Managing Clinical Trials

Adaptive Trial Design for Phase I, Phase II

Adaptive trial design is a hot issue in the drug development community. Adaptive conferences and web seminars abound, and suddenly, every consultant or vendor to the industry has become an adaptive expert. The FDA and EMEA are also much more receptive to adaptive trials than they were a few years ago. 

However, the picture is a shade different from what the industry had expected. Originally, much of the focus was on adaptive phase III trials as well as on seamless phase II/III trials. Those are, indeed, successfully being implemented today. But the real action is in phase II dose-finding trials and even in phase I trials for safety.

In today’s new issue of Peer Perspectives in Oncology, Medelis talks with Ranganath Nayak, Ph.D., the CEO of Cytel, Inc., about the benefits, opportunities, and challenges presented by adaptive trial design in phase I and phase II studies. Cytel has designed more adaptive trials for industry sponsors than any other service provider and in virtually every therapeutic area, including medical devices.

Dr. Nayak begins by discussing why adaptive trial design is gaining so much momentum in early stage studies. "First, adaptive trials are most helpful when you do not know enough at the beginning of a trial to design it with confidence," he says. "This is much more likely to be true in phases I and II than in phase III.  

"Second, the best way to make expensive phase III trials more successful is to do more thorough work in phases I and II," he continues. "Getting the dose right through well-designed phase I and phase II trials is the best way to maximize success in phase III, which then leads to a higher rate of NDAs. “

Dr. Nayak offers insight and expertise on a variety of issues surrounding adaptive trial design, including:

• Commercial, ethical, and budgetary benefits of the adaptive trial model;
• Statistical and data issues;
• Changing to the adaptive model across multiple sites;
• Safety issues to consider;
• Budgeting for an adaptive trial;
• Dealing with independent decision-making bodies;
• Patient consent and communication issues;
• Medical supply logistics;
• Other best practices and planning issues.

Download the abstract here; you’ll also gain access to the other issues in the series, and we’ll notify you of future publications as well.  

Dr. Alan Sandler, Dr. James Cassidy Join Medelis' Medical Advisory Board

We’re pleased to announce more company news today:  Two leading oncology researchers, Dr. Alan Sandler of Portland, Oregon and Dr. James Cassidy of Glasgow, Scotland, have joined our Medical Advisory Board.  

Alan Sandler, M.D. is a Professor of Medicine in the Division of Hematology & Medical Oncology, Department of Medicine, at Oregon Health & Science University in Portland, Oregon. Board-certified in Medical Oncology and Internal Medicine, he serves as the Division Chief of the Hematology & Medical Oncology Division and holds the DeArmond Chair for Clinical Cancer Research. He specializes in cancer and blood disorders with a special interest in lung cancer, and he is widely considered a key opinion leader in the development of targeted therapies in the treatment of thoracic malignancies.

Dr. Sandler is a member of the American Society of Clinical Oncology and the Eastern Cooperative Oncology Group, where he serves as the Co-Chair of the Thoracic Committee. 

James Cassidy, MBChB, MD, MSc, FRCP is a leading researcher in anti-sickness compounds and innovative approaches to drug-resistant tumors. Dr. Cassidy is a Professor of Oncology and heads the Medical Oncology Department and the Division of Cancer Sciences & Molecular Pathology at the University of Glasgow, Scotland. He heads the Centre for Oncology and Applied Pharmacology (COAP) and has his own Cancer Research UK (CRUK) lab based program exploring methods for gene and drug delivery. He also heads the Glasgow Experimental Cancer Medicine Centre (ECMC) which is focused on Good Laboratory Practice (GLP) quality assured assessments of molecular markers, pharmacodynamics and pharmacokinetics of novel agents at the clinical/lab translational interface.

On the clinical side, Dr. Cassidy runs a service for colorectal cancer patients and has a major commitment to early phase clinical studies of innovative therapies. 

