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International Clinical Trials

Late Riser

David Selkirk of Omnicare Clinical Research goes in search of growing global opportunities in late phase research

In 2009, late phase research was the only sector of the clinical research industry that grew amid a sea of shrinking budgets (1). With the landscape of healthcare currently in a state of significant flux, late phase research is set to become a truly global phenomenon and outsourcing of these studies is on the rise (2). There is a misconception that peri- and post-approval investigations are simple in design and execution, and that their foundation in marketing detracts from their potential benefit to society (3). In fact, the field is incredibly diverse with the science under investigation being very rigorous, and their benefit to society has been clearly documented (4). A customised approach is needed to ensure success, with careful consideration as to how the data will be used. With detailed planning and diligent execution, late phase research can be a boon to the pharmaceutical, biotechnology and medical device/diagnostic industries.


With the healthcare reforms currently ongoing in the US, it seems probable that there will be at least a minimum amount of medical coverage for the US population at large (2). In such a scenario, there will be enormous competition for sponsor companies to have their products listed on the drug formularies of thirdparty payers. From the perspective of the payers, they want to list the least expensive formulations of established therapies wherever possible. International market pressures are similar; however, it is generally the government paying for the healthcare therapies instead of the insurance companies. Regardless of the financial sources available for covering healthcare costs, there is a desire to pay for only those therapies that offer a clear benefit to the patient, and minimise the impact on society (for example caregivers at home, psychological support, decreased productivity at work and so on). As a result, any given therapy or drug will need to demonstrate a clear advantage to the patient for it to be listed on a third-party payer formulary. Figure 1 demonstrates how market pressures will come to bear in this arena.

The traditional realm of the multinational pharmaceutical companies is in small molecules. With such large revenuegenerating products losing patent protection over the next few years, generic companies will launch low-cost versions of the top selling international brands. Given a broader array of similar therapeutic choices, health outcome measures will be a critical tool to distinguish amongst the options (5). A product will be more readily reimbursed if it provides a clear benefit for quality of life and/or a significant advantage to the healthcare system. Outside of the current social systems that bolster various therapeutic products, there is also a large patient population with significant financial means. This group will place pressure on healthcare workers to make the best decision for them as individual patients. In turn, the healthcare workers making the prescription decisions will rely on peer-reviewed health outcome publications that outline the practical benefits of various therapies. Figure 2 outlines the trend (past and present) in the amount of money spent in research and development in the healthcare industry.


There was a strong and growing level of investment in healthcare research throughout the initial years of this millennium. The global financial crisis of 2008 put a stop to that trend and resulted in a significant decrease in healthcare research growth. The situation further soured in 2009 with zero growth for that year. Despite these troubling figures, late phase research managed to rise over this same period. Approximately, $12 billion was spent on late phase research globally in 2007, with projected growth of 20 per cent annually (6). With the rate of outsourcing of late phase trials on the rise, the investment in this sector is outpacing early phase and pivotal trials (7). Figure 3 shows how significant that outsourced clinical trial market is. With so many billions of dollars at play, there can be no mistake that sponsor organisations want to make strategic investments to optimise the life cycle of their products.


Once therapies are on the market, the reporting of adverse drug reactions (ADRs) from standard patient use is dependent upon patients and busy healthcare workers. As a result, it is widely believed that the number of post-launch ADRs is significantly under-reported (8). The Food and Drug Administration Amendments Act (FDAAA), as well as the FDA’s Risk Evaluation and Mitigation Strategies (REMS) initiative, will continue to significantly impact late phase research and logistics (9,10). Internationally, there are also requirements for significant post-marketing pharmacovigilance across the EU (11). In general, safety surveillance responsibilities and expectations are increasing and will ensure that patients in the general public are watched more closely than ever before. When late phase trials are undertaken, adverse events are generally proactively solicited from patients and thus systematically collected for analysis. This heightened post-marketing surveillance helps to keep the safety profile of marketed therapies as current as possible.

Via both FDAAA and REMS, the FDA now has more resources and authority for more comprehensive NDA reviews (12). Sponsor companies that are required to implement REMS must often invest in medication guides and communication plans for both patients and healthcare workers. There can also be limitations on which physicians and/or pharmacists are permitted to prescribe and dispense medications. The logistics of distribution and access can be affected significantly as well. Figure 4 shows the components of all REMS approved to date by the FDA. Please note that multiple components can be required for any given REMS.

