1. What, in your opinion, is currently the single largest trend with respect to the preclinical market?
JD: From my perspective, it appears many companies are paying more attention to value or getting the most service for invested dollars. I am referring to value not in the sense of the lowest price, but rather to include the intangibles such as quality, responsiveness, flexibility, and on-time reporting. With shrinking budgets and/or venture capital, it has become more of a priority to consider these intangibles as they can reduce the overall cost of the preclinical program and ensure the integrity of timelines.
DB/KS: From an in-vitro drug metabolism perspective, it’s drug transporter research. These membrane-bound proteins play an important role in absorption, distribution and excretion of xenobiotics and can be involved in drug-drug interactions (DDI). Due to their potential to affect drug safety, they are gaining increased attention from regulatory agencies.
This is a relatively new and evolving field of research, with new transporters being discovered and new test systems developed regularly. There are still some differences of opinion about which transporters to test routinely, and a variety of approaches as to how and when those studies are performed. The European Medicines Agency (EMA) recognizes 9 transporters of significance, while the International Transporter Consortium (ITC) paper of 2010 lists 7. The FDA highlighted only one transporter in its guidance document of 2006; however, the expectation is that their list of recommended transporters will grow significantly in the highly-anticipated 2011 guidance document. Even with the recommendations of industry thought leaders and regulatory organizations, there is no definitive early screening or direct approach to transporter investigations like those that exist for the major drug metabolizing enzymes, such as cytochrome P450s, and designing clinical studies is difficult due to the lack of specificity of the substrates and inhibitors. Some transporter studies can be as unique as each compound under development, which can also add to the cost of drug development efforts.
EK: The single largest trend is the volume increase of outsourcing that is occurring today versus a few years ago. There is a new push for reducing FTE onsite while still meeting aggressive timelines. For that reason, many companies are shifting towards more of a virtual or outsourcing business model. For the large pharma companies, their structural changes to adopt this outsourcing model are most evident. Many want to keep preferred provider relationships with “established” CROs because they think it is reasonable to pay some extra money for more robust and integrated services. On the other hand, small- to mid-size companies in the biotech sector have also moved toward adopting the outsourcing model, but many want to have options in selecting multiple qualified partners to develop their compounds more efficiently (cost and time).
LB: The increasing demand for sophisticated drug discovery service. This is driven by the need to de-risk the Phase II study by ensuring adequate confidence in mechanism of action and efficacy in a biological system rather than simply by in vitro modeling. The rapid decommissioning of global pharma research centers is also accelerating the demand. Rather than maintaining expensive overheads, global pharma are using specialized, highly sophisticated niche providers to help them with early research need.
MK: It is biologic for old giants but biosimilar (super generic) for new players in drug developers.
ND: A major trend in the CRO industry is Asia’s continued emergence as a global CRO player. Moreover, because of unmet healthcare needs, pharma is continually globalizing in China and many CROs had organized to capture their share of that market. Fueling this trend is a focus on cost-effectiveness, with the challenge of balancing price and quality. However, a focus on price pressures and cost over quality to gain business from North American and European clients may not be an optimal long-term value proposition. Quality needs to remain the priority when it comes to preclinical development to optimize clinical outcomes and success. Previously, the relationship between a preclinical CRO and a pharma or biotech firm was more contractual in nature, but we see a shift from it being transactional to a more collaborative and partnership based relationship. Along with gaining cost efficiencies, this has become an emerging business model because of the pressure to reduce time-to-market and increase product pipelines. A strategic partnership is a great way to gain market share in a very competitive, yet fragmented outsourcing supply chain of CROs.
NG: In a word – innovation. In the past, innovation was considered timely and expensive, but today we are offering our clients flexible arrangements that support their accelerated drug development programs. We are also seeing our clients focus on early discovery work so they can make informed go/no-go decisions early in the R&D process. This enables companies to weed out candidates earlier in the process and focus on those that have the best chance of success. The past few years have been very challenging as the industry consolidated. Companies restructured and realigned their portfolios as drug approvals from the FDA reached record lows. In 2011, we are seeing the difficult decisions from previous years support the development of innovative new medicines. As an industry, we have shifted our focus from therapeutic areas that have proven medicines to targeting unmet medical need in very complex diseases, which require very complex treatments using combination therapies. The days of the “me too” drugs are gone. Today, we are seeing a focus on developing innovative, quality medicines.