In our formal news release, Medelis president and CEO Bob Bosserman says, “Medelis is very privileged to add Dr. Cassidy and Dr. Sandler to our distinguished group of expert advisors. They strengthen our ability to provide clients with cutting-edge expertise and assistance in the development and advancement of personalized therapies, which will ultimately help improve the treatment options for clinicians.  They also further strengthen our relationship with the clinical research community that directly cares for cancer patients and closely understands their needs.”

“Both of these physician/researchers can now bring their clinical experience to bear on the unique study design and management issues that our biotechnology and pharmaceutical clients face in the oncology drug development process,” Bosserman adds.

You can find Dr. Sandler’s full bio here and Dr. Cassidy’s bio here.

"Context of vulnerability" and its role in targeted drug development

Renowned cancer researcher Dr. Daniel Von Hoff and his team at TGen are fervent believers in a new approach to developing novel therapies for patients with pancreatic cancer. Their rationale, dubbed “context of vulnerability,” is a powerful new drug development paradigm that’s generating impressive results.

Medelis has just published a free downloadable interview with Dan (download it here) as part of our “Peer Perspectives in Oncology” series.  In the abstract, Dan explains how this model has already led to promising discoveries and is changing the future of oncology drug development. 

“Context of vulnerability,” a term coined by TGen’s Spryo Mousses, Ph.D., refers to the genetic configuration in a patient’s tumor that makes it susceptible to a specific drug.  “Context of vulnerability provides the genetic rationale for a targeted therapy,” Dan explains.

In the abstract, he provides examples of context of vulnerability in use.  “One way to establish the context of vulnerability is to work backwards from the result,” he says.  “For instance, in a phase I or phase II trial, you treat a certain number of patients, and when someone responds, you have to ask yourself, ‘Why did that patient respond?  What was the vulnerability in this specific tumor or patient?’  The patient either had a genetic lesion or tumor stroma that was susceptible to the drug in some way.”

Dan explains that context of vulnerability can improve a sponsor’s chance of seeing efficacy during an early-stage trial with a much smaller n.

“If you let context of vulnerability guide drug development, you would put only those patients who have the appropriate susceptibility to the drug on trial,” he emphasizes.  “It’s essentially how Herceptin® got approved with an n of 480.  If they hadn’t pre-selected patients for the context of vulnerability, estimates say that it would have taken about 23,000 patients to get the drug approved.”

Throughout the interview, Dan addresses many of the questions and opportunities presented in this model:

• How context of vulnerability provides a genetic rationale for a targeted therapy;
• How to establish a patient’s context of vulnerability;
• How using context of vulnerability to guide drug development can improve your chance of seeing efficacy with a much smaller n;
• Incorporating context of vulnerability as the oncologist’s “sixth vital sign;”
• A case study of context of vulnerability in use and how it improves patient care and new agent development;
• The gap between known contexts of vulnerability and available therapeutics;
• How CMOs can flip their drug development planning to leverage this approach;
• Feedback from the FDA, national and international groups;
• Targeted therapeutics and the future of oncology.

The abstract is the fifth in Medelis’ “Peer Perspectives in Oncology” series, and you can download the entire series here.  You’ll receive email notices when future issues are published as well.

The "Lost Opportunity” in Phase I Oncology Trials

Cancer drug developers traditionally use the phase I trial solely to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a drug.  Today, we’ve published a free new downloadable abstract, "The Lost Opportunity in Phase I Oncology Trials," an interview with renowned oncology investigator Daniel D. Von Hoff, M.D.  In the interview, Dr. Von Hoff advocates for a phase I approach that looks beyond toxicity and gleans meaningful efficacy data, creating a more compelling rationale for further investment and improved patient care.

“A Chief Medical Officer looking at the phase I typically sees it as a toxicity trial, not a therapeutic trial, because of course it is not randomized,” Dr. Von Hoff explains. “But we - doctors at the bedside and the patients themselves - do not see it that way. We are looking for improvement and survival. [The phase I] is an opportunity to look for therapeutic effect as well because it might just be there.”

