Drug development is a long and costly process, and companies struggle with efforts to compress cycle times and reduce costs. A new CenterWatch analysis of new molecular entities (NMEs) approved by the FDA from 2014 through 2016 shows no signs of dramatic, industry-wide improvement. Sponsors interviewed by CenterWatch cited multiple factors that influence the speed of their development programs. In particular, the selection of investigative sites and vendors (including CROs), and the relationships forged with them, were an important focus of companies seeking to improve the speed and efficiency of clinical trials.
The length of clinical development cycles is linked to the overall cost of developing a new drug, which continues to rise. EvaluatePharma recently reported that the average spend per NME is $4 billion. This cost varies significantly among individual companies. Pharma veteran Bernard Munos, senior fellow at FasterCures, who recently conducted a study of company spending on drug development, said, “We noticed extreme variability in R&D spending per NME approved. The best companies in the industry spend about $2 billion to $2.5 billion for each NME approved; the worst spend about $25 billion. The $25 billion is clearly an outlier, but quite a few companies come in at $5 billion to $8 billion per NME.”
Recent studies also show that clinical protocols are becoming increasingly complex, which can lengthen clinical trials. “Overall, the clinical phase of development from first-in-man to approval has decreased, but the individual trials have become harder to execute, longer in duration and require an increasingly specialized workforce,” noted Rob King, COO of Novella Clinical. A 2017 report in Nature Reviews Drug Discovery showed that the clinical development duration of a trial was a key factor in driving up its cost, and found that each additional month in a phase III trial added a median expense of $671,000.
Speeding development with transformative therapies
To assess the progress of companies trying to address sky-rocketing costs by reducing clinical development duration, CenterWatch examined the performance of sponsors with at least two NMEs approved in the time period. The developer with the overall shortest median clinical duration times was Gilead Sciences. Gilead’s Harvoni, a fixed-dose combination therapy for hepatitis C, was the fastest program in the anti-infectives therapy area with a 20 month clinical duration, and one of the fastest overall. It was also faster than any anti-infectives in the 2014 study. Gilead did not respond to requests for an interview. Gilead’s Genvoya, a fixed-dose combination therapy for HIV, was also in the top five fastest program for anti-infectives.
Many of the fastest programs had one or more expedited approval designations from the FDA; however, the CenterWatch study shows that programs without these designations can also move quickly. Expedited status offers regulatory advantages to developers, including increased access to FDA guidance. The FDA grants expedited status when it is convinced that the compound is of high quality and is likely to change the standard of care. “Some companies have become very adept at leveraging accelerated programs,” observed Munos. “They understand that cost and speed of a clinical trial, and the timeline for FDA approval, is directly related to the treatment effect. If you have a big treatment effect, then you have an impressive drug and things are usually much easier.”
Two of the fastest development programs identified are Gilead’s Harvoni and AstraZeneca’s Tagrisso (NSCLC). “In the case of Harvoni and Tagrisso, both had Breakthrough Therapy designations, so both were deemed by the FDA as being transformative and capable of changing the standard of care,” noted Munos. Both drugs had multiple expedited designations, as did the 10 fastest oncology programs, the top five of which had clinical durations of 25 months or less. Both Gilead and AstraZeneca obtained FDA approval with relatively small clinical programs. “Gilead was able to clinch the registration with a smaller program than would have been required if the compound had not been that good,” noted Munos. “I don’t think anyone wanted to keep it from reaching the market as soon as possible.”
Despite some clear success stories, pharma companies overall still have a long way to go to speed up development. “There has not been much change in the industry as a whole,” observed Munos. “Even when there is slight improvement, it is not on the order of magnitude of what the large companies need to improve their sustainability.” To explore what steps individual companies are taking to compress clinical development cycle times, CenterWatch interviewed sponsors with programs that showed significant advantages of speed either overall or within their therapy area.
High–impact treatment effect facilitates development
Game-changing therapies have a clear advantage. Hank Fuchs, M.D., president of Worldwide R&D at BioMarin Pharmaceuticals, emphasized the importance of a high-impact treatment effect in accelerating development. BioMarin focuses on treatments for very rare genetic disorders. “We work with devastating pediatric diseases for which there are no current therapies. That puts a lot of spring in everything and can really catalyze a program,” noted Fuchs. “Also, the pharmacological agents that we pursue are fundamental to the disease. We are treating the core essence of the disease.” Vimizim, which was approved in 2014 for treatment of mucopolysaccharidosis type IVA, had a clinical duration of 22 months, which is one of the fastest programs identified. The company noted that a first-in-man trial began in the U.K. in 2009. Also, BioMarin’s Brineura, approved by the FDA in 2017 to treat a form of Batten disease, had a total development time (measured by first patient to FDA approval) of 45 months.
