Magazine Article | February 2, 2014

Lilly's Approach To The Clinical Trial Paradox

Source: Life Science Leader

By Rob Wright, Chief Editor, Life Science Leader
Follow Me On Twitter @RfwrightLSL

When I sat down with Eli Lilly (NYSE: LLY) and Company’s chief medical officer and coleader of the company’s Development Center of Excellence, Timothy Garnett, it was shortly after the drugmaker’s annual investment community meeting where bankers grilled the leadership team with questions. Although sensationalistic headlines of Lilly’s recent Phase 3 trial failures (e.g. the antidepressant edivoxetine) may have attracted the eyes of the uneducated, those of us in the industry know that long-term success in drug development — like investing — requires patience and perseverance. That’s why it should come as no surprise that when I asked Garnett what he is doing to speed up clinical trials he responded, “Sometimes you have to slow down in order to speed up.” Indeed, a counterintuitive notion when you consider Lilly will be losing patent exclusivity for another one of its blockbusters, Evista, this March. Yet during our interview Garnett, a 20+ year industry veteran, made a strong case for following this paradox (slowing down to speed up) if improved productivity and performance is your goal.

Slow Down To Speed Up
Businesses fearful of losing their competitive advantage make the common mistake of spending too much time and resources seeking ways to pick up the pace, when instead they should try slowing down. Here’s why. A Harvard Business Review (HBR) study of 343 businesses revealed that companies that embraced business-accelerating initiatives in order to gain an edge ended up with lower sales and operating profits than those pausing at key moments. Firms that “slowed down to speed up” improved their top and bottom lines, averaging 40 percent higher sales and 52 percent higher operating profits over a three-year period.

These findings appeal to Garnett who revealed Lilly’s average lifetime development cycle for a molecule is about six months longer than the industry average of 12 years. The company wants to shorten its clinical development time by five years by the year 2020. But Garnett admits there is much work to be done and unfortunately no magic bullet. “We know there are a number of approaches we can take to really improve our chances of clinical development,” he states. One of these is to make sure you have done the right Phase 2 studies. According to Garnett, many companies go into Phase 3 without having performed the proper experiments. As a result, these companies end up having to do large Phase 3 studies. “They are essentially doing their dose findings in Phase 3,” he says. “You can’t afford to do that. Though one of the most basic components of Phase 2 studies, dose finding is also that which gets compromised most frequently.” Rather than trying to rush through Phase 2 in an attempt to get quicker approval, Garnett advises taking more time in Phase 2 if you want to accelerate your Phase 3 study. In addition, he suggests looking closely at comparator data. “In the current environment it is no longer just about proving efficacy and safety, but about proving you have an innovation that is an advance on what is already available,” he states. Garnett thinks the sooner you can get comparator data the better. Then, be honest with yourself about what you find, making sure your study is big enough to give you a sense of confidence that it is reproducible. Garnett attributes many of the recent Phase 3 failures to companies failing to slow down in Phase 2 or seeking a shortcut. “Researchers have not confirmed they have a differentiated molecule with a strong enough signal and, unfortunately, discover this fact in Phase 3,” he says.

Conducting scenario planning during Phase 2 may have the appearance of slowing you down, but will actually speed you up when entering Phase 3. Garnett says, “By scenario planning during Phase 2 you are attempting to anticipate various outcomes, potential development programs, and so on, based on a subset of data.” Doing so, he says, can accelerate a company’s ability to enter Phase 3 by a year or more. He admits there are certain limits to how quickly you can move from Phase 2 to Phase 3 (e.g. meeting with the FDA), yet he admonishes, “There is really no excuse for it to take a year or a year and a half, which is quite common.”

One of the challenges with attempting to implement clinical trial scenario planning is that, often, scientists want full data — to ensure certainty — before planning. Garnett suggests communicating the value of scenario planning to scientists in not only time and dollars saved, but the potential revenue generated for your company. “I think you can easily shave six to nine months off of every development program if you do it properly, and that means getting the drugs to the patients sooner.”

Practicality Of Patient Centricity
It should come as no surprise that treating a person as a human being, as opposed to a number, results in better patient outcomes. Why can’t these same patient-centered healthcare delivery principles be applied in the clinical trial space? “We talk a lot on the commercial side about patient experience as being one of the triggers for why a patient presents for treatment,” says Garnett. Lilly is starting to apply lessons learned on the commercial side in the clinical trial world — starting with patient recruitment.

