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Effective ways for sponsors to reduce risk when embarking on comparative clinical trials.
As a population, we have greater access to information than ever before. Couple this with challenging economic times and the result is an environment in which things are no longer accepted at face value. This trend is impacting all industries, including drug development.
(PHOTOGRAPHY: GETTY IMAGES ILLUSTRATION: PAUL A. BELCI)
Given this climate, intensified interest in comparative trials should come as no surprise.1,2,3 Economists, insurers, health care professionals, and the public seek more compelling evidence on how drugs compare in safety, efficacy, and cost. At the same time, governments around the world are promoting the use of comparative effectiveness trials in an attempt to control the inflation of health care costs and provide additional information in support of the approval process (see sidebar).
The State of Comparative Effectiveness
Investment in these trials is expected to increase as companies seek to better demonstrate the value of new therapies and make the case for inclusion in hospital and government formularies and reimbursement under insurance coverage.
Comparative effectiveness studies for new drugs, however, are not yet commonplace. Most often, clinical trials compare investigational drugs to placebos rather than subjecting the drugs to rigorous evaluation against existing treatments. While comparison against a placebo is generally required by regulatory authorities, trials must also include an active comparator when a pharmaceutical company seeks to claim superiority versus the competitor drug in its marketing materials; or an active comparator may be the only control agent in cases where giving trial participants a placebo would not be ethical.
As pressure mounts to conduct comparative effectiveness trials, pharma companies must put in place robust strategies to first select a comparator drug and then source and supply that drug in an uninterrupted manner to all trial sites.
Sourcing and supplying comparator drugs for global clinical trials presents a number of obstacles and potential pitfalls for the trial sponsor.
The inability to obtain the necessary pedigree and product documentation for the comparator, lack of supply chain security with possible introduction of counterfeit comparators, and delays in resupply throughout the course of the trial are some of the problems that can lead to significant operational, regulatory, and financial setbacks for the trial sponsor. As such, drug developers must have a comprehensive view of what is involved in the process and formulate a customized, strategic approach to best support their trials.
To minimize the risk of delayed or interrupted clinical trials and the financial implications that can result, a comparator sourcing and supply strategy should include a number of elements. These include demand planning that can accommodate changes in the quantity of comparator drug needed in light of fluctuating patient enrollment or unexpected changes to a trial; changes in regulatory opinion, or temporary or permanent regulatory noncompliance by the source manufacturer; loss of the project's consulting global regulatory expertise; changes in global sourcing capabilities and logistics; and loss of connection to the comparator manufacturer via a sourcing specialist.
Exposure to operational, regulatory, and financial risks can increase if comparator sourcing is considered a series of transactional events (e.g., buying a comparator from a wholesaler as needed) rather than a process requiring a well thought-out strategy. In situations where sourcing becomes an afterthought amidst all of the other trial requirements, a transactional approach vs a strategic approach to supplying comparator drugs can jeopardize the progress of a trial.
Probably one of the simplest ways to reduce risk during the comparator sourcing process is to start planning early, typically during the protocol design phase.
A head start on planning is imperative, as comparator drugs are likely to be available from a wide variety of sources across a number of geographies. Each source, however, may exhibit regional variations and will be governed by different trade regulations, all of which must be considered prior to selecting the most appropriate source.
Advance planning allows time to:
The ultimate goal of comparator sourcing is to get the right drug to the site at the right time. Indeed, the efficient management and movement of trial supplies, including comparator drugs, is an important factor in the success of any trial.
Making this process more challenging is the growing number and increasingly global nature of clinical trials. Significant growth in the number of clinical trials conducted is expected in many regions, in particular: Africa, the Middle East, Eastern Europe, and South America.4 A recent benchmark study by Bearing Point and AMR Research on the clinical supply chain found that only 38% of respondents' trials would be conducted within North America and Europe.5
An expanding number of trials and their geographic diversity place an added burden on both regulatory and supply/logistics teams to establish and maintain a compliant, efficient, and secure supply chain across many borders.
Requirements established by local regulatory agencies regarding the source of comparators (i.e., whether a comparator sourced in the United States can be used in an EU-based trial) as well as general trade regulations governing import and export must be understood and followed. Further complicating supply and logistics are comparators that require special handling, such as cold chain requirements, controlled drugs, or those that involve complex, small dosage forms.
All of these factors are converged to put additional pressure on the supply chain, and if not managed effectively can result in delayed delivery of the comparator to the site, which in turn, can lead to costly delays or trial interruptions.
An agile, global inventory and logistics management process supported by extensive regulatory expertise is more critical than ever to ensure compliance, supply chain security, prompt delivery of comparators, and global batch traceability in the event of a recall. Regulatory expertise specific to the countries the comparator is being shipped to also helps ensure that proper documentation accompanies the drug.
It is therefore critical that trial sponsors remain updated on and attentive to the constantly evolving regulations affecting the geographies in which trials are running and also maintain close relationships with key regulatory bodies and customs should sourcing related questions arise.
Once the desired comparator has been identified for the trial, the task turns to locating an appropriate source or sources for the drug. While the comparator may be available from a variety of sources, regional variations in the drug itself such as dosage form and strength, API concentration, and visual aspect make it important to have as broad a view as possible of available sources across many geographies.
Detailed knowledge of the global comparator sourcing landscape enables assessment of a range of options, leading to selection of the most appropriate, reliable, and reputable source for a particular clinical trial.
Caution must be exercised, however, when evaluating sources for a comparator. Only those sources that are audited to ensure supply chain security and minimize the risk of counterfeit products should be considered.
Global sourcing capabilities also enable rapid identification of alternative sources for a comparator should there be an unexpected change in production or formulation of the original source material. Immediate access to information on alternative sources helps minimize the possibility of delays in delivering comparator drugs to trial sites.