“We saw big treatment effects in both drugs,” said Fuchs. BioMarin was able to obtain approval based on small clinical programs, which vastly shortened development times. The results of a small phase I study of 20 patients for Vimizim enabled BioMarin to proceed directly to phase III. Similarly, Brineura was approved on the basis of a single 24-patient study. “In the case of Brineura, the effect was so large that we were able to skip phase III entirely.” With respect to expedited designations, Fuchs explained: “They’re all nice to have. We have found that we have more interaction with the FDA when the data show the therapy is making a big difference in people’s lives.”
Organizing R&D for speed
Many pharmaceutical companies have focused efforts on reorganizing clinical R&D to achieve greater speed and efficiency, including Sanofi. Praluent, a novel cholesterol-lowering treatment approved in 2015, was developed by Sanofi in collaboration with Regeneron Pharmaceuticals. Praluent’s clinical phase duration of 61 months was among the fastest development programs in the cardiovascular therapy area. “We focused on several key areas to optimize our clinical development operations by cutting out redundancies and making sure that everyone was on the same page with priorities,” said Ji Zhang, Ph.D., head of R&D Operations at Sanofi. “An example is our integrated platform for Clinical Sciences & Operations, which consolidates local and global R&D and Medical Affairs clinical operations, as well as the Clinical Supply Chain, into one collaborative, cohesive unit.” The platform combines traditional clinical operations functions with biostatistics, programming, medical writing, medical experts, GCP quality and IT. “We look at this as a strategic unit, with fairly comprehensive skill sets, expertise and capabilities,” said Ji. “It has created value for the company by developing the medicine faster and more cost effectively.”
Ji also noted that the quality of the relationship with development partner Regeneron was important. “A strong partnership has been established with Regeneron, taking the best of both companies’ strengths in research, development and marketing,” said Ji. “A key success factor in the clinic has been a very well-articulated governance at all levels of both organizations, from top management in R&D to operational teams, which led to an efficient execution of this program.”
Use of new technology
“Technology offers a great opportunity for improving cycle times and efficiency,” said Sanofi’s Ji. “The whole company is engaged in a digital strategy.” Ji noted that much of the information contained in documents submitted to the FDA is standardized and repetitive in nature. “We accelerated the FDA submission of Praluent by developing an automated system for the generation of narratives. We can leverage the medical writers and experts to review this draft and complete it,” said Ji. “This makes it much faster and of higher quality.” Sanofi is also using artificial intelligence tools to write the case study report. Another advanced tool, which was also used in the Praluent program, is CluePoints risk-based monitoring software.
Novo Nordisk’s Tresiba, which had a clinical duration of 48 months, was the fastest program in the endocrine therapeutic area. “Clearly, the goal is to use technology to speed things up,” said Novo’s Todd Hobbs, M.D., vice president and North America CMO. “And that generally is the case, especially in communications. More patients in trials like to communicate via text.” Novo is further embracing technology through partnerships with Glooko IBM Watson to develop insulin titration support technologies for diabetes patients. The companies are collaborating to apply cognitive computing and develop apps to monitor and analyze patients’ glucose levels and insulin use.
Novella’s King pointed out that the drug industry has been slow to adopt new technologies and processes. “If we think back to the evolution of EDC, it took us more than seven years to move from discussions in journals and conferences to early adoption,” said King. “Other industries, such as banking and space/aviation, require the same level of precision in data analytics and safety, but tend to adopt new technologies much faster.”
Protocol complexity and amendments
Companies are aware of the impact that protocol complexity and amendments can have on clinical development duration. “One of our best practices is to engage sites and patients proactively so we can lessen protocol complexity,” said Sanofi’s Ji. “We have taken certain steps within the organization to manage that in a very disciplined way to increase the initial quality of the protocol, but also to really think through what is a really necessary amendment. We have reduced the level to 1.2 amendments per study on average.” A 2015 Tufts CSDD report found an average of 2.1 substantial amendments per protocol across the industry.
The need for amendments, especially in complex protocols, can increase if the initial protocol design is rushed. “It begins with protocol design and feasibility, which may be rushed in the achievement of site activation or first subject enrolled,” said Novella’s King. “This then results in protocol amendments to address the details of the more complex protocol as a result of regulatory, ethics, radiological board, investigator or CRO feedback, which in turn may delay activation and subsequently enrollment.”
Novo’s Hobbs highlighted the importance of keeping protocols simple in a recent cardiovascular outcomes trial for Tresiba. “We designed the protocol to be as straightforward as possible,” said Hobbs, noting that they kept the number of secondary endpoints low. “To our knowledge, from start to finish, it’s been the fastest cardiovascular outcome trial that has been done.” Novo also tries to minimize the use of diagnostics technologies in trials when possible. “The number of imaging or diagnostic endpoints adds to the complexity. In every trial, we look to see what is absolutely necessary.”
The pace of trials can be slowed by challenges enrolling patients. More complex protocols can cause enrollment issues. “The competitive nature of trying to recruit some patients is a barrier,” said Hobbs. “When the protocol is a little more complex, and the treatment is more advanced, the more challenging it can be.”
