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Time Trial

Despite aggressive industry efforts over the past 15 years to improve the speed and efficiency of drug development, new, unpublished findings from CenterWatch revealed no substantial gains have been made in shortening median clinical duration.

An analysis of more than 300 drugs approved between 2000 and 2013 shows clinical development – from investigational new drug (IND) filing to new drug application (NDA) submission – took a median of 5.6 years, a statistically insignificant change from the results of a comparable CenterWatch study conducted in 1999 (1).

The results also found a high variability between the fastest and slowest drug developers in overall median development cycle times, which ranged from 47 to 125 months among the companies analysed, and within specific therapeutic areas.

“Speed is an important performance measurement because it drives the cost,” says Bernard Munos, an industry veteran and founder of the InnoThink Center for Research in Biomedical Innovation. He continues: “You really need to contract the timeline as much as possible. Some Phase 1 trials have been enrolling for 10 years and are still enrolling. There is something wrong there.”

Company Differentiation

A small group of businesses, however, distinguish themselves in the 2000-2013 analysis: Johnson & Johnson, Abbott, Sanofi, Shire and BioMarin. During the 13-year period, these five companies delivered as much as a 20-month clinical development speed advantage over the median rate, and generally held regulatory cycle times flat. These firms also had less cycle time variability across their project portfolios than many of their peers.

Speed and efficiency have become a critical part of drug development strategies as businesses look for ways to control R&D costs, which continue to rise 9-11% each year. The rewards for speeding up clinical development can be great, as the out-of-pocket expenditures for Phase 1 to NDA submission activities carry a daily cost of around $40-45,000, and organisations lose an estimated $1.3 million in prescription sales for each day a drug is delayed entering the market.

Companies that shorten their Phase 1-3 clinical programmes can launch their products earlier, extending their patent-protected sales and gaining a competitive advantage over rival drug firms. The quickest businesses gain 12-20 months, which can be used to generate sales, grow target markets and invest in future R&D activities.

“Today, we are proud that our average cycle time from database to submission is better than the industry median, which means that patients in need typically benefit from our medicines more quickly,” says Ann Van Dessel, Head of Global Clinical Operations at Janssen R&D, Johnson & Johnson’s pharmaceutical R&D arm. “These factors, along with a leading R&D pipeline, position us well to continue to innovate and bring important new treatments to patients who need them.”

Interviews with senior R&D executives at the fastest sponsors confirm clinical development speed is not a mere stroke of luck; the quickest drug developers make this a priority in their development strategies and implement efficient R&D practices consistently across their portfolios. They look for ways to improve processes and streamline trial conduct. Importantly, these sponsors also promote company-wide cultures that value getting medicines to patients quickly, and give their teams the ability to innovate and work efficiently.

Speed Advantage

The 2014 findings of clinical duration update CenterWatch’s Speed Demon study conducted in 1999, which analysed more than 725 new chemical entities (NCEs) approved between 1981 and 1998. Data for both analyses came from the FDA.

In the earlier study, a sponsor needed 10 approved NCEs, across multiple therapeutic areas, during the 17-year period to be included in the overall company comparisons. For the 2014 analysis, the number of approved NCEs required within the 13-year period was lowered to three, in order to comprise a more diverse group of businesses – both large and small – in the examination of strategies implemented by the fastest developers. Only drugs with IND filing data available were used.

Of the roughly 165 sponsors that had approved NCEs since 2000, the five fastest were able to move their entity from IND filing to NDA submission between 18% and 30% quicker than the median development time. For example, Janssen R&D and Abbott – which spun off its research-based pharmaceutical business into the public company AbbVie last year – can develop a new drug in 3.9 years, compared to the overall 5.6 year median needed to move a drug through clinical phases. The median development time per project for Sanofi is 4.2 years, while Shire and BioMarin typically develop their drugs 12 months faster than the industry average.

