" terminology: the Kangaroo Group, formed in the 1980s to support the EU attempts to create a single market, is dedicated to facilitating trade by leaping over internal borders and the protectionism they embody - hence its name. But leaping should have its limits, at least as far as pharmaceuticals are concerned, the group concluded at its February meeting. Europe is threatened by products leaping into it from abroad, and by researchers leaping out of it to more attractive countries.				

"During the last decade, Europe's leadership in the pharmaceutical sector has lost ground, with a steady transfer of R&D activities to the US, where conditions are more favourable to pharmaceutical innovation," warned Tom McKillop, president of the European Federation of Pharmaceutical Industries and Associations (EFPIA) and chief executive of AstraZeneca. Pharmaceuticals remain Europe's most regulated products, and - despite their contribution to scientific progress, public health, Europe's society and its knowledge-based economy - "the core problems faced by the R&D-based industry remain," he stressed. McKillop called on Europe to encourage pharmaceutical innovation, attract R&D investment and stimulate industry's competitiveness: "Europeans increasingly depend on pharmaceutical R&D conducted elsewhere. And if current trends continue, Europe will further lose on all fronts: public health, public finances, employment, growth and education." And veteran German Euro-MP Karl von Wogau, a longstanding member of the Kangaroo Group, also expressed his preoccupations that research is moving more and more to the US.	

The enlargement of the EU on 1 May will extend the walls of the fortress still further. Bringing in 10 new countries - Poland, the Czech Republic, Hungary, Slovakia, Estonia, Latvia, Lithuania, Slovenia, Cyprus and Malta - will make the area covered by the fortress larger, but will involve some tricky adaptations in the new terrain, and also require thousands of kilometres of new walls to be created and patrolled on the enlarged EU frontiers to the east and south.				

The prophets of doom have been hard at work on this scenario too. Even hard-headed commercial organizations with no political axe to grind have perceived some risks for the pharmaceutical industry from enlargement. A new study from the UK market analyst Datamonitor suggests that the upside of the pharmaceutical industry's access to relatively untapped markets with long-term revenue potential has to be set against the uncertainty of product success. Changes in regulatory practice, increasingly complicated pricing and reimbursement policies, and economic disparities between the current EU member states and the 10 new members all represent threats, says Datamonitor.	

The industry is under ever-mounting pressure to decipher the growing maze of regulations post-accession - a necessary component of gaining rapid access to prescribers. And in any case, average government health care expenditure per capita in the acceding countries is about 2.5 times lower than that in the current EU states, explained Datamonitor. The choice and availability of new drugs entering the accession markets is bound to be influenced by their national governments' ability to pay for them, it adds.	

Worse, several of the acceding states are moving towards a regulated pricing system, with the aim of cost-containment in their health care budgets. Datamonitor cites the example of Slovenia, "currently reforming its pricing policy into a formal reference pricing system, weighted towards 'cheaper' imported generics." Post-accession, it is anticipated that key accession markets will also remodel their pricing systems following Slovenia's example, it adds.	

That isn't the worst scenario, either, suggests Datamonitor. "EU expansion may also encourage some current EU states to take into account accession countries' drug prices when assigning health care budgets. If these countries continue to use the average lowest prices set in the EU, this parameter will be influenced by drug prices set in accession countries. Importantly, if downward pressure on drug pricing continues post-accession, its impact on pan-European pricing will affect companies' decisions to launch innovative drugs, since there is no incentive to maximize drug revenues."	

The only bright spots Datamonitor perceives in this gloomy outlook are the enhanced prospects for generics and for parallel imports - two developments that are guaranteed to depress executives in the innovative pharmaceutical industry even further, and to fuel their sense of impending disaster.	

The inclusion of the Central and Eastern European pharmaceutical industry will boost the growth of the European generics market, as generics traditionally forms a major part of their business models. These companies are currently undergoing re-organization and repositioning strategies to ensure their competitive advantage is increased to capitalize fully on post-accession revenue opportunities. It is anticipated that importing 'cheaper' generic drugs from accession countries, because of lower operating costs, would provide increased incentives for western European governments to implement measures promoting generic substitution even further. The lowering of generic drug prices by EU governments (such as in Germany and Italy) will also place more pressure to lower the price of branded products because of the existence of reference pricing systems.	

And, continues Datamonitor, parallel trade is expected to escalate post-EU accession. Lower operating costs in the accession countries will escalate drug price differentials between the EU's new and current members. The impact on the pharmaceutical industry after accession will be a shift of parallel trade from the central and eastern European region to the higher priced 15 EU markets. Furthermore, the growth of parallel imports for branded and even generic products will be encouraged by the recent EU government-endorsed initiatives to reduce overall drug costs. Germany, for example, introduced a parallel import quota requiring pharmacists to dispense at least 5.5% of drugs as parallel imports after April 2002. This quota was further increased to 7% from January 2003, indicating that parallel imports remain a strong focus of cost containment.	

The protection that the western European industry was supposed to be provided by the toughly-negotiated Accession Treaty is unlikely to function well, warns Datamonitor. "From a legislative perspective, the EU has done little to address the issue of parallel importing with regards to accession," and the pharmaceutical industry is "expected to have great difficulties in securing the protection it requires." Successful integration of the 10 new member states with current EU health care provision policies is dependent upon each accession country's timely implementation of regulatory and intellectual property laws relating to prescription drugs - and the current picture, just weeks before enlargement takes place, is far from complete.	