With so much effort going into ensuring that patients have all the product information they could possibly need, budgeting considerations come into play. Moreover, if the cost of a REMS is significant, the price point for product launch can be affected. Consequently, sponsor companies will be reviewing their early phase data with great scrutiny, keeping in mind the requirements that could be imposed further down the road. Smart companies will build a REMS as an inherent part of their late phase development programme. In fact, if a REMS is strategically implemented, it can be a significant opportunity for a sponsor to communicate its message to the public at large. Sponsors must embrace this new reality and learn to use it to the advantage of both patients and their shareholders.


Despite the establishment of a product’s efficacy and safety in Phase I, II and III clinical trials, challenges may remain relating to patient access to the therapy, or to the appropriate use of the therapy by medical practitioners. Late phase studies, such as compassionate use trials and registries, can be effective means to ensure patient access to what might otherwise be costly therapies. The same is true for formulations which are more complex to handle. Any misconceptions within the medical community about a product’s use or place in therapeutic practice can be clarified in a Phase IV trial. Such an investigation can also help to properly align prescription patterns and reinforce proper administration among patients. Increased product awareness by healthcare professionals, coupled with improved patient compliance with therapy, will result in better health outcomes. This scenario is also conducive to a more successful product brand.

Of course, the ultimate consumer (the patient) must want to use the medication and must be able to afford it. Access to information increases exponentially year on year, and patients will increasingly demand more value for their money. Consequently, it is important that sponsors establish that their products provide a unique benefit to patients. From the perspective of efficacy and safety, the degree of distinction between products is often quite minor (13). As a result, the distinction between two competing therapies is increasingly being demonstrated through health outcomes. Examples include epidemiological trials, pharmacoeconomics, time in motion measurements and patient reported outcomes, such as quality of life assessments. Research in these disciplines can demonstrate that there is a cost advantage to the healthcare system, and/or that patients are able to live more productive, fulfilling and happier lives by using one product over another.

Operating within the modern international healthcare system, today’s sponsor organisations clearly understand the importance of late phase research. Their principal challenge is to produce a good design for these investigations, and to conduct them efficiently. When evaluating how best to carry out a late phase investigation, the old adage of ‘start with the end in mind’ is eminently germane. The methodology employed must match the intended use of the data produced. As a general rule, sponsors must remember that simpler designs will often work best. Established healthcare organisations often have large clinical research departments that are accustomed to conducting complex global studies. In late phase trials, the best return on investment comes from a tight focus on the endpoints being measured. Sponsors must avoid the early/mid phase ‘trap’ of collecting large amounts of potentially superfluous data as both costs and time will needlessly increase. Figure 5 shows how advantageous that tailored approach can be.

Lastly, when measuring health outcomes such as pharmacoeconomics, health-related quality of life, employment status, social and family relationships, and so on, the appropriate model (sometimes a disease-specific paradigm) is not always available (14). If a sponsor needs to proactively build the model, much time and money will be required up front.


Investigations such as compassionate use programmes, investigator-initiated trials and health outcomes and so on often incorporate questionnaires collecting quality of life measurements and patient diary data (15). These patient-reported outcomes are not generally subject to strict data reconciliation, as the source of the information is the patient directly, rather than the healthcare practitioner. Consequently, data collection and analysis systems for late phase trials must be tailored to this setting. Equally important is the experience of the group handling the data collection, reconciliation and analysis. If a traditional pivotal trial methodology is employed, there will be a tendency to squander much time and money. The true test of how well positioned the data management and statistics groups are to handle late phase data is found in the data management plan and the statistical analysis plan (16). There must be documentation for how missing and incomplete data will be handled efficiently, while ensuring the validity of the study’s endpoints.

As with all clinical trials, patient recruitment is typically a challenge. Careful consideration must be given to the type of medical facility that patients will be treated in – that is, walk-in clinics, family practitioners, hospital emergency departments, and so on. The plan to attract and retain patients needs to be highly specialised to the setting and the type of data to be collected. With late phase trials, the duration of the study can often span multiple years. Patient and site retention plans are extremely important in this setting. Additionally, it is important to plan for the evolution of both sponsor and service provider staff working on the trial. In the modern workforce, it is common for staff to be promoted and/or change positions as time passes over several years. It is worthwhile to ensure that there is a system in place to capture the best practices learnt by earlier generations of study staff. There must also be an interface medium so that the lessons learnt can be easily transferred to the incoming tiers of clinical research professionals.

The established healthcare companies of the world will be increasingly selective about the vendor with whom they partner for late phase research. Preferred providers must be able to provide not only customised late phase study operations, but the full-service pre-marketing services (namely specialty pharmacy, commercialisation, patient access programmes, REMS and so on) needed by a sponsor to optimise the life cycle of its products.