“The biggest determining factor of how long it is going to take to run a Phase 3 study is the amount of time it takes to recruit patients,” says Garnett, who sees no reason why companies can’t have patients ready from the start. One way to do that is to get better at engaging with patient support groups, something done well by rare/orphan disease drugmakers. “Why can’t you do that for Alzheimer’s?” he asks. “There is no shortage of Alzheimer’s patients.” Garnett believes if patient engagement works well for healthcare providers like hospitals, why not take the same approach when trying to recruit for clinical trials. “We are looking at running a Muscular Dystrophy trial. As a result, we are in very close contact with MD support groups,” he shares. “We know that when we are ready to start, we will have every patient ready to be screened and entered.” Getting better at recruiting is a critical component to successful clinical trial execution. So too is getting folks to want to participate more than once.

One of the realities in the clinical trial space is the majority of patients and investigators who participate in a study do so only once. “What factors make this an experience participants often don’t want to repeat?” asks Garnett. “How can we become more patient and investigator friendly in an ever increasingly competitive environment?” Garnett thinks the industry needs to challenge itself to improve the patient and investigator experience. One solution involved the collaboration between Lilly, J&J, and Merck to share trial investigator good clinical practice (GCP) training information. Prior to this, if investigators worked for one of these companies, they had to do three separate, and essentially the same, training sessions. The collaborative effort to share the GCP info was well received by the industry. It eliminated redundant training, saving money for everyone, and the investigators’ most valuable resource — time. TransCelerate BioPharma, which now numbers nearly 20 member companies, built upon this in developing its site qualification and training resources.

There are a number of ways to improve the clinical trial experience for patients. For example, participating in a placebo-controlled trial is not very appealing for someone seeking real therapeutic benefits. Garnett admits in early phases it is difficult to avoid the placebo problem. Though it can’t always be eliminated, it can be mitigated through modeling via new statistical approaches. “These models allow you to create a very large virtual placebo group so the actual placebo group can be small.”

Garnett believes improving communication with participants can also be helpful — especially when you consider the likelihood of increased reliance on patient-reported outcomes. A means of doing this will be through the use of patient-friendly devices (i.e. their smartphone) to gather information and provide real-time feedback. Device familiarity and real-time feedback can create greater patient engagement. “As a result, it is a little easier to educate them about what the clinical research is all about,” he states. “Further, they become an active partner, as opposed to a passive participant.”

He says another opportunity for improvement is the reduction of the number of pages in informed consent documents, which can range from 20 to 50+ pages. The key is to try new approaches and have a willingness to learn from failures as well as successes.

Learning From Failures As Well As Successes
“Like every other company, Lilly has had Phase 3 failures, which are extraordinarily expensive and demoralizing for an organization,” admits Garnett. For example, the company announced in December that edivoxetine did not meet primary end points of Phase 3 clinical studies as add-on therapy for major-depressive disorder. Prior to this, Lilly announced Phase 3 failures of enzastaurin for large B-cell lymphoma, solanezumab for Alzheimer’s disease, and ramucirumab for breast cancer. Despite these and other setbacks, the company continues to plow forward, announcing an additional late-stage trial of solanezumab and an FDA priority review of ramucirumab for the treatment of gastric cancer. The lesson to be learned here isn’t to fear failure, but rather to learn from it and overcome — a key longstanding component of the Lilly culture. For example, in 1999 Lilly halted trials of an experimental chemotherapy drug, Alimita, after discovering three significant adverse events. Many thought this might be the end of Alimita. However, researchers did not want to give up on the drug because of the strong evidence it could reverse tumor growth. In this case, persistence paid off with the drug gaining FDA approval in 2004. Today, Alimita has four different FDA-approved cancer indications. More recently, positive Phase 3 results for Lilly have led to a record seven regulatory submissions of four molecules in 2013 and the expectation of launching three drugs in 2014 — empagliflozin, which was codeveloped with Boehringer Ingelheim for type 2 diabetes; dulaglutide, a once weekly treatment for type 2 diabetes; and ramucirumab.