Against this sombre background, students of siege history may recall that one of the stratagems used by attackers was to catapult dead and diseased bodies into the fortress, to spread alarm, despondency and germs. And if Europe is really in as parlous a condition as some forecasters suggest, it may be that Europe's only remaining defence would be to reverse the process and start catapulting victims of its own decay outwards towards the attackers. Albedo does not subscribe to this pessimistic scenario and is not volunteering for catapult duty.  	

Articles

Features

Perils are perceived as pressing ever more intensely on the health of the evolving Europe. The reports of Europe's death may, however, be somewhat exaggerated.

Strengthening the Walls of Fortress Europe?

The US Food and Drug Administration (FDA) is proposing a multifaceted approach to halt the spread of counterfeit drugs in the US that centres on establishing an electronic tracking system able to ensure product integrity. At the same time, FDA is requiring drug manufacturers to add linear barcodes to containers and packages of drugs going to hospitals (see sidebar "FDA requires barcodes on hospital drugs"). The barcode initiative aims to promote patient safety, but could delay efforts to adopt e-chip tracking technology. Moreover, the voluntary nature of the anticounterfeit initiative has raised complaints that it is inadequate to ensure the safety of the nation's drug supply. Ironically, successful implementation of this plan to identify and block distribution of bogus medicines could remove obstacles to broader importing of lower-cost prescription products. 	

The task of implementing these policies will fall to others at FDA, following the appointment of commissioner Mark McClellan to be administrator of the Centers for Medicare and Medicaid Services (CMS) in the Department of Health and Human Services (HHS). A top priority for the Bush administration has been to name a knowledgeable and credible individual to begin implementing the Medicare prescription drug benefit and quell complaints from seniors before the November elections. 				

A physician and economist, McClellan knows a lot about drug pricing and reimbursement and their impact on biomedical innovation. He shaped health policy for the White House as a member of the Council of Economic Advisors before coming to FDA in late 2002 and advised the administration in crafting the Medicare bill. 	

In shifting McClellan to CMS, the administration also calculated that FDA could weather the change. Deputy commissioner Lester Crawford served as FDA acting commissioner before McClellan's arrival, a period that saw him launch FDA programmes to modernize good manufacturing practices (GMPs) and consolidate biotech therapies with drugs. Recently, he has been heading up food and animal safety and antibioterrorism initiatives - prime HHS concerns. 	

McClellan made the smart move last autumn of detailing Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), to the Office of the Commissioner (OC) to help implement many of his risk management and strategic plan initiatives. Now Crawford has asked Woodcock to remain as one of three acting deputies instead of returning to CDER in April as planned. Woodcock will be deputy for operations; Murray Lumpkin deputy for special programmes; and Amit Sachdev deputy for policy.	

Woodcock says she can extend her OC stay because CDER is in good hands under acting director Steven Galson. The main priorities for Galson are to continue integrating biologics staffers into CDER, plan for the centre's move to new offices next year and to deal with the constant lawsuits related to generic drugs. Among many initiatives, Woodcock remains in charge of GMP modernization, developing guidance on protein characterization, and crafting a policy for generic - or follow-on - biologics, which is expected this spring. 	

Although FDA will continue to function well, McClellan's departure leaves a big hole at the agency. An outspoken and highly visible commissioner, he advocated for policies to spur medical innovation and gain more equitable global drug pricing. He did not shy away from controversial issues, as seen in his campaign to block drug importing and illegal Internet sales. He leaves FDA with a mountain of unfinished business, but with its drug approval and oversight systems in good shape. He also sets a high standard for future commissioners who want to leave a mark on FDA and the pharmaceutical industry. 	

FDA's report, "Combating Counterfeit Drugs," combines incentives for adopting new product authentication and tracking technologies with proposals to stiffen legal authorities and expand educational efforts to stem the flow of bogus drugs into the US supply system. The centrepiece of the plan is to encourage manufacturers, distributors and pharmacists to adopt a new drug "track and trace" system in 4 years. The envisioned system would use embedded radio frequency identification (RFID) chips that would record data on a drug product's movement from plant to pharmacist and ultimately to the patient. In addition to thwarting illegal operators, the e-tracking system could improve inventory control programmes for all parties and make it easier to recall products that develop safety problems.				

FDA sidesteps some of the more controversial issues that arose at its October 2003 open meeting on drug counterfeit proposals (Pharm. Technol. Eur. 15(12) 22–24 [2003]). Most notably, the agency is not requiring manufacturers to put finished dosages in unit-of-use packaging, as advocated by some pharmacists and providers. FDA officials acknowledge that such a change could enhance patient safety, but decided that it would not control counterfeiting enough to warrant the cost for manufacturers. For now, FDA is encouraging manufacturers to analyse the costs and benefits of unit-of-use packaging, starting with newly approved drugs, injectibles and the products most likely to be counterfeited. FDA also supports independent efforts to develop standards on the size, shape and organization of unit packaging that could reduce costs. 	