2. How, in your mind, has the landscape of the preclinical market shifted post-recession?
JD: While the large CRO/large pharma or biotech partnerships have captured headlines in past years, I see more formal collaborations from small to mid-size pharma/biotech with small to mid-size preclinical service providers. These relationships offer advantages to the pharma/ biotech companies such as preferred timeslots, reduced costs, improved communication and offers scheduling and forecasting advantages to the CRO.
DB/KS: Mergers & acquisitions (M&A) continue to reduce the number of large pharma companies, resulting in restructuring of their resources and initiatives, including their drug development pipeline mix. Normally, this would mean more outsourcing; however, many companies are placing priority only on those drugs in their pipeline that are close to market approval, often slowing or halting their preclinical development program until economic pressures lessen. Some of this reorganization has severely cut internal “expert resources,” increasing the need for external expert advice.
Competition in the CRO market has grown as a combined result of new start-up specialty labs, often spun from the laid-off workforce from M&A; large CROs adding additional services for convenience and price bundling; and from new providers in India and China, who attract growing interest in the cost-savings that they might offer.
EK: As the global economy recovers post recession, both development activities in the pharmaceutical/biotech industry and the operating rates of preclinical CROs are on the rise. However, it seems cost structure changes during the recession have been locked in due to the sponsors’ cost consciousness learned during recession. Many CROs had to be more competitive to fill their animal rooms or LC/MS-MS capability in the US and Europe, while cost-efficient Chinese CROs matured improving not only their facilities but their compliance (GLP compliance and FDA compliance/inspections) and experienced associated cost increases in addition to the general cost increases in China.
LB: Obviously, investment decreased in 2008 to one third of prior years, but biotech investment in 2010 rebounded to exceed even that of the genomics-crazed 2000 era. The landscape is more focused on globalization with an almost automatic reflex to look for outsourced services in low cost environments. However, the industry is also learning that total cost differential between east and west is actually not so different when both direct and indirect costs are taken into consideration.
MK:
- Geographic diversification like clinical trial happened back to the 1980’s from western oriented to Asia including China, India, Korea, and Singapore.
- Increased demand on large animal studies including NHP and mini pigs to assure greater translational power and to support gene-based drug discovery.
- Increased demand on large animal disease models to enhance efficiency and effectiveness in drug discovery.
ND: Along with consolidations and an overall evaluation of cost structures, the landscape shift is due to the move toward new service offerings. For example, a CRO that had traditionally provided pharma services is now offering and promoting medical device development capabilities. Conversely, some traditional device CROs are now providing extensive drug and biologics development capabilities. These CROs are often more experienced with combination products due to their knowledge of drug delivery systems and polymer chemistry. The landscape has also changed due to advancements in biomarker technology and nanotechnology. These breakthrough platforms expedite the entire preclinical development process and can yield high quality and tangible decision-making data. Additionally, transgenic animal, systems biology and simulation models are allowing CROs to overcome preclinical research obstacles.
NG: Our client base is undergoing significant change and their efforts to create a more efficient drug development model will involve increased outsourcing. As a result, we are seeing more sponsors make the shift to strategic relationships. A strategic model offers both the sponsor and the CRO numerous benefits, including a relationship at multiple levels. Strategic relationships often have governance committees comprised of individuals from operations to the executive level, which enables issues to be easily escalated and ensures that programs stay on track. The strategic model creates deeper relationship on both sides, which results in better service, consistent communication, and stronger commitments. In addition, the scientists with the CRO become part of the client’s team because there is more knowledge sharing, which creates a greater level of trust.
We are also seeing increased price sensitivity. Our clients want superior scientific expertise, accelerated timelines, and quality, all at a competitive price. We understand and are working with clients to develop flexible arrangements. This enables our clients to benefit from the value of our high-quality and scientific expertise at a competitive price.
3. What country/region, in your opinion,is currently leading the way in the preclinical market and why?
JD: I believe the Bay Area and Boston/Cambridge remain strong in the preclinical market. While both geographical areas have suffered from downsizing and restructuring similar to the rest of the country, these two areas have recovered more quickly and seem to be leading the path to recovery. I believe this strong recovery can be attributed in part to the fact that many of the companies in these two areas are mid-size (i.e. small start-ups lost much of funding from venture capital and large pharma/ biotech shifted resources to programs in late stage development).