The most recent analysis also found significant clinical development speed variability within individual therapeutics. In each area, the fastest companies were not necessarily the same as those comprising the overall top five. Nevertheless, BioMarin was among the quickest sponsors in endocrine drug development and Janssen R&D was among the fastest in central nervous system (CNS) therapeutics.

The median industry-wide development time for an oncology drug is 6.5 years, yet the fastest sponsors – Cell Therapeutics, Novartis, Bristol-Myers Squibb and GlaxoSmithKline – developed their cancer treatments in less than half that time (a median of 2.8 years).

For CNS drugs, the difference between the industry median and that of the quickest sponsors is even wider. Whereas CNS clinical development for the average sponsor takes nine years, the five fastest CNS sponsors can develop a drug in a median 2.8 years. Since 2000, the most rapid sponsors in this area are New River, Prestwick, Janssen R&D and Daiichi USA.

All together, from 2000 to 2013, the variability within a given therapeutic area ranges from two to six years around the median; this range of clinical duration represents a significant speed advantage for the fastest companies and higher costs for slower drug developers.

Leading Practices

In interviews with the fastest sponsors, senior R&D executives often found it difficult to pinpoint one or two specific practices that led to quicker development timelines. Instead, these companies implemented a range of practices and strategies to improve operational efficiencies and accelerate cycle times.

“Operational effectiveness is multifactorial,” suggests Jorge Insuasty, Managing Director, Head of Development and Senior Vice President of R&D at Sanofi. “It includes setting clear objectives focused on execution and clinical study metrics, ensuring that the ‘white space’ between phases is reduced as much as possible, but being proactive in planning, simplifying protocols, having a network of investigators, early planning of study protocols and simplifying the governance for decision-making.”

Conversations with executives from the fastest sponsors identified the following success factors:

Standardising Operational Processes
Although the strategies of the quickest developers vary, these firms consistently standardise practices across all functional and therapeutic areas in their organisations. The 2014 CenterWatch analysis found that the top sponsors have a steady level of performance across a portfolio of projects – for example, the speed of Shire’s clinical development programme varied only 20% from drug to drug, and BioMarin’s had a range of just 28%. By comparison, development speed at the slowest companies varied up to 64% across their portfolios, implying the need for more consistent practices.

At Janssen R&D, key to the business’s ability to accelerate cycle time is its flexible R&D operations organisation, which can pivot from the execution of mega trials to those of rare diseases. Standard practices implemented across the company are designed to increase speed, improve efficiencies and reduce risk, and have an important role in making the firm more adaptable.

“We seek out transformational practices, internal and external, and apply them across the organisation,” says Janssen R&D’s Van Dessel. “We incorporate learnings in a systematic way to improve processes and tools.”

Prioritising Resources
The fastest sponsors concentrate their resources on a few key disease areas in which they can prioritise their investments and make a difference. Janssen R&D, for instance, focuses on developing novel treatments in five major therapeutic areas – neuroscience, infectious diseases and vaccines, oncology, immunology and cardiovascular/ metabolism – and BioMarin specialises in rare genetic diseases. Meanwhile, Sanofi streamlined its pipeline after conducting an in-depth review of its drug candidates, development organisation, talent and processes: “We now focus our resources behind higher quality projects that have a higher likelihood of approval,” emphasises Insuasty.

Leveraging Global Development Capabilities
Leveraging the breadth and scale of global development organisations can be a critical way for sponsors to shorten clinical duration. Effective project planning can minimise the number of duplicate studies conducted both in the US and around the globe. Some companies have also developed international standard operating procedures and clinical practices that meet FDA principles, in order to conduct studies the same way anywhere in the world and be able to submit data from any country as part of their NDAs.

Van Dessel explains that Janssen R&D’s “global capabilities have allowed [them] to simultaneously develop, file and launch drugs across the globe with industry-leading efficiency, quality and success rates.”

Simplifying Protocol Design Procedures

The fastest sponsors are focusing on ways to improve the efficiency of study conduct by reducing the complexity of protocol design, bettering study feasibility, collaborating with patient groups and strengthening relationships with investigative sites.