Similarly, FDA is not requiring manufacturers to adopt any specific anti-tampering packaging or product authentication systems, such as holograms, coloured labels and chemical markers. Such approaches may be helpful in preventing counterfeiting, but FDA believes that there is no one "magic bullet" able to foil illegal operators sufficiently to justify specific mandates. Moreover, agency officials fear that recommending any one product authentication technology would only alert counterfeiters to industry practices, and could also stifle further innovation. Manufacturers, instead, should explore the range of anticounterfeiting technologies to determine which best fits the specific product and dosage form and the company's capabilities. 	

To spur adoption of new technologies for existing products, FDA says it will review its policies on postapproval manufacturing changes. The agency plans to issue guidance on how companies can adopt anticounterfeit packaging and labelling changes without the need to obtain prior FDA approval, possibly through a changes-being-effected supplement or notification in an annual report. 	

The prospect of establishing a national electronic tracking system for all prescription drugs in four years is prompting FDA to once more postpone plans to implement the paper pedigree system required by the Prescription Drug Marketing Act (PDMA) of 1987. After several delays because of high costs and technical difficulties, FDA was scheduled to launch the paper pedigree system on 1 April. Instead, the agency is backing this new electronic approach as a better way to meet PDMA objectives, but will reassess in 2006 whether industry is progressing sufficiently to keep paper pedigrees on hold. 		

Manufacturers and wholesalers have begun feasibility studies of RFID systems, notably a pilot test by wholesaler McKesson for Wal-Mart. RFID tracking involves inserting tiny electromagnetic chips with unique mass serialization numbers that carry an electronic product code (EPC) in drug labels and packages. When incorporated into systems with data readers and computer information bases, the chips automatically authenticate and track products moving through the distribution system, creating a de facto electronic drug pedigree. RFID chips can hold much more data than barcodes and do not have to be read manually by scanners. 	

Next year, FDA expects that manufacturers will begin applying RFID chips to pallets, cases and packages of pharmaceuticals most likely to be counterfeited, and that wholesalers, chain drug stores and some hospitals will begin acquiring and installing information systems able to read and use this tracking information. An FDA timeline calls for these actions to be extended in 2006 to more products, pharmacists and hospitals so that there is a full RFID tracking system in place in 2007. 	

During this process, FDA will examine whether it needs to revise rules for labelling, electronic records and adherence to good manufacturing practices (GMPs) to accommodate new technologies. Another task is to ensure that any electronic tracing system complies with patient privacy protection policies. FDA and manufacturers are also examining whether RFID systems present any pharmaceutical safety issues. Researchers are conducting stability tests on drugs with labels or containers that have chips and will test if frequency emissions from chips could affect sensitive biotech products. 	

In announcing the anticounterfeit plan, McClellan noted that the private sector - and not FDA - should establish and maintain the e-tracking database. FDA expects all stakeholders will help develop standards for unique mass serial numbers to identify a pallet, case or package; protocols for reading tags; and compatible software requirements to ensure system interoperability. Manufacturers should also work with FDA and other members of the supply chain to address regulatory and economic issues that could delay adoption of the RFID tracking approach. 	

In addition to encouraging technological innovation, FDA proposes changes in laws and policies to further deter production and distribution of counterfeit products. These include 				

Stiffer criminal penalties. FDA is asking the US Sentencing Commission to increase jail terms for drug counterfeiters. Currently, making a counterfeit drug brings only a 3 year maximum sentence, compared with up to 10 years for counterfeiting a drug label. 

Stronger state wholesaler regulation. The National Association of Boards of Pharmacy (NABP) has issued revised model rules for wholesalers that FDA would like states to adopt. 

Broader input on counterfeit activity. A counterfeit alert network will collect reports on counterfeit incidents from national health organizations, consumer groups and industry, and disseminate FDA alerts to members and subscribers. 

Identification of likely counterfeit targets. Some states and organizations are developing lists of those high-priced, high-volume and scarce products most likely to attract counterfeiters. Pharmacists and providers feel that such lists should also include therapies likely to cause the most harm if counterfeited, such as AIDS and cancer treatments and injectibles. FDA supports compilation of a national list by NABP and other stakeholders to avoid redundancies and to help the public identify suspect products, but prefers that private organizations lead this effort. 

Heightened security. FDA is promoting secure business practices and expects to develop guidance for industry on securing facilities and production sites. FDA also plans to increase site inspections of drug re-packagers, which have served as an avenue for counterfeits to enter the supply chain. FDA advises firms to name a high-level individual or team to co-ordinate anticounterfeiting activities and to check the legitimacy of suppliers and other business partners.

International co-operation. FDA also plans to collaborate with international organizations in identifying counterfeiters and establishing tracking systems. The agency is supporting efforts headed by the World Health Organization and will work more closely with the Permanent Forum on International Pharmaceutical Crime and the Interpol Intellectual Property Crimes Action Group to implement worldwide anticounterfeit drug strategies.

Another FDA goal is to increase public information on the dangers of counterfeit drugs. The agency plans to issue more advisories on buying drugs safely through the Internet, an activity that also supports its campaign to halt the sale of illegally imported drugs through the Internet. 				