DB/KS: North America has the advantage here, mainly due to the relative economic stability, established scientific experience and logistical advantages to the majority of the pharmaceutical industry. There are many newer CROs popping up in various regions of the world and their pricing is very appealing, but often the ultimate price of conducting a study overseas can end up being quite costly when you factor in things like the cost and experience required to successfully ship study samples overseas, the required travel to audit and qualify labs in other countries for GLP purposes, and the unfortunate situation when a study must be completed in its entirety, due to poor laboratory practices or inexperience with studies meant to meet regulatory requirements.
EK: The US continues to play a dominant role because more than half of new drugs are still developed in the country and the gap in outsourcing quality/cost between US, Europe and China has been diminished during and post recession as stated in the previous section. However, EU or Canadian CROs might be more attractive with the possibility of a French or Canadian R&D tax credit. As seen by recent French government solicitations, a preferential corporate tax incentive is available to smaller to mid-size biotech/pharma companies for establishing small offices or laboratories within the country and outsourcing within EU. Creative incentives such as this R&D tax credit could play an important role in determining a new leader in outsourcing services in the future.
LB: No one country is leading the way. There are regional differences in direct pricing and scientific sophistication and execution. Market leaders remain US, Europe and Japan. Translational research is largely led by focused US academic groups and regionally by Singapore. India and China are regionally second tier service providers as a result of cultural hurdles that impede transnational workflow. These cultural hurdles are being eroded, but this comes together with an increased direct cost implication.
MK: In terms of quality credibility, it is still north Americas as well as western European CRO. However cost strategy of sponsors (clients) drives to seek possibility from Asia especially mainland China. Chinese CRO has strong capability in capital investment as well as local governmental willingness. This doesn’t mean that the sponsor move dramatically into China but also looking for bridge market including Korea and Singapore. Singapore has been recognized as a global city with multicultural atmosphere without a linguistic barrier. Good Laboratory Practice (GLP) is the most important global standard in the preclinical CRO business. Singapore is considered suitable for conducting GLP studies with increased reputation in biomedical science. Of course, Singapore has been accepted OECD MA since Sept 2009.
ND: North America still leads the preclinical market because of the quality and history of these firms that have historically operated in the U.S. There are many countries in Europe with a strong presence in the preclinical market, but many European and Asian pharmaceutical and biotech companies still seem to prefer using US-based preclinical CROs for more successful entry into the US market. However, we cannot discount the emerging presence of Indian and Asian competition. US based academic institutions have also been at the forefront of basic research and pioneering new product discoveries, which ultimately are supported generally by US-based CROs for commercialization. For example, Toxikon recently announced that we are expanding our Efficacy and Surgical Research Services Wing to meet the demand for more animal models, trainings, demonstrations, and remote visualization of procedures and surgeries. This demand was fueled by the Boston area’s high concentration of academic institutions, research hospitals, start-ups, private equity and venture capital-based organizations.
NG: We are continuing to see clients outsource their discovery chemistry work to companies in Asia. In addition, there is evidence that companies in Asia want to demonstrate their ability to produce novel molecules via the biobetter route rather than being copiers of others’ designs.
The design and implementation of a rapid and valuable safety and efficacy program is key to defining the potential of new compounds. I believe that this development work will largely remain in North America and Europe. Safety assessment is the first major step toward regulatory approval, and our clients remain committed to conducting this work in North America and Europe.
4. If things progress as they have the past five years, what can we expect in the next five years, in the preclinical market?
JD: Like many businesses, the pharmaceutical industry has historically been cyclical. I see no reason why the next five years shouldn’t see a dramatic increase in all aspects of preclinical research. Even before the latest industry slowdown (2009-2010), the number of new molecular entities (NMEs) filed has been lower than average, but I anticipate a surge as budgets ease and venture capital loosen the purse strings. Since the beginning of 2011, we have witnessed more interest in our early phase discovery services and as lead compounds are identified, IND supporting programs will soon follow.
DB/KS: It’s all about generating new, safe medicines faster. We can expect to continue to see improvements to operating efficiencies, test systems and assays, data handling, data interpretation and clinical prediction capabilities that will help companies keep a competitive edge. If they have downsized their company, then pharmaceutical companies will look toward CROs and/or consultants who can take the place of lost scientific resources.
