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International Clinical Trials

Mightier than the PDA

Researchers are discovering the benefi ts to the post-marketing world of data accessed in realtime, report Subash Sadanandan at Greens Datamatica and Ken Ashman at Pharmanet i3

At a time when much of the business world is in the midst of a global economic crisis, doing more with less is a harsh reality we are increasingly faced with. With the additional pressures facing the drug development world such as the much talked about ‘patent cliff’, with annual sales of more then $140 billion being lost in the next four to fi ve years, and the lack of new potential blockbusters – we are all looking for more efficient ways to complete studies (1). The Tufts Centre for the Study of Drug Development agrees with the feeling of crisis in the pharmaceutical industry, specifically pharma companies needing to develop new drugs more quickly, while reducing expenses. Tufts place the value of developing a new drug at about $1.3 billion as compared to previously quoted fi gures of approximately $800 million (2,3). Without doubt, the drug development process continues to increase in complexity and cost, and there is little indication that this trend will abate. The increase in development costs can be partly attributed to the increasingly complex clinical trials and the subsequent lengthening of trial timelines to accommodate this additional complexity. For example, between 2000 and 2007 the median number of procedures per clinical trial increased by 49 per cent and the total time taken between protocol design and database lock rose by 70 per cent, from 460 to 780 days (4,5). These are just a few reasons why clinical trial budgets continue to increase and effective cost containment will continue to be sought by those individuals responsible for R&D expenditure.

Given the current gloomy economic outlook and ever increasing costs, professionals involved in clinical trials are looking for alternative ways to manage the burgeoning costs and resources associated with the drug development process. Following tried and tested management processes from other industries seems to be a safe route for the pharmaceutical world. Strategic functional outsourcing and functional partnerships, with wholesale outsourcing of functions, services and clinical programmes, have been much publicised as effective cost management strategies that can be adopted between the drug developers (pharma/ biotech companies) and the service providers (CROs). These functional outsourcing strategies seek to reduce costs and timelines by specialisation and division of labour, similar to Taylor and Ford’s practices in the earlier part of last century (6). CROs are generally considered to be more effective at conducting clinical trials, while the pharmaceutical organisations focus on the actual science revolving around the drug discovery and refi nement processes. However, operational costs will continue to increase within the CROs as they continue their global expansion and meet shareholder expectations on annual growth earnings. These costs will ultimately be passed on in the chain of supply and consumption, and therefore CROs and pharmaceutical sponsors must look at alternative methods of cost containment in order to ‘do more with less’.

Successful partnerships develop close collaboration across their clinical trial teams, and are extremely efficient at collecting and managing the myriad of information generated by the clinical trial process. This enables the effective and timely decision making that is critical to clinical trial conduct, and provides ample opportunity to review study design (strategy), study conduct (operational delivery) and drug evaluation (performance qualification). Effective and timely information management enables both the strategy and operational delivery to be tracked and evaluated across the entire trial process. Indeed, adaptive trial management relies on the basis of timely and relevant information in order to adapt and re-align the trial design (strategic adaptation) and operational parameters (operational adaptation) (7). Focusing on choosing the appropriate solutions for trial data collection is a vital and integral strategic component of clinical trial conduct and cost management.

DATA CAPTURE MEDIUM

Traditionally, life science companies have used paper based case report forms (CRFs) as the original source data collection medium, with subsequent data processing to enter and validate trial information within a data management system. Over the last decade or so, electronic data capture (EDC) solutions have become increasingly popular, where trial information is entered directly into a data management system via electronic CRFs on PC/PDA screens.

Where appropriate, a hybrid combination of both paper and EDC has been used as part of the data collection process.

Both modes of data collection have advantages and disadvantages associated with them. Paper-based solutions typically entail a lag phase for collection by study monitors prior to data entry, and generally require more data query cycles and time for data validation. EDC solutions tend to provide information quickly, and are more efficient in reducing post processing query rates due to direct data entry being performed at site, and are often thought to be more complex and expensive per trial than paper due to the software licensing and overall adoption costs associated with them. In truth, paper and EDC data collection modes will co-exist as media for data collection. A solution that is as simple and intuitive as pen and paper data completion (either by investigator or patient) requires little training and little infrastructure, combined with all the advantages of EDC data processing (by CRO and sponsor) is considered the ideal solution for trial management, merging the best of both media, while reducing overall costs. Digital pen and paper (DPP) technology addresses this gap, developed and licensed by Anoto AB, as a solution to capture and database written data electronically during paper forms completion via the use of digital pens.

As detailed in Table 1, DPP technology merges the advantages of both paper CRF and EDC completion. This unique ability has seen the adoption and usage of the DPP technology increase significantly within the clinical environment.