While not all illegal imports are counterfeits, Internet purchasing opens the door for bogus products to enter the US market (see sidebar "Counterfeit or just illegal?"). The surge in shipments of unauthorized drugs to US customers has prompted an FDA crackdown. An agency "sting" operation in January netted evidence of counterfeit and misbranded products being mailed to Americans and led to actions against Texan importers. The tension heated up in February when several state and local governments launched new efforts to help citizens obtain drugs from Canada. Members of Congress threatened to block McClellan's appointment to CMS until he explained his anti-import stance. 	

Data from IMS Health shows that sales of prescription drugs reimported from Canada to the US topped $1 billion in 2003 compared with $500 million in 2002. The growth trend may level off as manufacturers limit sales to Canadian mail order pharmacies shipping products to the US. Pfizer informed several Canadian firms in February that it would cut off supplies, similar to earlier action by GSK.	

While Congress debates drug import proposals, FDA analysts are examining what resources the federal government would need to make drug reimporting safe, as required by the new Medicare reform legislation. HHS established a drug import task force to examine these issues publicly. A main argument against importing is that FDA has no way to ensure that a product from Canada is genuine and has been shipped and handled correctly, and an electronic tracking system could reduce this concern.  	

FDA relies on e-chips to thwart bogus products, and drops paper pedigrees and unit-of-use packaging.

McClellan Moves to Block Counterfeits and Require Barcodes Before Leaving FDA

Although life sciences standards are still in the early days of development, some are available for use today. Specific standards are needed for a large variety of products such as toaster plugs, bank cards, compact discs, railroad tracks and the interchange of information between computer systems. It is important for organizations to utilize, follow and participate in these global standard initiatives because they help reduce costs and provide a more efficient exchange of information. 	

The ever-increasing complexity of developing new products and services benefits from the use of information systems technology. This applies to both commercial and scientific development. The most fundamental exchange or processing of information can only be enabled with speed, accuracy and reliability when supported by standards, and building proprietary interfaces is costly and time-consuming. 	

Information technology (IT) standards facilitate interoperability, which is defined as "the ability of two or more systems or components to exchange information and to use the information that has been exchanged." IT standards include specifying which information needs to be exchanged (syntax) and the meaning of the information (semantics). Syntax information includes the specific information to be exchanged and the associated structured format, for example patient last name (15 characters, alphanumeric) and date admitted (6 characters in MMDDYY format, numeric). Additionally, semantics provides a common understanding of the information, that is, a common vocabulary or thesaurus (for example, M=Male and F=Female or 1=male and 0=female). 	

Research focussed standards organizations

This article highlights some of the emerging life science standards and associated standards organizations in research, clinical trials and clinical genomics. These organizations differ in size, the formality of their structure and procedures to create standards, and how often they meet. 				

Research focussed standards organizations include Interoperable Informatics Infrastructure Consortium (I3C), Object Management Group-Life Sciences Research (OMG-LSR) Committee, Microarray Gene Expression Data Society (MGED) and Global Grid Forum's Life Sciences Grids Research Group (GGF LSG-RG). Standards organizations focussed on developing clinical trial standards include Clinical Data Interchange Standards Consortium (CDISC) and Health Level Seven's Regulated Clinical Research Information Management Committee (HL7 RCRIM). Health related clinical genomics work is being undertaken by the HL7 Clinical Genomics Special Interest Group.	

Figure 1:  Research focussed standards organizations.	

MGED has created a specification for microarray data to produce standards that allow sharing of microarray data. MGED worked with OMG to create the gene expression specification, which is flexible and robust. Microarray gene expression object model (MAGE-OM) defines the objects of gene expression data independent of any implementation. MGED has also translated the MAGE-OM into an XML-based format (MAGE-ML) for facilitating the exchange of the data - an important international standard within the life sciences community. Enhancements to MAGE are being worked on collaboratively by OMG-LSR and MGED. MGED members represent an international community of biologists, computer scientists, data analysts and enabling vendors. MGED board members represent organizations including US and UK-based academic institutions.				

OMG-LSR committee is focussed on creating interoperability standards that benefits researchers. OMG has a structured modelling process and methodology to create standards. OMG-LSR works with other standards organizations and takes their specification through their formal standardizations process, for example, I3C's life science identifier (LSID). OMG-LSR's joint creation with MGED of MAGE (in October 2002) provides a way to represent and exchange gene expression data and associated annotations. 				

Started in 2002, I3C aims to accelerate life sciences discovery through software interoperability. Some of its current work includes				

Developing a schema for unique life sciences identifiers that provides a common way to find and name biological data (see LSID section).

Enabling interoperability based on the naming, description and discovery of services and data in the life sciences.

Fostering interoperability between de facto standards in pathways and systems biology.

Participating in joint standards work with HL7 and CDISC, based on the US Food and Drug Administration (FDA) 2003 draft guidance pharmacogenomics data submissions.

I3C has a diverse membership including pharma and biotech companies, academic research organizations and supporting vendor organizations that have come together to create specifications that eliminate barriers to interoperability and promote the integration of life sciences information. 	

The GGF is an international community-driven forum of individual, academic, government, and corporate researchers and practitioners working on distributed computing or grid technologies. In October 2002, the GGF established its first industry-academic focussed research group, the Life Sciences Grid (LSG-RG).				

LSG-RG explores issues related to IT integration within life sciences on a grid infrastructure. Some of its goals include identifying clear examples and the diverse use of life sciences and health grids; discussing issues of access to data in life sciences; identifying how the grid is being challenged by the life sciences and where there is need for activity; and identifying different solution areas and possible reference architectures.	