Preclinical testing is not only about the parent drug anymore, but also its metabolites, which can cause some serious safety issues. As always, earlier detection is best. This need continues to push technology to develop earlier screening options for detecting the formation of harmful metabolites and innovative methods to assess potential for DDIs/toxicity with high-content data.
Growing areas, such as drug transporters, rely on in-depth knowledge of the discipline and highly-reliable test systems. Cell-based assays, transfected cell lines and the discovery of specific testing reagents will be in demand, as well as strategic drug-development consulting services.
The industry has been busy developing portfolios of biologics/protein therapeutics. This class of large molecules will attract increasing regulatory oversight, requiring suitable in vitro and in vivo tests to evaluate safety and efficacy. Like the evolution of small molecule drug development efforts, once acceptable assays are identified, companies will focus on the technology to speed up preclinical timelines and reduce late-stage attrition rates.
Other expected changes include the use of in silico modeling to improve the prediction of clinical outcomes; and revising test methods to investigate commonly co-administered drugs and protein therapeutics as more and more of the population are taking multiple medications. The increased use of biomarkers and the development of specialty animal models and new test systems indicate that industry is looking for improved ways to predict safety and efficacy of increasingly challenging molecules earlier in developmental efforts.
EK: In the next five years, the gap in outsourcing quality/cost between US, Europe and China will be diminished further and the globalization of drug development will be accelerated. Although Chinese CROs may become less attractive due to the cost increase, preclinical outsourcing to China may increase to support INDs in China as more western companies try to target the Asian market for product launch.
LB: Two outsourcing populations will establish; the globals and the biotech. The biotech have been the most dynamic of outsourcers having embraced the virtual development model. The mantra has been ‘speed above all’, which has led to some high profile catastrophic failures in drug development. We must see better science and we must see the financial community’s realization that there is a non-regulatory driven development pathway that is equally as valuable. Getting to first–inman as quickly as possible is not an automatic win. The globals will increasingly turn to trusted outsourcing partners (in a true sense) to execute their research programs on a fee-for-service basis thereby eliminating fixed overhead that may not produce a viable product.
MK: It has been a difficult period to most CROs in the world. Over supplying of CRO capacity after a number of leading drug companies sold out their own campus (facility) to commercial CRO. In addition, more CRO stepped into global competition since more and more drug developers tried out sourcing. Price efficiency was the only criteria for last years in the competition. Especially many American CRO offered lower price to compete CROs from emerging countries. This has caused some quality arguments.
From this year, more sponsors respect quality and time efficiency. In this regard, CROs from Asia have more chance in order to satisfy time efficiency for sponsors. There are more sponsors requesting works to be given Asian CROs instead the used to given to western because themselves have own ability to managing study outsourcing and enjoy price and efficiency benefits from regional CRO service providers.
ND: The global market for preclinical services will continue to grow. You will see more mergers and acquisitions and new, small CROs continuing to enter the marketplace, creating a more competitive landscape of products and services. As a result, CROs may become more specialized and competitive, and compel them to differentiate themselves in the marketplace in order to maintain market share and succeed.
NG: Innovation will continue to drive the R&D process. As the industry moves away from “me too” drugs, we will see a wave of new innovative medicines receive FDA approval. These new treatments will be developed using the efficient, accelerated paradigm. We will continue to see the growth of virtual biotechs as companies shed overhead costs to focus on R&D.
5. In your opinion, what research field currently benefits the most from preclinical testing and why?
JD: Certainly small molecules, regardless of therapeutic indication,benefit from the standard toxicology testing format. Historically, the results from the traditional two species (rodent and non-rodent) IND supporting studies have proved useful and predictive of potential safety issues in humans. Large molecules also require safety assessment, but the standard two-species format is not a “one size fits all.”
First, and often a huge first step in the development of large molecules, is that relevant species selection will dictate the extent of safety work to be conducted. Certainly the less “uncertainty” regarding the safety of molecule the better, but large molecule development CAN be done without ever touching an animal. With the MABEL approach to understanding receptor saturation, etc., in vitro work CAN guide a first dose in humans without ever doing an animal study (the idea is “start low and go slow” in the clinic). Irrelevant data in a non-responsive model can be more dangerous than a good in vitro receptor occupancy study. Large molecule drug development will always be science driven and case-bycase with respect to the most appropriate development program.
