Rapid progress in pharma RFID

RFID in healthcare is rapidly growing and predicted to become a $2.1 billion global business in 2016.¹ This is partly a result of the increasing applications of the technology; for example, patient compliance-recording blister packs that electronically record when each pill is taken — or more strictly, when it is removed from the pack. Aardex (www.aardexgroup.com) has a version where the pills in a plastic bottle are continuously weighed by a load cell in the base, which records when a pill is removed.

Compliance

These packages are used in drug trials and incorporate RFID so that a record can be linked to a specific patient. They deal with a problem arising from the fact that 50% of patients take their medication incorrectly, either in quantity, time or duration. In rheumatology the figure is 65%; arthritis and migraine is 7–15%; but most other afflictions are in the 40–60% range for noncompliance — a severe problem for the patient, those prescribing and those trialling the drugs. Indeed, the end-point must be smart packs that both prompt and record compliance, and yet are low cost, disposable and environmentally friendly. It is achievable, possibly commencing within 10 years as new printed electronics replace silicon chips and conventional electronic components.²

Inks and electronic packaging

Meanwhile, new finer silver conducting ink for sensors and interconnects can now be used in rapid litho, flexo and gravure printing. Semiconducting and dielectric inks are being developed by Merck (www.merck.com) and others, and some of these will be suitable for high-speed printing of replacements for the silicon chip in labels and packaging within 10 years. Indeed, 60 organizations are developing printed transistor circuits. The printed alternatives are cheaper, more damage-tolerant and thinner. Packaging companies Dai Nippon Printing (www.dnp.co.jp) and Mreal (www.m-real.com) are among those developing printed electronics for packaging.

Figure 1

Marketing, patient and professional advantages

When two equally efficacious drugs enter the market, the one with better compliance is likely to be more widely used. Noncompliance is costly and risky. In the US, it:

• Costs $100 billion and 125000 deaths annually.

• Is responsible for 10% of hospital admissions (at an annual cost of $31 billion/380000 patients).

• Is responsible for 23% of nursing home admissions ($15 billion/3.5 million patients).

• Costs the drug industry over $8 billion annually in unfilled new and refill prescriptions (source: The National Institutes of Health [NIH]).

Unnecessary suffering and depressed sales of drugs

Patients are often confused about the reasons for being prescribed the medication. After all, they spend an average of only 6 min when meeting their physician. Many patients also question whether their treatment is necessary. They fail to get refills where prescribed, and 28% of over 45 year olds admit to discontinuing the prescribed medication prematurely — antidepressants are particularly bad in this respect.

Drug companies have come to realize that spending heavily on creating new blockbuster drugs is risky and less cost-effective, whereas encouraging patients to take medication correctly benefits the patient, reduces the workload on physicians and hospitals, and sells more of existing, noncontentious drugs.

Reducing false data, benefiting patients

The smart blister pack and plastic bottle reduce the amount of false data recorded in drug trials. Eventually, such packs will appear in the home — probably enhanced by self-adjusting electronic use-by dates (you overheated it for so long, therefore, dispose of it at this earlier date) and electronic monitoring of degradation in storage and transport.

Compliance monitoring packages roll out

Drug packages that record when a given tablet was removed (and presumably taken) are at last receiving serious attention. The packages are starting to be used for two purposes — establishing compliance levels for existing drugs and improving the quality of information from trials of new drugs. In 2006, during a 6-month trial in 12 academic institutes, NIH tested the antibiotic Azithromycin using 30000 smart packages that recorded which tablet was taken and when. We estimate that these smart packages were sold for around $20 each to the trial operator.

Fischer Clinical Services (www.fischerclinicalservices.com) performed the trial using smart blister packs from Information Mediary (http://informationmediary.com).

Additionally, Novartis (www.novartis.com) has performed a drug trial, in this case using smart blister packs from Cypak (www.cypak.se), a company that uses packager MeadWestvaco (www.meadwestvaco.com) for some of its marketing. This first trial involved 200 patients and 20 pharmacies, and lasted for 3 months.

Novartis drug trial

In September 2006, Novartis commenced a second clinical trial with compliance monitoring packaging on its high blood pressure medication, Diovan 160, and will last for at least 12 months. Novartis is conducting this second trial to maintain and improve compliance on a wider scale than the first. The European Communications Consultancy Team (www.ecct.com) is conducting the trial. Based in The Netherlands, it designs medical consumer electronic devices.

Figure 2

Ten thousand patients and 200 pharmacies in The Netherlands are involved in the project. There are an additional 400 pharmacies on the waiting list that ECCT expect to join once the trial has started. Dr Willem Kort, co-director of ECCT, reports that pharmacies in other European countries will also participate. "Pharmacies in Austria, France and Germany will join the project. We presented to the Ministry of Health in Austria and it reacted favourably. The Ministries of Health in France and Germany will follow quickly, and take the initiative with the technology," revealed Kort.

Patients with compliance issues were nominated by their doctors for the trial. Those volunteering to improve their compliance, or get more guidance on how to take their medication, are also taking part. ECCT expects the Ministry of Health in Finland to also take the technology on now it has the chair of the European Commission.

Although the first Novartis compliance trial, which ended in May 2006, used Cypak's Intelligent Pharmaceutical Packaging (IPP), Kort said that Cypak's technology will probably not be used in this trial. However, Cypak is still co-operating with the project, as is NXP (www.nxp.com).