One of its projects involves creating a listing of all global grids relating to life sciences, including research, clinical trial and health/medical imaging. An additional project under discussion includes creating best practices of life sciences grids. LSG-RG will also collaborate and provide focussed content for GGF workshops. 	

Clinical trial and clinical genomics standards

CDISC and HL7 work together to create clinical trial standards, while HL7 is also independently creating clinical genomics standards.				

Created in 1997, CDISC develops the industry standards that support the electronic acquisition, exchange, submission and archiving of clinical trial data. CDISC's international membership includes pharmaceutical companies, contract research organizations (CROs), labs and information technology vendors. The consortium includes a European group (ECG) and Japanese group (JCG), and works closely with HL7's committee on clinical trial standards.				

CDISC work groups include the lab operational data model (ODM), submission data standards (SDS) model and the analysis dataset model (ADaM). The lab model is discussed in more detail later in the article; below is an overview of the remaining work groups:	

The SDS model encompasses data that is required for electronic submission to FDA for approval. It describes the content, structure and attributes of submitted data. 

The ODM provides a format for clinical trial information representing study data, metadata and administrative data, including audit trial data that would be exchanged during or archived after a trial. It provides the vendor a neutral platform for the exchange of data in XML format. The model incorporates (and is fully compliant with) FDA guidance and regulations governing the use of computer systems in clinical trials.

The ADaM provides analysis datasets and related documentation to assist FDA in its statistical review of a sponsor's findings. 

HL7 is recognized as the key standards developing organization within the international health care community. Accredited by the American National Standards Institute (ANSI), it produces standards that facilitate the exchange of medical records, clinical data and administrative/demographic data. Two areas of interest to the life sciences community are HL7's work relating to clinical trials and clinical genomics.				

There is an active international community participating in HL7, with local country affiliates groups. Hospitals are active participants in HL7 committees and it is not unusual to have medical doctors participating in standards development. FDA has a strong presence in HL7 since it was mandated to use ANSI-accredited standards.	

HL7's clinical trials committee, regulated clinical research information management (RCRIM), works in conjunction with CDISC to create clinical trial standards. The committee is creating standards for exchanging data regarding and generated by regulated clinical research. Standards will include HL7 messages and structure documents to exchange clinical trial lab, operational and submission data.	

In January 2003, HL7 began work on clinical genomics standards and formed the Clinical Genomics Special Interest Group (SIG), which is the first standards work in the industry on the use of genomic data in health care. The scope of the SIG is the personalization (differences in an individual's genome) of genomic data and its link to relevant clinical information. The SIG is currently defining use cases for clinical genomics in areas including diagnostic testing for cystic fibrosis and breast cancer, tissue typing and clinic genomics data within clinical trial information exchange. Participating organizations in this SIG include the Mayo Clinic and Fred Hutchinson Cancer Research Center, as well as others with medical, genomics or information technology domain expertise. Organizations are encouraged to sign up for the SIG distribution list and participate in conference calls and meetings.	

Microarray experiments generate a wealth of gene expression data, providing important insights into a variety of biological processes. It is very hard to interpret or analyse gene expression results without being aware of the many variables, such as experimental setup, biomaterial used and treatment procedures. 				

The microarray standards provide a means for specifying what data and associated annotations are needed to represent a microarray experiment. Included are the structure and format of microarray-based experiments that can be communicated, describing a comprehensive representation of microarray data. MAGE object model (MAGE-OM) describes microarray experiment setup, array designs, manufacturing information, gene expression data and analysis results. Components of microarray experiments that are represented in the standards include experimental design, samples used, the extract preparation and labelling, array design, hybridization procedures and parameters, and measurements. 	

MAGE-OM describes a comprehensive representation of microarray experiments based on different types of arrays. It includes the structure and format of microarray-based experiments that can be communicated. MAGE-OM can be used to map data structures in different platforms including Perl, Java and C++. 

Markup Language based on XML (MAGE-ML) is a document exchange format derived from the object model. 

Open source software toolkit (MAGE-stk) assists users in creating MAGE-ML. This toolkit, which is available in Perl and Java, helps to facilitate ease-of-use of the standard.

The CDISC laboratory standards team (CDISC LAB) team began work in 2000 on developing a model for the acquisition and interchange of clinical trial laboratory data. This standard is for interchange across central laboratories and their clients.  Participants in this work included pharmaceutical companies, central labs, a CRO and technology companies. A high percentage of clinical trial submission data is lab data.								

According to Susan Bassion, leader of the CDISC LAB team, the new model standard provides the opportunity for central labs, pharmaceutical companies and CROs to agree on a single standard format for data interchange that can support each organization's varying data content. Central labs providing clinical trial services to the pharmaceutical industry have had to write propriety interfaces for each organization and sample type, a process that requires considerable time and money for development. 	

As Bassion states, some labs are working with more than 1200 different interfaces. In addition, pharmaceutical companies report that it may take up to 6 months to work out the data interchange process with a new laboratory. Some central labs are already discussing providing preferential pricing to companies that will accept lab data transfers in a CDISC format that reflect the time savings made possible through use of the standard.	