EK: Currently GLP- and GMP-related areas are considered most beneficial because outsourcing GLP or GMP projects enables bill-splitting for large initial and continuous investments for establishing and maintaining GLP or GMP facilities. Other specialty services like human primary tumor xenographt or stem cell models are potential areas for growth.
LB: ‘Testing’ is probably not an appropriate word to use in this question as ‘testing’ implies a fail/no fail end point… ‘research’ is probably more appropriate. Research will always follow the money. We see huge scope for bio-similar development given the >$20b of offpatent biologics sales (in 2009). This is attractive as the drug targets are already established and risk is thereby lowered. We also see the end of patent life for a massive dollar value of small molecule products and stakeholders are struggling to replace this future loss of revenue with a range of strategies. Cardiovascular disease remains the world’s no. 1 killer and with statin treatments coming off-patent, there is an ongoing massive research effort to find something better. Diabetes is becoming a disease of increasing awareness as the world population of diabetics spirals upwards. A more effective treatment will gather massive return. The developed world is living longer and is increasingly concerned about mental deterioration. Given the levels of disposable income among the elderly in the developed world and willingness to spend to retain mental faculty, research dollars will continue to flow into Alzheimer’s, Parkinson’s etc. Cancer is now recognized as a simple term for a massive variety of disease condition with a common root, but nevertheless, increasing age means increasing risk of error in the replication of genetic coding and a cancerous consequence. Again, pressure to develop treatments from the more affluent of the world’s population.
Which field benefits the most from research? Probably neurological as there is now more sophistication in investigative tooling available.
MK: Non-invasive preclinical imaging in experimental medicine for drug development is the key research area which will benefit the most. Preclinical imaging offers a wide range of methods for the support of drug development and has the capability to offer longitudinal read out, that are able to address major questions related to target validation and molecule bio-distribution, target interactions and pharmacodynamics.
All therapeutic development areas benefit from preclinical research. Everyone has to establish proof-of-concept, efficacy and safety. It’s the prelude to any development program, no matter what disease area. There are more prevalent disease focus areas, such as cardiovascular, oncology, ocular, and others. However, we see emerging research in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and now autism treatments are beginning to emerge. Medical device technology is advancing through new delivery platforms and evolving relative to prior implantable device technologies. The development of novel surgical procedures is also advancing on the device side. Minimally invasive medical technology benefits from preclinical research and surgical programs. Preclinical development is not limited to pharmaceutical and biotech; medical device require significant preclinical support programs.
NG: Immunotoxicology using elispot technology is the research field that currently benefits the most from preclinical testing. Elispots detect specific cellular immune responses. Elispot technology is enabling toxicologic, and immunotoxicologic evaluation of the increasing number of vaccine/therapeutic vaccine strategies aimed at inducing a permanent induction of cellular immunity. This is especially important as therapeutic research is now aggressively approaching the cellular response to treat malaria, AIDS, cancer, and autoimmune disease. Risk assessment prior to clinical trials in this area is critical since permanently elevated immune responses are sought in human patients.
6. What recent improvements/methods have been implemented to in the preclinical market?
JD: The ethical use of animals has always been a focus of the preclinicalindustry, but I have recently witnessed a more concerted effort to reduce, refine, and replace the use of animals in preclinical research. Whether micro sampling, understanding relevant endpoints, or welldesigned pilot studies, these efforts serve not only to reduce the costs of preclinical research, but also demonstrate a more thoughtful process of drug development. For biologics; should the standard consist of a control and three dose levels? The FDA has accepted reduced designs (control, low-dose, and high-dose) and I am sure that more refinements will arise as the industry concentrates on answering specific questions and not “checking boxes.”
Another “old” area that is truly an emerging market is understanding preclinical biomarkers and how they can be applied to humans. Whether physiological (i.e. safety pharmacology) or relevant serum/bioanalytical markers, this is a science that is becoming more and more relevant. It is important to be able to think further than just the current safety study and try to design the methodology and the thought behind identification of relevant markers that CAN be translated to the clinic. After all, if histopathology is the only sensitive safety endpoint, that is NOT a useful clinical marker. This is truly an area that I see a huge push coming in the next few years especially with large molecules.