DPP DATA FLOW

DPP technology enables traditional forms completion via the use of a digital pen encompassing an infra-red camera, a built-in clock and Bluetooth communication stack. The digital pen essentially records the writing strokes as a paper form overprinted with Anoto’s unique dot pattern is completed. The data is then sent electronically via either Bluetooth enabled mobile phones or via PCs connected to the internet. This encrypted data-packet is recoded via a secure server and presented as an exact image copy (PDF, PNG, JPEG formats) of the completed form. Additionally, the data is automatically extracted, and data-based, appropriate validation checks and logic rules can be run against the data – much like EDC – and anomalies are automatically highlighted ready for verification and querying.

DPP technology is able to combine the best of the traditional paper and EDC worlds. Investigators, patients, CROs and pharmaceutical companies appreciate the simplicity of the form completion process, the flexibility in data handling, the advanced audit trailing capabilities, and the cost-effectiveness the solution offers. The investigator can focus entirely on the patient while data collection occurs without the need to navigate through multiple eCRF screens via third party EDC systems. The DPP solution requires little training; indeed, if you can use a standard pen then you can use the technology, it really is that simple. A study by Cole et al compared different electronic devices for clinical data trial collection and concluded that the DPP was simple to use and proved to be more accurate and faster then paper-based data cleaning and reviewing (8). Patients too, can complete quality of life questionnaires and patient diary forms at home, and data compliance can be validated by the real-time clock built into the pen, negating the need for expensive PDA-based diary solutions. CROs and sponsors have trial data captured rapidly in real-time or close to real-time, based upon the trial requirements and design, for subsequent validation and analysis. Immediate, fast access to global trial data, including access to electronic images of the actual CRF pages, provides ample opportunity for data quality checks across the range of trial parameters. Patient data, site data, enrolling rates and quality conformance of data items (query rates and so on) are available for central review throughout the trial, irrespective of site or patient location, thus enabling tighter control, management and informed decision making.

From a CRO’s perspective, the flexibility of the DPP solution provides ample opportunity for tighter trial management by providing absolute data transparency and greater reporting metrics with extremely accurate audit trailing across the range of trial parameters. Access to electronic CRF and patient data and subsequent project reports with appropriate drill down capabilities also provides scope to substantially reduce the number of site visits from a monitoring perspective for data reviews. In turn, sponsors too are satisfied as they have access to real-time reports on trial management, are able to conform to the protocol, while making substantial time and cost savings from a streamlined clinical trial. With rapid access to data, as much as four weeks can be saved across each decision cycle; in early phase trials this can translate to a reduction of 50 per cent or more in trial timelines (10).

Unlike EDC, original source data is maintained via the physical paper forms which are usually archived, as electronic images of the paper forms are available and stored for reference within the secure trial portal. Similarly to many of the leading EDC solutions, the DPP system is capable of exporting data in a variety of formats, from simple CSV, flat ASCII and XML. As expected, the data output is formatted in the CDISC-compliant format, ensuring standardised data exchange across a variety of different systems and companies. According to research by Gartner, standardising on CDISC provides the greatest opportunity for clinical study performance and processes improvements per trial, saving an estimated eight months in study startup, conduct, analysis and reporting, and with an associated $9 million cost saving (3). Given this magnitude of savings, standardising on CDISC-compliant solutions for data interchange across entire clinical programmes offers scope for greater process efficiencies, along with time and cost savings.

REAL WORLD USAGE

There is an increasing trend towards observational research to provide real world data. This is in part due to requests from regulatory agencies (EMA and FDA) and the national bodies responsible for reimbursing new pharmaceuticals and devices (insurance companies in the US or NICE in the UK), to provide evidence of how they perform in the real world, but is also being driven by the pharmaceutical companies gaining a greater understanding of the value of this real world data. Right up until a new drug/device is launched onto the market, it has been tested in controlled studies within strict protocols and under extremely close scrutiny. However good the data leading up to the approval of a new entity is, we never know how it will perform in the real world with almost infinite possibilities for variation in age, concomitant medication, gender, ethnicity and severity of illness. We are all aware of high profile withdrawals of pharmaceutical compounds from the market in recent years, where previously unobserved effects have become apparent. So it is critical to continue to provide high quality data within real world, post-marketing studies to ensure patient safety and cost effectiveness.