Released in 2002, CDISC LAB Model V 1.0 defines the standard content for transferring clinical laboratory data to sponsors. It defines 90 fields to accumulate different types of lab data. Implementations are available in ASCII, SAS, XML and HL7. The CDISC Lab standard is aligned with logical observation identifier names and codes (LOINC), a lab code standard.	

Extensions for microbiology have been added to the model as Version 1.1 and the team is currently developing a urology model. Additionally, the CDISC lab team works with HL7 to co-ordinate the LAB model with the HL7 clinical trial LAB standard. 	

In 2003, the I3C completed a specification on life science identifiers (LSIDs), which provide a simple and standardized way to identify and access distributed biological data. Biological data could include anything that can be expressed in bytes. This vast list includes everything from medical images, spreadsheets and publications right through to protein structures, chemical analysis reports and DNA sequences; LSIDs refer to persistent, location independent, resource names.				

An LSID can assist a scientist not only in fetching the data that the identifiers name but in collaboration between multiple scientists who can now be sure that they are referring to exactly the same thing. Since LSIDs provide a globally unique name for any item of data, they are ideal for retrieving, referring to, or annotating any piece of information held in one database by an unrelated third party application.	

The LSID resolution process fetches the data named by an LSID. IBM has created several resolver software implementations of the I3C LSID specification that have been contributed to the I3C. Any organization can download the resolver open source code from 

http://ibm.com/developerworks/opensource/lsid/

This article looks at some of the current and emerging standards that are shaping the life sciences industry, and how pharma and biotech companies can benefit by implementing them.

Emerging Life Sciences Standards

Hard capsules have been developed as an edible container to mask the taste and odour of medicines. Traditionally used for powder or granulated formulations, capsules have also been adapted to contain oily liquids, tablets and even powders for inhalation. They are popular because of their relative ease of manufacture (compared with other dosage forms such as tablets) and their flexibility to accommodate a range of fill weights. Additionally, capsules readily demonstrate bioequivalence between different strengths of the same formulation.	

The solubility of many compounds used in potential new drugs is very low because they are selected for their affinity to receptors, which increases as the lipophilicity of a compound increases. Although these compounds are expected to have a high clinical performance, they often fail to become new drug entities because of their low absorption in the gastro-intestinal (GI) tract - a result of poor dissolution. 	

The authors developed polyvinyl alcohol (PVA) acrylic acid methyl methacrylate polymer (PVA copolymer) capsules following research indicating that the bioavailability of some insoluble drugs was enhanced when dissolved in macrogol 400 (polyethyleneglycol [PEG] 400), but conventional hard capsules could not tolerate macrogol 400. An earlier study reported that the solubility of a drug in macrogol 400 is approximately 100 times higher than in water (Table I).1 When the drug/water mixture was administered in a suspension to dogs, only 2.2% of the dose was absorbed, but when administered in a solution of macrogol 400, absorption was 91%.

Table I:  Solubility of insoluble drugs in macrogol 400 and PK parameters after administration in dogs.	

This suggests that pharmaceutical manufacturers could develop dosage forms of insoluble drugs with macrogol 400, improving the solubility of such entities. Because the formulations and manufacturing processes are simple, no scale-up studies would be required - possibly reducing drug development times.	

Because of the large potential of capsules that can hold macrogol 400, the authors developed new capsules, synthesizing materials that are suitable as capsule shells. By copolymerizing acrylic acid (AA) and methyl methacrylate (MMA) on PVA as a skeleton and then using the obtained PVA copolymer as capsule shells, the authors successfully developed capsules that can be filled with macrogol 400.

 In this paper, the physical properties of the PVA copolymer, and the characteristics and pharmaceutical applications of PVA copolymer capsules, are investigated. 	

Initially, the authors examined why conventional capsule shells do not tolerate macrogol 400. When gelatin capsules were filled with macrogol 400, they became brittle and broke easily because the moisture in the shell was absorbed by the macrogol. When hydroxypropyl methylcellulose (HPMC) capsules were filled with macrogol 400, the agent oozed out through the capsule shell. 				

The authors believed that new synthetic polymers would be more suitable for capsule shell materials rather than natural polymers or polysaccharides. Thus, different polymers were synthesized, using styrene resin, polyurethane, acrylic polymer and chitosan as a skeleton. 	

PVA copolymer was developed by the authors (Figure 1). Commercially available, partially-saponified PVA was used as the raw material for the skeleton of the copolymer. AA and MMA were emulsion-polymerized onto the PVA skeleton.	

Figure 1:  Typical synthesis of PVA copolymer.				

Dissolution of PVA copolymer. Capsules made only of PVA are available, although they are easily softened by surrounding moisture. In the PVA copolymer, MMA was used to increase the hardness of the capsule shell; however, increasing the amount of MMA decreases the polymer solubility. Thus, AA was copolymerized to increase the solubility at neutral pH. The composition ratios of PVA, AA and MMA in the PVA copolymer can be modified; the best copolymer is formed when the levels of PVA, AA and MMA are 70–80%, 2.5–5.0% and 15–25%, respectively.	

Drug capsules should dissolve in purified water, as well as in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) of the disintegration test method listed in the Japanese Pharmacopoeia (JP). The dissolution of PVA copolymer cast film in the above media was examined. The result showed that the film was soluble in all three fluids, indicating that the copolymer has suitable dissolution characteristics. The film showed no erosion, swelling or dissolution in macrogol 400.	