DB/KS: We’ve seen more efficient ways of testing, including the use of automation in novel ways. With automation comes smaller sample sizes and integration with some high-accuracy instrumentation providing some very efficient assays that yield reliable, high-content data. Transporter technology continues to progress, with improvements in transfection techniques for cell lines and discovery of more specific substrates and inhibitors, allowing better interpretation of the data. New methods are being developed to look in vitro at co-administered drugs as more and more people are taking multiple medications, and predictive assays are being developed to test biologics in vitro for their potential to precipitate adverse events in vivo. Cell-based assays, stem cell research, biomarkers, specialty animal models and revisions of some commonly-accepted practices are all being implemented now to improve the success of clinical investigations before they begin.
EK: Some of the newest improvements are systems such as computer software that allows for real-time monitoring of GLP toxicology study or GMP API and DP manufacturing from remote (often vast distance) locations, which makes outsourcing a more viable and controllable option. A wider range of studies for preclinical development have become available as outsourced services such as the use of primary human tumor models and new animal disease models, which gives us flexibility to develop drugs as either a fully virtual company or using internal FTEs. For small- to mid-size companies in the biotech sector, the flexibility is indispensable to manage preclinical development using limited internal resources. Options such as FTE services now available through Chinese CROs and even some US CROs allow a small pharma/biotech company to stay lean on FTEs while still developing a drug for market.
LB: Janet Woodcock (FDA) advocated the Critical Path Initiative as a way of ensuring that sound science decreased clinical stage failure. In essence, this means the application of biomarkers and imaging technologies to the science of drug discovery and development.Identification and development of biomarkers as diagnostic tools as well as indices of clinical efficacy has since become a science in itself and the application of these tools to the drug development process enable very early read-out of efficacy in particular. The application of medical imaging (PET, CT and MRI in particular) has been slowly incorporated into preclinical development (probably as a result of the high capital cost of equipment needed). Nevertheless, medical imaging has become a primary feature of our clinical healthcare process and the application of such technologies to preclinical development an intuitive and obvious development in process. Use of sophisticated medical imaging can also contribute significantly to the three R’s applied to all thought regarding research using laboratory animals…Refine, Reduce, Replace. Imaging technologies allows non-invasive, clinically relevant, highly sophisticated and non-terminal end-points to be applied to a research program.
MK: Traditional drug market was more considered conservative chemical based discovery. However turning into area of biologic, biosimilars (super generic), and medical device will be an outstanding changes. In this regard, more advanced GLP compliance technology, utilizing bioimaging technology, and more advanced biologic analytical technology will be key to success for CRO business competition from now on.
Another area we need to focus on is integrating between preclinical and clinical trial studies.
ND: There’s been significant progress in the development and validation of disease models. This technology significantly enhances proof-of-concept and efficacy timelines for product development. Additionally, there’s been an increase in biomarker discovery, imaging techniques and other cell-based technologies are continuing to emerge. On the data delivery side, there are more technology solutions for preclinical CROs to make improvements, including IT infrastructure, and laboratory management systems. Microsoft and their life science solution partners, for example, offer validated technology solutions for preclinical lab environments that were not previously available. The ultimate goal is to work electronically and paperless with all study sponsors and regulatory bodies.
NG: The breadth and availability of high quality cell-based and stem cell services have increased in the preclinical market. Our clients rely on us for stem cell therapy guidance and regulatory support in this growing area of drug discovery. Charles River was the first CRO to start a Cell Product Toxicology Program. The Program is staffed with experts in animal research models, molecular biology, veterinary pathology, immunology, regulation and pharmacology. We are also the first CRO to form a Stem Cells Research Oversight committee (S-CRO), an institution-wide review board that oversees the ethical conduct of cell therapy research – this is a requirement for running cell research funded by California (CIRM) and a number of other states.
Another recent improvement is the use of jacketed telemetry (JET). This technology combines safety assessments with repeat-dose toxicology studies to determine test article liabilities. In addition to cardiovascular parameters, respiratory capabilities (tidal volume, compliance, resistance) can also be obtained. The implementation of algorithms that apply distribution-based QT analysis for the derivation of accurate and reproducible individual QT rate-corrections in preclinical studies has markedly improved robustness. This preclinical methodology has recently been directly validated in humans (2011).
Holzgrefe HH, Ferber G, Morrison R, Meyer O, Greiter-Wilke A, Singer T. Character- ization of the Human QT Interval: Novel Distribution-Based Assessment of the Repo- larization Effects of Moxifloxacin. The Journal of Clinical Pharmacology. 2011;DOI: 10.1177/0091270011409234