Just as Lilly continues to learn from its failures, it also does so from its successes. The company designed and conducted an adaptive, dose-finding, seamless Phase 2/3 trial study with dulaglutide. According to Garnett, the design was outstanding, something to be proud of, and probably saved the company about a year on the entire Phase 3 program. “But that savings was lost because we spent a year gaining agreement on the design with the FDA, as well as internally,” he laments. Being one of the first companies to do a substantial Phase 2/3 adaptive trial design may have been one of the reasons why it took so long. “We need to take that learning and apply it to the next program. We paid a high price in terms of time because not only did we need to familiarize regulators to the approach, but internally, we needed to develop a level of comfort and confidence with the adaptive design concept,” Garnett states. “There were a lot of people within the organization who were nervous about it.” The lessons learned from this success include gaining alignment on the design internally first, and communicating your intentions with regulators clearly, frequently, and proactively throughout the process. Garnett feels there is no question the dulaglutide adaptive trial design saved the company time. In addition, he suspects more companies will begin using adaptive trial design because it provides high-quality data, reduces risk, and results in a much clearer direction for Phase 3 trials. “This is true as long as you aren’t spending too much time on getting folks internally aligned on the design,” he concedes. Obviously, there is a fine line to managing the clinical trial paradox when determining how much you need to slow down if you want to truly capitalize on the possibility of being able to speed up while improving productivity and performance. Having produced the strongest pipeline in its 137-year history, Lilly appears to have struck the right balance. At this writing, the company had 13 potential medicines in Phase 3, the final stage of clinical study, or under regulatory review. In addition, Lilly has 26 more projects in Phase 2, which is five times more than it had a decade ago. For the time being, slowing down and staying the course seems a sound strategy.

Staying On Task

When I had the opportunity to visit Lilly’s global corporate headquarter in Indianapolis, I was impressed with the size of its campus. With 10,000+ employees, it was larger than the town in which I grew up. However, Chief Medical Officer Tim Garnett quickly reminded me it is not the biggest company in the pharmaceutical industry. Though still in the top 10, Lilly generates about one-third the revenue of J&J and half that of Merck. “So when it comes to therapeutic focus, we have to be pretty disciplined on where we choose to play,” he states. For the moment, those areas are primarily neuroscience, diabetes, endocrine oncology, and auto-immune disorders.

Having a focused approach and staying on task can prove to be a challenge when it comes to drug discovery. “You don’t always know the potential indications of the compounds when you are first discovering them,” Garnett states. “History points us towards many molecules that weren’t what we thought they would be.” For example, Pfizer was seeking a new treatment for angina, but instead found a medicine for erectile dysfunction — Viagra. Similarly, Lilly’s blockbuster osteoporosis drug, Evista, started off as an oncology agent. “I think there was a time when industry had the freedom to run with those potential new therapeutic areas and indications,” reflects Garnett. “These days, we are a little more cost conscious.” To stay on task, Lilly seeks to find alternative ways of developing drugs — such as partnering with the NIH.

In September 2013, Lilly announced it had received financial support from the NIH Therapeutics for Rare and Neglected Diseases (TRND) program for its preclinical-stage research of a potential treatment for hypoparathyroidism, which causes a lack of parathyroid hormone. This can lead to a number of symptoms, such as anxiety, depression, cataracts, muscle cramping, convulsions, and irregular heartbeat. Lilly was the first major pharmaceutical company to gain support from the TRND program, which seeks to de-risk development of rare disease treatments. Rare disease drug development is clearly not a focus for the folks at Lilly, but neither is turning down the opportunity to deliver timely and valued medicines to patients. “We have a finite capacity to spread the R&D dollars,” Garnett reminds. “We can’t afford to place our bets too broadly, but we don’t want to be turning down the next potential Evista.” Participating in this type of program, as well as developing others (e.g. Lilly’s open innovation platform), facilitates staying on task and therapeutically focused, while also allowing for the serendipity of drug discovery.

So You Want To Be A Chief Medical Officer?

Since completing his medical degree, Lilly’s chief medical officer (CMO), Tim Garnett, has spent the bulk of his professional career working in the pharmaceutical industry. One of the greatest challenges he sees physicians face when making the decision to enter the industry is adapting to the corporate culture. “Physician training and practice are based on the concept of individual decision making and personal accountability,” he attests. “However, pharma companies are based on collective decision making and joint accountability.” This is a concept Garnett thinks many physicians struggle with when joining pharma companies. He says it also can prevent talented medical doctors from realizing their true potential to becoming industry leaders. “I initially struggled with the decision-making processes of the companies in which I worked,” he admits. “But success in this industry requires an understanding of the corporate culture and your role within the company. Once I came to understand this, I became less frustrated with what I saw as slow or illogical decision making, and I was able to more constructively contribute to the organization’s mission.” If you want to be a successful CMO, Garnett believes you need more than just the technical ability to perform the role. “Understand how decisions are made and influenced in an organization so you can best represent the medical function at the highest level,” he advises.