Film strength. PVA copolymer film was formed in 100 μm thickness using the casting method. The breaking strength and elongation rate of 40310 mm film segments were examined (Table II), which showed the breaking strength of the PVA copolymer film to be 32.2 N/mm

. The value was slightly lower than that of gelatin film (55.8 N/mm

), but comparable to that of HPMC film (30.8 N/mm

); therefore, the PVA copolymer film was considered acceptable for practical use. 

Table II:  Tensile strength of films and Table III:  Gas permeability through films.	

When the PVA copolymer film was moistened in a chamber (25 Â°C/75% relative humidity [RH]), its strength decreased by approximately 25%. Gelatin and HPMC specimens showed larger reductions (more than 50%) in strength when moistened at the same condition. 	

Although the gelatin and HPMC films showed a low elongation rate before and after moistening, the PVA copolymer film showed a markedly higher rate before and particularly after moistening (312% of the original rate).	

Gas permeability of the film. The 100 μm thick film was also used to examine gas permeability by the American Society for Testing and Materials (ASTM) method. Water vapour permeability through PVA copolymer film at 25 Â°C/90% RH was 323.2 g/m2/24 h, which was between the values of the gelatin and HPMC films (Table III). There was no marked difference in water vapour permeability between the three films. In contrast, oxygen permeability through PVA copolymer was significantly less than through gelatin and HPMC films, indicating that it should be impermeable to the PVA copolymer film.	

Moisture absorption and desorption isotherm. Generally, water-soluble polymers start to absorb moisture when relative moisture increases by more than 70% and the absorption rate dramatically increases when relative moisture exceeds 80%. The moisture absorption isotherm curve of PVA copolymer is similar to that of gelatin (Figure 2). The moisture desorption of PVA copolymer is similar to its absorption isotherm curve, whereas, for gelatin film, the desorption rate is slower than its absorption rate. 	

Figure 2:  Isotherms of moisture absorption and desorption at 25ÃÂ°C.	

Safety study. The authors developed hard capsules using the copolymer based on the properties described earlier. Because the PVA copolymer is a new additive, it is necessary to examine its safety. Recently, the number of newly developed additives has decreased because testing their safety is too expensive. In this case, Huntingdon Life Sciences (UK) performed the safety testing. A single administration test in rats; a micronucleus study in mice; an Ames test; a human lymphocyte chromosome aberration study; a single administration study in dogs; and a maximum tolerated dose (MTD) toxicity study were completed, all indicating no safety concerns. The single administration study in rats showed that the oral lethal dose was more than 2000 mg/kg. 	

No significant changes in autopsy, pathological or pharmacological findings were observed when the copolymer was administered continuously for 14 days at a dose of 500 mg/kg in dogs. Studies of the absorption, distribution, metabolism and excretion of 

C-labelled PVA copolymer are currently under way. After these are completed, a preliminary long-term oral administration study and a subacute study of the repeated administration for 3–6 months will be performed in rats. 	

PVA copolymer capsules were prepared by the dipping and forming method. Carrageenan (0.05-0.5%) was added as a gelling agent and potassium chloride (0.05-0.5%) was added as a gelling promoter. This method requires no additional investment for capsule manufacturers because conventional gelatin capsule manufacturing machines can be used. Prototype PVA copolymer capsules were coloured, showed a good gloss and were not different from conventional capsules. 				

Disintegration and dissolution. Prototype PVA copolymer capsules (size #0) were filled with macrogol 400 and the time taken for the contents to begin to leak out was measured (Table IV). The capsules were filled with the disintegrant croscarmellose sodium and the paddle method (50 rpm) was used to measure the disintegration time as an index of the start of dissolution. The capsules opened in less than 10 min in all the media. 		

Table IV:  Disintegration test and lag time in dissolution test of PVA copolymer capsules.	

Capsule hardness . The relationships between the brittleness and moisture content of PVA copolymer, gelatin and HPMC capsules were compared using a hardness tester (Shionogi Qualicaps, Japan). A 50 g weight was dropped at a height of 10 cm onto a capsule and the percentage of broken capsule was determined (Figure 3). At a water content of 8%, the gelatin capsules became brittle and the percentage of broken capsules was 100%. The HPMC capsules did not break, even at 1% water content. PVA copolymer capsules became brittle when water content was less than 4%, but were less brittle compared with gelatin capsules. PVA copolymer capsules did not become brittle or break easily, even when filled with macrogol 400 (which absorbs moisture from the capsule shell) or silica gel grains (desiccant). The authors concluded that these test conditions were too severe to estimate capsule brittleness.		

To evaluate capsule deformation, the load required to deform each capsule by 50% was measured using a load cell (Figure 4). The results illustrate that PVA copolymer capsules can be deformed by moisture absorption, but this can be prevented by controlling the water content of the filling and the humidity of the environment, or with moisture-proof packaging. 		

Figure 3:  Brittleness of capsules at different water content and Figure 4:  Load required to deform 50% of capsules at different water content.	

Filling dissolution. When dissolution testing PVA copolymer capsules (size #2) filled with macrogol 400, the bottom of the capsules quickly dissolved (2 min) in purified water, JP 1st fluid (pH 1.2) and JP 2nd fluid (pH 6.8), with the macrogol 400 leaking out from the bottom. 	