Whether this data is required to provide more evidence of safety, comparative effectiveness or quality of life, these studies must be operationalised in as observational a method as possible to maintain the naturalistic approach. Minimising the Hawthorne effect (the effect of a patient changing their behaviour simply by being observed) is critical to ensuring high quality data (11). Such studies should, therefore, be designed to watch over the shoulder of the physician and patient, rather than dictate their actions. Appropriate application of technology provides the pharmaceutical industry and CROs with the opportunity to do so and to achieve cost-effectiveness at the same time. It should be noted that each observational study has an almost unique set of requirements it needs to fulfil in answering the particular question. Each study should be designed and operationalised to suit the answering of that question, and there will be many technological solutions, the most appropriate of which should be selected for any given scenario. Within this context the DPP and its ability to store large amounts of data and upload this information at appropriate intervals to suit the patient and physician schedules, enables the patients to return to their physicians in a much more naturalistic way. On the other hand, the traditional, more interventional designs around more traditionally deployed technology require regular weekly, bi-weekly or monthly visits. This more rigid trial design brings an increased need to monitor the data and the sites. With the more observational approach, patients may be seen by physicians when required and the schedule could be more quarterly or every six or twelve months. Along with this reduced frequency of patient visits comes a reduced burden on the site, a reduced need to visit the site to monitor them and a reduction in overall trial costs.

This type of approach (naturalistic design with no scheduled patient visits) has always been possible with paper base diary cards, but the reliability of this data has always been questionable (12). Traditional handheld devices to collect data are relatively common in pivotal Phase 3 studies, where budgets are significantly greater than post marketing studies. So, to be able to deploy a relatively inexpensive device to capture data in the patient’s home or workplace and have that data reliably time stamped provides the post marketing research world with an innovative, efficient and fl exible tool that should always be considered within the armamentarium of CROs and pharmaceutical companies.

The following serves as a tangible example of how more observational studies can benefit directly from deploying DPP as opposed to a more traditional approach. In a recent diary study to assess patient improvement, while on one specific new medication as compared to standard of care, DPP was initially assessed in relation to the budget required to complete the study versus the traditional approach. The study budget was 39 per cent lower for DPP, which is a significant reduction, while maintaining a high level of data integrity and quality. Within this particular study, data from the pen would be collected when the patient returned to the site. However, a mobile phone could be provided to synchronise captured data with the database in real time. The latter would also provide a method to check on individual progress by the patient and allow for the site to contact them if diary completion was slipping behind, thus mimicking the benefits of EDC completion at scheduled visits or completion via handheld device. In this particular example the CRF pages required to be completed by the site were also designed within the DPP system itself, reducing the need for a separate database and thereby generating additional savings. Within this specific example, the investigator completes the initial CRF pages with the digital pen, and then attaches it to a spiral bound diary booklet containing the first few months’ worth of daily/ weekly diary pages. The patient would then take away the booklet, returning it and the pen at the final/follow-up visit, for the site to complete the closing visit CRF pages using the same digital pen. The pen could then be re-used for subsequent patients at that site.

CONCLUSION

The flexibility of DPP technology to reach out to patients and allow researchers to capture real world data in real time should provide significant advantages to the post-marketing world. The fact that it unifies the advantages of simple paper CRF completion and sophisticated EDC usage, while providing significant cost reductions, should see its adoption across a much wider range of studies over the coming years.

References

  1. Drug Discovery and Development, Pharma Outlook, Jan 2010
  2. Tufts CSDD, Drug developers are aggressively changing the way they do R&D, Jan 2011
  3. The costs of clinical trials, Drug Discovery & Development, 1 March 2007
  4. Tufts CSDD, Drug Developers actively improving efficiency of clinical trials, April 2011
  5. Tufts CSDD, Capacity planning is becoming a critical success factor for drug developers, Jan 2010
  6. Taylor FW, The Principles of Scientific Management, 1911
  7. Clinical Trials Handbook, Wiley & Sons, 2009
  8. Cole et al, A comparative study of mobile electronic data entry systems for clinical trials data collection, International Journal of Medical Informatics, 2005
  9. Raineri M, Anoto Functionality Conference 2007 1
  10. Rosenberg M, Combining agile design and operations white paper, Health Decisions, 2009
  11. Landsberger HA, Hawthorne Revisited, Ithaca, 1958 1
  12. Arnea V, Pharmaceutical Executive, March 2009

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Subash Sadanandan is Managing Director for Greens Datamatica and has worked in the pharmaceutical, CRO and clinical software development industries for over 24 years. He started his career as a research scientist and has in-depth expertise spanning all phases of clinical development. Subash has multi-industry experience in the development and implementation of clinical trials management solutions and EDC systems. He has held senior leadership positions for a number of global CRO and EDC organisations prior to joining Greens Datamatica, a company focusing on innovative digital pen solutions for the life sciences industry. Email: subashs@data-matica.com

Ken Ashman is Executive Director, Phase 4 Operations for Pharmanet i3. He has been in the drug development industry for just over 25 years from preclinical research right through Phase 1, 2 and 3 to his current position leading the Phase 4 group for Pharmanet i3 in Europe. With extensive experience in all stages of clinical study operations, a broad range of therapeutic expertise and considerable recent expertise in post-approval research, Ken leverages the Phase 4 team’s technical capabilities in safety and risk management, interventional and observational studies, and economic analysis for pharmaceutical, biotech and medical device clients in Europe. Email: kashman@pharmanet.com

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