Sanofi, for example, has implemented a programme that develops more realistic protocols without unnecessary and complex procedures that make it difficult for sites to recruit and retain patients. Data can only be collected in areas required to support the main evaluation and key secondary criteria. Furthermore, the company gathers input on protocol design and feasibility early in the clinical study process, from associates in the countries and regions conducting the trials. “Well-defined protocols, including simplification, early feasibility and ensuring data standardisation, have been key for Sanofi in accelerating development timelines,” says Insuasty.

Fast sponsors also improve efficiency and speed by involving patient groups throughout the clinical trial process, including early development, study design and trial execution. Participants, for instance, can identify areas in which design feasibility can be improved, as well as being a critical resource in recruiting volunteers for trials.

Henry Fuchs, Managing Director, Executive Vice President and Chief Medical Officer of BioMarin, tells CenterWatch: “Patients are integral to the process of designing, conducting and analysing clinical trials. They are integral to motivating and mobilising participation in the trials and adherence to the trials… A partnership philosophy is a common element of our success story.”

Additionally, in areas that have a critical mass of trial activities, Sanofi has created a network of pre-qualified sites, which Insuasty says allows the business to ‘jump-start’ its clinical pre-study processes.

Optimising Processes Through Pre-Competitive Collaborations

The quickest developers are looking for ways to optimise clinical development procedures and streamline the conduct of global trials. One way they are achieving this is through pre-competitive collaborations.

Three of the five fastest sponsors (AbbVie, Johnson & Johnson and Sanofi) are founding members of TransCelerate BioPharma – a non-profit organisation through which members can share resources and work towards improving overall R&D efficiency. The consortium has completed five projects to help standardise drug development processes and reduce inefficiencies – including improvement of clinical data standards, and mutual recognition of site qualification and training. New plans involve creating a standardised template for protocols and a global registry of qualified investigators.

“One of the problems with clinical trials is we have tended to reinvent the wheel every time,” reasons InnoThink’s Munos. “Every trial is different. It does not need to be so. There are some commonalities that we could exploit so we do not have to reinvent the wheel and spend the cost of reinventing the wheel every time. That is what TransCelerate is all about.”

Creating Efficient and Dedicated Project Teams

Forming an environment that encourages innovation and teamwork will further decrease project timelines. Employees should be motivated to work together and develop new therapies as quickly as possible. Companies that achieve this will give project teams a high degree of autonomy to solve difficult problems and make decisions about how to carry out their work.

At BioMarin, the business’s emphasis on developing therapies for children with rare diseases helps keep teams focused on the fastest possible track to getting a drug into the hands of patients.

“BioMarin has been incredibly effective at creating a culture that has a sense of urgency tied to its purpose,” says Fuchs. “There is an openness to innovation and seeing things that other people do not see. If I went to a large pharmaceutical company and said, ‘We can get this drug developed in five years,’ the answer might be, ‘I don’t see how that is possible’. At BioMarin, the reaction is, ‘What is it we have to do to make it possible?’”

Many sponsors have also made an effort to create and support independent project teams, allowing decisions to be made more quickly and preventing duplication of effort. Sanofi, for example, has created integrated development project teams responsible not only for strategy, but also for execution. “Teams are incentivised to deliver on progress of projects according to agreed timelines,” believes Insuasty.

Improved Collaborations with Regulatory Authorities
The recent CenterWatch analysis found that, while many firms are able to get their NCEs through clinical development quickly, they lose that speed advantage during the approval phase. Between 2000 and 2013, the industry’s median regulatory review time – from NDA submission to approval – was 10 months. However, there was a high variability in the median times, ranging from a low of six months to a high of 33.

The fastest sponsors work proactively with regulatory agencies, seeking advice about products that will be more difficult to review and ensuring all necessary data are included with dossier submissions.