Two sets of capsules for the insoluble drugs tolbutamide and indomethacin were prepared. One capsule was filled with the drug as a solution of macrogol 400 and the other was filled with a mixture of the drug, lactose (as a filler) and croscarmellose sodium (as a disintegrant). The dissolution behaviour of the capsules was compared using the JP paddle method (50 rpm). The tolbutamide/macrogol 400 capsules almost dissolved completely in 10 min in all the test solutions. However, for the capsules filled with the drug, filler and disintegrant, only 80% of the drug had dissolved after 60 min (Figure 5). 			

Figure 5:  Improvement of tolbutamide capsule (size #2) dissolution when filled with macrogol 400 and Figure 6:  Improvement of indomethacin capsule (size #2) dissolution when filled with macrogol 400.	

Indomethacin in macrogol 400 solution quickly dissolved in all of the three test fluids, as observed with tolbutamide (Figure 6). However, the dissolution rate of indomethacin with filler and disintegrant was slow, particularly in JP 1st fluid where the solubility was low and the dissolved percentage at 60 min was approximately 20%. 	

Based on the above data, the dissolution of encapsulated insoluble drugs can be improved when they are dissolved in a solution of macrogol 400.	

Absorption of indomethacin in rats. Indomethacin PVA copolymer capsules were prepared using either a solution of macrogol 400 or a mixed powder formulated with lactose and croscarmellose sodium. Both sets were filled into mini-capsules (size #9) and administered to rats to compare the plasma profiles of the drug (Figure 7).

 The results illustrate that between 180-360 min, the capsule containing the drug as a solution of macrogol 400 demonstrated a higher plasma concentration (8 μg/mL) compared with the capsules containing the mixed powder (1 μg/mL). The data suggest that PVA copolymer capsules filled with macrogol 400 improve the bioavailability of insoluble drugs.  		

Figure 7:  Indomethacin absorption improvement after administration of macrogol solution to rats and Figure 8:  Stability of PVA copolymer capsules.	

Tolerance of PVA copolymer capsules. The solubilizing agents macrogol 400, Tween 80 and Labrasol were filled into PVA copolymer capsules and stored in accelerating conditions (40 Â°C/75% RH) in a sealed container to examine the tolerance of the capsules to the agents. The capsules showed no change in appearance after 6 months (Figure 8).	

When a solubilizing agent with a high water content is filled into a capsule, the moisture causes the capsule shell to soften and/or deform. This can be prevented by controlling the water content of the agent and the humidity of the manufacturing environment, and by using moisture-proof packaging, as done for conventional capsules. 	

Comparison with conventional capsules. Current commercially available hard capsules are made of gelatin or HPMC. Table V lists the advantages and disadvantages of PVA copolymer capsules compared with these capsules. PVA copolymer capsules have similar advantages to HPMC capsules because both have been developed to overcome the drawbacks of gelatin capsules. The advantages of PVA copolymer capsules include no animal-derived material, a low water content, no Maillard reaction and a low electrostatic propensity. Additionally, PVA copolymer capsules demonstrate the unique properties of having very low oxygen permeability and the ability to contain macrogol 400. 	

A recent report suggests that the successful development of one or two new drugs requires approximately 100 discovery projects and initial in vitro screening of approximately 7 million compounds.

 After in vitro screening, pharmacological and preclinical safety studies are performed followed by clinical studies to confirm the efficacy and safety of the drugs in humans before being marketed. 				

The development of high throughput screening and information technology are making the selection of candidate compounds at the initial screening stage extremely efficient. However, subsequent research still requires trial and error experiments; when compounds are extremely insoluble or unstable, a large number of such experiments are necessary that may lengthen the drug development time and increase the costs.	

Figure 9 shows how PVA copolymer capsules can help develop insoluble drugs. With capsule drug development, the formulation should remain constant between preclinical and Phase IV studies. This avoids issues with changing bioequivalence because of formulation changes and scale-up. Additionally, it may be easier to develop a formulation having a high bioavailability. PVA copolymer capsules, therefore, are favourable for the quick and low cost development of insoluble drugs.	

Figure 9:  Efficient development of insoluble drugs with solution-filled capsules.	

PVA copolymer does not have chemically active groups such as those in gelatin and it is more tolerable to different agents than gelatin and HPMC capsules. Before PVA copolymer can be used in marketed drugs, further safety studies are required and the authors anticipate that this will take a further 2 years.				

Patents of the capsule have already been filed and the authors plan to supply PVA copolymer capsules globally.

 The authors also intend to develop equipment that will give the capsules a protective oxygen barrier.	

It is said that more than 200 billion capsules are currently used globally. More than 100 years have passed since gelatin capsules were first developed. HPMC capsules were developed at the end of the 20th century,

and the authors hope that PVA copolymer capsules will help drug development in the 21st century.		

Table V:  Comparison of capsule characteristics.	

The bioavailability of some insoluble drugs is enhanced when they are dissolved in the solubilizing agent macrogol 400, although conventional hard capsules cannot tolerate the agent. This article investigates a PVA copolymer, which has been developed by the authors, examining its properties and its suitability as a material in capsule formulations.

Pharmaceutical Technology Europe-04-01-2004

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