Probably one of the most effective ways in which the risk can be taken out of the sourcing process and ensure comparator availability throughout the course of the trial is to source directly from the comparator's manufacturer. This direct route can be problematic, however, as most trial sponsors wish to maintain anonymity during the sourcing process. It should also be noted that a comparator's manufacturer may have no interest in making a drug available to a sponsor seeking to prove superiority of their compound.
Trial sponsors can leverage this direct sourcing route while preserving anonymity through partnership with a sourcing specialist that maintains extensive relationships with manufacturers and can negotiate on the sponsor's behalf. Working with a specialist who has such connections also brings additional benefits beyond confidentiality.
A sourcing specialist can liaise directly with the manufacturer to schedule production runs to meet both short- and long-term comparator requirements. This demand planning helps ensure reliability of supply throughout a trial with the same quality of material and can help maintain flexibility of supply should comparator requirements change due to a study being extended or through fluctuations or delays in anticipated patient enrollment.
In addition to effective demand planning, sourcing directly from a manufacturer enables access to large, single lots of the comparator with maximum shelf life, and specific batch numbers when possible. Securing comparators with a lengthy shelf life provides time for characterization, demonstration of bioequivalence, relabeling and repackaging, if needed, while minimizing the frequency of costly resupply.
Securing the proper paper trail for the comparator can reduce exposure to risk, and this is much easier when dealing with the manufacturer. The manufacturer can routinely provide full pedigree documentation reflecting the chain of custody from the source to your designated point of delivery along with full product documentation, including certificates of analysis, certificate of conformity, package inserts, GMP compliance, equivalency data, material safety data sheets, and TSE/BSE documentation.
The availability of these documents is not guaranteed when sourcing comparators via wholesalers, putting a company at risk in terms of meeting regulatory requirements. While a wholesaler may be able to offer the lowest product cost, the lack of robust relationships with manufacturers and supply quota restrictions may result in an unreliable supply of comparator throughout the course of a trial, ultimately leading to a much higher total acquisition cost.
Many sponsors are interested in the concept of single sourcing, which is the supply of a comparator drug from a single geographic source to sites in multiple countries. When considering single sourcing in support of a trial, it is important to weigh the pros and cons associated with this strategy. Single sourcing offers a number of benefits to the sponsor including:
Along with these benefits come a number of challenges. A sponsor should carefully evaluate single sourcing options from a regulatory standpoint and understand what is required in terms of supporting documentation. The FDA, for example, provides no formal guidance on single sourcing, so it's best to consult your comparator sourcing specialist who has the capabilities to advise on a case by case basis and be in direct contact with agency officials on your behalf.
While single sourcing can ease the demands on internal supply and logistics departments, the dependency on one source for the comparator presents a different form of risk and requires stringent evaluation and verification of the supplier. A sourcing specialist will ensure that these risks are fully quantified and mitigated.
Clinical trials are a major component of the R&D process for new drugs. Each additional day a drug spends in development can cost a company as much as $600,000 in lost revenue for a small or niche drug and $8 million for a blockbuster.6
A clinical trial can come to an abrupt halt if the comparator drug is not available throughout the duration of the study, affecting trial timelines and having a financial impact on the sponsor. Delays in the start of a trial due to the inability to locate a reliable, secure source for the comparator or lack of the required product documentation are just as costly.
A transactional approach to sourcing where the focus is on finding a comparator as quickly and inexpensively as possible can increase the likelihood of these setbacks prior to and during the course of a clinical trial.
In contrast, effective demand planning, direct manufacturer relationships, regulatory expertise, global sourcing capabilities, and logistics all combine to create a comparator sourcing strategy that will minimize the risk of delayed or interrupted clinical trials and, in turn, minimize the financial implications that can result.
Tony Dutta is senior vice president of operations at IDIS, IDIS House, Churchfield Road, Weybridge, KT13 8DB, United Kingdom, email: email@example.com
1. "Comparison Shopping," The Economist, pp. 68-69, (January 10, 2008).
2. J. Wechsler, Reformers Seek More Comparative Effectiveness Information to Control Healthcare Spending," Formulary, http://formularyjournal.modernmedicine.com/formulary/Policy+News/Reformers-seek-more-comparative-effectiveness-info/ArticleStandard/Article/detail/521928?searchString=%22comparative%20effectiveness%22 (June 5, 2008).
3. United States Congressional Budget Office, Research on the comparative effectiveness of medical treatments: Issues and options for an expanded federal role, http://www.cbo.gov/ftpdocs/88xx/doc8891/12-18-ComparativeEffectiveness.pdf.
4. P. Van Arnum, "Globalizing Drug Development," Pharmaceutical Technology, http://pharmtech.findpharma.com/pharmtech/Article/Globalizing-Drug-Development/ArticleStandard/Article/detail/513925 (May 9, 2008).
5. R.S. Kumar, "Clinical Trial Supply Chain Management," Contract Pharma, June 2008, 74-78.
6. Cutting Edge Information, Accelerating Clinical Trials: Budget, Patient Recruitment, and Productivity, http://www.acceleratedclinicaltrials.com (2004).
7. Institute of Medicine, What Works Best: The Nation's Need for Evidence on Comparative Effectiveness in Healthcare, http://www.iom.edu/Object.File/Master/43/390/Comparative%20Effectiveness%20White%20Paper%20(F).pdf (September 2007).
8. S.D. Pearson and M.D. Rawlins, "Quality, Innovation, and Value for Money: NICE and the British National Health Service, Journal of the American Medical Association 294, (20) 2618-2622 (November 2005).
9. Canadian Agency for Drugs and Technologies in Health, http://www.cadth.ca/index.php/en/compus/about/backgrounder.