“Enrollment is the classic barrier,” said Fuchs of Brineura, noting that BioMarin faces a paucity of patients that suffer from the rare diseases the company works with, and that enrollment is also restricted by disease progression. “In addition to the rarity of the disease, half of the patients are too far advanced to enroll in a clinical trial. In the case of Vimizim, we had to restrict both the top and the bottom of the wellness spectrum.” Although companies developing drugs for rare disease face particularly difficult enrollment challenges, multiple and complex inclusion/exclusion criteria can slow many programs.
Novella’s King cites proper planning and feasibility as key factors influencing a trial’s speed and execution. “Without taking the time up front to develop a protocol that is executable in a real-world clinical setting, performing an assessment of historical enrollment rates and providing comprehensive protocol training, the chances of achieving the forecasted timeline are reduced significantly,” said King. “Subject enrollment accounts for 35 to 50% of a trial timeline, depending upon the indication. Assuring that enrollment is achievable, and that the population enrolled matches your intended inclusion/exclusion criteria, is paramount.”
Working with vendors and CROs
Sanofi has developed what it calls a flexible operational model for working with vendors and CROs. “We recognize we cannot and should not do everything,” said Ji. “We leverage the full capabilities of both internal expertise and the external expertise and resources, so we can deploy at the right time, in the right place and for the right skillset.”
Novo Nordisk runs its own clinical trials, although it uses vendors (including CROs) in some trials for specific purposes, including event adjudication, post-approval safety studies and real-world data projects. Hobbs cited improved lines of communication with sites, decreased potential for disruption, faster trial closure and data cleaning and capture as some of the reasons for keeping development programs in-house. “We have a very short list of vendors that we use,” said Hobbs. “We try to limit the number of vendors involved in a trial. Having multiple vendors would lead to more frustration, possibly confusion and communication challenges with everyone involved in the trial.”
Relationship with the investigative site
Novo’s Hobbs emphasized the importance of building strong relationships with investigative sites. “We know our investigators,” said Hobbs. “We have a really solid relationship with them.” Novo Nordisk has made various operational changes over the past 10 years, including bringing the CRA function in-house. “The investigators know who their contact is, and know that if they have a question or a problem, they’re going to get an answer,” said Hobbs. Another key change was to shift to using central IRBs. “The vast majority of our sites will be asked to a use a central IRB. That can speed things up dramatically.”
Building relationships with investigative sites over time has helped Novo run more efficient trials. “We’ve had significant streamlining in regards to country allocation with regard to the sites,” said Hobbs. “We do go to those sites that have performed well in the past.” Hobbs also points to a high level of engagement with investigators. “We have state-of-the-art investigator meetings with tremendous attendance,” he noted. “We invite top-notch external speakers to talk about the science, and we use a lot of technologies and engagement.” Finally, Hobbs cited the importance of working with researchers up front to avoid surprises down the road. “The worst thing you can do is to surprise them with a lot of extra burden that they weren’t aware of.”
Alignment with the FDA
Companies that achieve expedited approval status benefit from working closely with the FDA to resolve any issues that might arise. However, companies can be proactive regardless of expedited approval and review status. Alkermes’ Aristada (schizophrenia) had a clinical phase duration of 49 months, which is much shorter than the CNS therapy area median duration of 60 months. “Early alignment with the FDA is a strategic aspect of the clinical development process and allows for consistent feedback to help influence the most successful outcome,” said Elliot Ehrich, M.D., executive vice president, Research and Development at Alkermes.
Focusing on high-quality, innovative compounds that will change the standard of care is paramount. Fuchs noted that this strategy is essential to the speed of BioMarin’s development programs. “Nothing will motivate people to move quickly like evidence that we can stop a devastating pediatric disease and turn it around.”
Greenlighting high-impact programs while halting mediocre ones is key to accelerating development and cutting expenses. “The companies that have raised their standards are now moving some really good drugs into the clinic,” said Munos. “Good drugs with large treatment effects go through the clinical research timeline a lot faster and at much lower cost than others.”
Finally, investigative site and vendor selection are critical factors in reigning in cycle times. Collaboratively engaging with investigators, and motivating them to perform well in tasks such as recruiting and retaining patients, can speed trials and increase their efficiency. Similarly, forming strong relationships with specific vendors and CROs, leveraging their expertise and setting clear expectations for performance helps sponsors to optimize operations and speed development.
Barbara Bolten is a consultant and writer providing services to biotechnology, pharma and consulting companies. She has nearly 20 years as a market research professional at Decision Resources and in independent practice with a focus on therapeutics, diagnostics technologies and business strategies. Barbara also has extensive industry experience in biotech licensing, marketing and research. Barbara holds a Master’s of Science in biology from Tufts University and an MBA from Northeastern University. Email firstname.lastname@example.org.
This article was reprinted from Volume 24, Issue 08, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>