ECCT is developing its own RFID blister pack system for compliance packaging, which will be launched soon. It can be applied to existing blister packs, saving cost. Meanwhile, it is also in talks with several intermediate technology companies to conduct the clinical trial. For example, the Information Mediary smart blister pack currently used in US drug trials may be a candidate, and Bang and Olufsen Medicom (www.medicom.bang-olufsen.com) in Denmark is also developing suitable products.

Widespread benefits

The improved compliance benefits through smart packaging include:

• Assisting the medical provider by explaining the optimal prescribed regimen.

• Enrolling the patient as a participant in their own therapy.

• Simplifying medication administration for the patient.

• Providing interaction and prompting, reinforcement and cueing.

• Creating a permanent and continuous intervention that demands little involvement from the physician or pharmacist.

• Supporting the brand message.

• Building efficacy and integrity.

• Reducing medication errors.

• Reducing the development of antibiotic-resistant bacteria.

Anticounterfeiting

The World Health Organization (WHO) estimates that counterfeit drugs annually cost the pharmaceutical industry $40 billion. The Centre for Medicines in the Public Interest projects global counterfeit drug sales to reach $75 billion in 2010 — a 92% increase on 2005. Drug counterfeits average 6–10% worldwide, according to WHO and the UN, and "Up to 15% in the global medicines supply chain" according to 2005 analysis by PloS Medicine. Russia, Africa and South America are significant markets for counterfeit medicines and more than 100000 people die from counterfeit drugs every year in China alone according to some reports.

At the Rome (Italy) WHO meeting in February 2006, Nils Behrndt of the European Commission noted that 27 incidents of counterfeit drugs in the EU legitimate supply chain were identified between 2001 and 2005. Alexander Vladychenko, director general of social cohesion of the Council of Europe, noting the increasing sophistication of drug counterfeits said: "Counterfeit drugs are on the verge of becoming a silent pandemic."

Key points

To combat this, RFID on each small package, with unique identification of that precise package ("mass serialization" under EPC global numbering and network), permits reverse audit, called "pedigree" by the pharmaceutical industry. Pedigree, combined with sophisticated software, ensures the origin and destination of even the smallest package is known at all times.

FDA was expected to legislate on this within the next year or so when certain aspects are resolved, such as the best frequency to use. However, it has recently softened its stand, and is now unlikely to force through the necessary standards. Meanwhile, Pfizer (www.pfizer.com) is RFID tagging, at item level, all Viagra for the US; GlaxoSmithKline (www.gsk.com) is tagging Trizivir, and AstraZeneca (www.astrazeneca.com) and others are following. They use high frequency (HF [13.56 MHz]) RFID because they get a guaranteed 99.95% read rate and no ghost reads. It is the most proven RFID frequency with over one billion of these tags in operation. Cardinal Health (www.cardinal.com), TAGSYS (www.tagsysrfid.com) and others have developed smart shelves in cabinets, refrigerators and trolleys that can read these HF tags for error prevention, automatic reordering and theft prevention.

In addition, by the end of 2006, Wal-Mart (www.walmart.com) had taken delivery of over four million tagged drugs at item level for improving automation of stocktaking, customer service and theft prevention in its pharmacies. Company policy is to use ultra high frequency (UHF [in the US 915 MHz]) exclusively. However, Wal-Mart and the leading suppliers of UHF labels no longer recommend the so-called 'far field' versions, but support 'near field' UHF for items because it is just as insensitive to water and metal as HF (unlike far field UHF), but may give a lower cost label than HF.

However, there are disadvantages. Near field UHF is unproven in mass production for these environments, and radio regulations will never allow it to be one frequency, bandwidth, signaling protocol or even power level, worldwide. In many countries, mobile phones and the military got there first and will not free up the same bands, although it is at least becoming legal in more areas and sometimes the permitted RFID power level is being increased.

Unique identity with 2D barcodes

Machine-readable unique identity can be provided by 2D barcodes, such as DataMatrix, or by RFID. In the US, the work mainly involved RFID because FDA and its members originally felt that this gives the most accurate and rapid result. There is some linkage with 2D barcodes, when the blister pack is barcoded to save cost and the blister pack is RFID tagged. Sixty companies are considering how to print electronic circuits, such as RFID, directly on to products and packaging in the way that 85% of barcodes are applied today — therefore, replacing the silicon chip; but this will take many years before full production.

Summary

RFIDcompliance monitoring is increasingly used in drug trials, and it may be generally mandated to improve data integrity. Later, it will appear in the home. Drug counterfeiting imperillizes public safety and strikes at the heart of the industry. RFID is one of the best defences, enabling checks to be automated and frequent, but 2D barcodes are more affordable in the short term, which FDA accepts. There needs to be a decision on RFID frequency and further clarification on what is in the secure database and who has access through the value chain. Sadly, these standards are unlikely from FDA in the near term. This is in contrast to the International Air Transit Association taking a lead with RFID baggage tagging — another security application.

In 2005, the European Federation of Pharmaceutical Industries and Associations declared RFID to be too expensive for item-level drug anticounterfeiting until at least 2010. It advocated mass serialization on 2D barcodes in the meantime.³ As there is no single equivalent of FDA in Europe, it remains to be seen whether the various European regulatory authorities will take a stronger view on RFID technology to prevent counterfeit drugs. Fully printed RFID with no silicon chip will get the price down.

Further reading

1. www.idtechex.com

2. www.printelec.com

3. www.efpia.org

Peter Harrop is chairman of IDTechEx, an consultancy, publisher and conference organizer specializing in printed electronics, smart packaging and RFID. He was chief executive of Mars Electronics and has been chairman of 15 high-tech companies over the years. He travels widely, assisting the world's largest electronics, printing and packaging companies, lecturing and writing on these subjects.