The growth of speciality pharmacies has created a new opportunity for sponsor companies to help patients obtain their products. Not only can these groups bridge the gap of patient access for costly medications, they can also be an excellent source of information on where the ‘holes’ are in a product’s function. There are many more vendor and systems options available for managing and analysing post-marketing surveillance data. The companies which capitalise on these developments to build targeted post-marketing research programmes around the world will garner significant dividends in product sales.


Late phase research is like a locomotive building speed; it has shown itself to be recession-proof, and it brings great value to patients, healthcare workers and sponsors alike. Not only does this sector of clinical research address the global regulatory move toward increased post-marketing surveillance, but it also provides practical information to evaluate which products are optimal for society in general. Sponsors must partner wisely with service providers that can deliver a customised late phase approach as well as flexibility of systems and procedures. With a win-win scenario, all stake-holders are sure to seize the opportunity offered by late phase research, and this sector will undoubtedly grow by leaps and bounds.


1. Windley D, Evans TC and Hilgenbrink A, Let’s talk about R&D, baby? Jefferies & Company, Inc, 22 Jan 2010

2. Bergner A, US health care reform, Mercer,, May 2009

3. Pratt T, The value of post marketing studies, PharmaVOICE, PharmaVoice_PostMarketStudies.pdf, April 2006

4. Chamnan P, Simmons RK, Khaw KT, Wareham NJ and Griffin SJ, Estimating the population impact of screening strategies for identifying and treating people at high risk of cardiovascular disease: modelling study, BMJ 340: c1376, April 2010

5. Szucs TD, Health economics in the genomic age: Recent Results, Cancer Res 166: pp299-313, 2005

6. Levaux HP and Janowitz G, Late phase studies benefit from EDC, Applied Clinical Trials Online, appliedclinicaltrials/Feature+Article/Late-Phase-Studies- Benefit-from-EDC/ArticleStandard/Article/detail/ 500440, 2008

7. Hart SL and Okamoto LJ, Outsourcing Phase IV, Late-stage research is one of the fastest-growing areas in outsourcing, here’s how to get the results you need from your post marketing studies, Inside Outsourcing, iv.pdf, 2007

8. Gony M, Badie K, Sommet A, Jacquot J, Baudrin D, Gauthier P, Montastruc JL and Bagheri H, Improving adverse drug reaction reporting in hospitals: results of the French pharmacovigilance in Midi-Pyrénées region (PharmacoMIP) network two-year pilot study, Drug Saf 1; 33(5): pp409-416, May 2010

9. Guidance for sponsors, industry, researchers, investigators, and food and drug administration staff, Certifications To Accompany Drug, Biological Product, and Device Applications/Submissions: Compliance with Section 402(j) of The Public Health Service Act, Added By Title VIII of The Food and Drug Administration Amendments Act of 2007, 0224-GDL.pdf, 2009

10. Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications, RegulatoryInformation/Guidances/UCM184128.pdf, 2009

11. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medical Products for Human Use, enterprise/sectors/pharmaceuticals/files/eudralex/vol- 9/pdf/vol9a_09-2008_en.pdf, 2008

12. Shane R, Risk evaluation and mitigation strategies: impact on patients, health care providers, and health systems, Am J Health Syst Pharm 15; 66 (24 Suppl 7): ppS6-S12, 2009

13. Seruga B, Hertz PC, Wang L, Booth CM, Cescon DW, Krzyzanowska M and Tannock IF, Absolute benefits of medical therapies in phase III clinical trials for breast and colorectal cancer, Ann Oncol, [Epub ahead of print], Nov 2009

14. Miller D, Rudick RA and Hutchinson M, Patient-centered outcomes: translating clinical efficacy into benefits on healthrelated quality of life, Neurolog 27;74 Suppl 3: ppS24-35, Apr 2010

15. Reay N, How to measure patient experience and outcomes to demonstrate quality in care, Nursing Times 106(7): pp12-14, 23 Feb-1 Mar 2010

16. Ramsey S, Willke R, Briggs A, Brown R, Buxton M, Chawla A, Cook J, Glick H, Liljas B, Petitti D and Reed S, Good research practices for cost-effectiveness analysis alongside clinical trials: the ISPOR RCT-CEA Task Force report, Value Health 8(5): pp521-533, 2005

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David Selkirk is Vice President, Late Phase Research, for Omnicare Clinical Research, a global Phase I to IV clinical research organisation. With nearly 20 years of experience in the clinical research industry, David has been involved with numerous late phase trials in the US, Canada, Europe, Latin America and Asia. He has conducted an array of late phase trials, including observational studies, registries, surveys, chart pulls, expanded access programs, health outcomes, pharmacoeconomics and safety surveillance. David obtained a BS (Hons) in Biology from the University of Western Ontario, Canada.
David Selkirk
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