At BioMarin – which moves its drugs through the approval phase in a median of six months – Fuchs highlights that developing a “good, effective partnership” with regulatory authorities is key to drug development efficiency. Direct communication between the company and regulatory authorities is particularly important, since many of the tools used for developing therapies for common diseases are less available in the rare disease space, in which the business focuses.

Fuchs continues: “They respect that what we are trying to do is hard… they respect that we endeavour to apply as good a science as can be applied to assessing the balance of benefit and risk. The conversations that lead them to conclude that we are good guys and we are trying to do the right thing are an important element of our success record.”

Potential Barriers


While sponsors have centred drug development strategies on accelerating clinical duration over the past 15 years, Munos points out that overall speed has not changed because the industry is yet to successfully address the challenge of patient recruitment. In fact, a recent Tufts Center for the Study of Drug Development report found that the time it takes for sites to reach their target enrolment rates has nearly doubled (2).

Munos adds: “Patient recruitment remains the number one problem in the industry, and that is one of the major causes of inefficiency and poor productivity, and causes all kinds of problems in clinical research. The industry has not found a way to adequately deal with that.”

Leading sponsors are exploring new ways to improve patient recruitment. Improved site selection practices use metrics to choose those which are high-performing and statistical programs to better predict the numbers needed for a study. Some sponsors are trying to gain better access to electronic patient records to select more targeted groups of people even quicker. Furthermore, sponsors also use social media and other new methods to recruit participants, increasingly from collaborations with patient groups, and have begun to design clinical trial protocols and informed consent forms with their needs in mind.

“There is some attempt now by some folks who run trials to be more patient-friendly,” suggests Munos. “I think this is a step in the right direction. If we improve the patient experience, I think we will have more patients willing to engage in it.”

Sponsors face many other barriers to reducing development and regulatory cycle times, including growing demands from regulatory agencies. Yet, Gordon Bernard, Managing Director, Associate Vice Chancellor for Clinical and Translational Research at Vanderbilt University School of Medicine, says sponsors themselves have offset gains made in shortening cycle times by allowing clinical trial contract negotiations to become increasingly difficult and complex, which can delay study start-up by more than a year. An increased focus on risk management, intellectual property rights, subject injury coverage and other legal issues – which must be re-negotiated with each contract – and an inefficient negotiation process, have lengthened drug development cycle times at many large sponsors.

“They are their own worst enemy in many, many cases,” underlines Bernard. “The large pharma companies are assuming that their legal offices are doing the right thing. But they are not always doing the right thing. They can have inexperienced lawyers who turn a straightforward process into several processes and not gain anything out of the negotiation, but they think they have done some good by dragging things out.”

Different groups – including a taskforce of the Clinical and Translational Science Award programme – are working to develop a pre-negotiated master contract, or template, that could be used by institutions, sites and industry to decrease contracting delays going forward.

Looking Ahead


CenterWatch’s latest analysis suggests the fastest drug developers are able to reduce clinical development and regulatory cycle times with identifiable practices that can be learned and implemented by other sponsors. Although it can be challenging to sustain speed advantages for long periods of time – turnover in management or major portfolio changes may make maintaining a consistent level of efficiency difficult – executives at the fastest sponsors indicate they will continue to seek out practices that can shorten cycle times.

References


1. Henderson L, The speed demons of drug development, The CenterWatch Monthly 6(11), 1999. Visit: http://store.centerwatch.com/p-188-november-1999-the-centerwatch-monthly.aspx
2. Getz K, Landscape threats and opportunities for investigative sites, Presentation at the Inaugural Forum on Optimizing Clinical Research Performance, Spring 2013

Acknowledgement

The authors would like to thank Tracy Lawton, Research Analyst at CenterWatch, for her contribution to this article.



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Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master of Science degree from Columbia University Graduate School of Journalism, US.

Annick Anderson
has been conducting market research since 1998, in both the healthcare and consumer packaged goods industries. Annick holds an MBA from Boston University School of Management, US.
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Karyn Korieth
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Annick Anderson
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