Dr. Von Hoff supports an additional analysis that uses a cancer patient as his or her own control.  Rather than solely relying on the traditional data captured in normal phase I protocols, he recommends measuring the tumor’s “time to progression” on the current drug versus the tumor’s “time to progression” on the patient’s previous treatment.  This data — time to progression on each drug — should be systematically tracked in the protocol so it becomes part of each patient’s data bank.

“I have never seen a CMO plot time on a new drug versus the time on a just-prior therapy to build a story for raising money,” Dr. Von Hoff continues. “This idea of using the patient as his or her own control is a lost concept in drug development. Dr. Bob Temple at the FDA, an icon in clinical trial design, calls it a lost art. He’s referring to the ability to document changes in the natural history of a patient’s tumor, and how this information can give you a sense of whether the drug will work.”

“If you treat 30 patients and 30% stay on a new therapy for a longer time than the just-prior drug they had progressed on, then that would justify a deeper investment,” he explains.  “Patients’ tumors grow at an inexorable, ever-quickening rate. If you find an agent that can taper that growth, then it is probably doing something and should be pursued.”

“There is no question in my mind that, if a CMO started comparing time on new drug versus time on just-prior therapy, the rewards are there – both for the patients and for the progression of the drug. All it takes is a more proactive approach to the phase I. It is so simple yet I have never seen a CMO adopt this.”

In the abstract, Dr. Von Hoff answers many questions about this “lost art” in the phase I trial.  Download the full issue here; you’ll also gain access to the other issues in the series, and we’ll notify you of future publications as well.  

Dr. Dan Von Hoff honored at Governor’s Celebration

Our colleague Dan Von Hoff, M.D., a founder and shareholder of Medelis and the chairman of our medical advisory board, was recently named Arizona’s ‘Community Service Leader of the Year’ at the 2008 Governor’s Celebration of Innovation in Phoenix. 

A member of the NIH’s National Cancer Advisory Board, Dr. Von Hoff is a world-renowned cancer researcher who has devoted more than 35 years to two primary goals: identifying the best new anti-cancer agents to treat patients and curing pancreatic cancer. He has published more than 540 scientific papers, more than 130 book chapters, and nearly 950 scientific abstracts. He also holds a dozen patents for new anti-cancer agents and medical devices.  (Full bio here.)

The annual award honors an organization or individual who contributes to Arizona's technology industry through relentless community involvement, leadership, visibility and excellence in economic development activity.

Medelis will soon publish a new issue of “Peer Perspectives in Oncology” featuring an in-depth interview with Dan about oncology phase I trials.  He describes how Chief Medical Officers can design better phase I trials to glean meaningful efficacy data by using the patient as his or her own control. He further explains how a CMO can gather evidence showing a drug changes the natural history of a patient’s disease, demonstrating improved care and a stronger case for moving a drug into phase II. 

In our summer 2008 issue, Dan offers a detailed look at “The Complete Phase Ib,” a clinical trial structure that creates rapid accrual rates, substantial economies of scale and significant time savings for sponsors versus the traditional sequential approach.

You can download past issues and sign up to be notified of future publications here.

Personalized Genomics: The First Report of a Cancer Genome

As reported by the New York Times last week, Washington University recently completed a study that decoded the entire genome of a cancer patient. The patient, a woman in her 50s who died of leukemia, became the first cancer patient and the first female to have her entire genome decoded.

To protect the patient’s identity, the data will be available to scientists only.

While the finding won’t help patients right away, the controversial project, funded primarily by a private donor, could open the door to entirely new approaches to treat cancer.

A cancer expert not involved with the study, Dr. Stephen Nimer, chief of the hematology service at Memorial Sloan-Kettering Cancer Center, called the research a “tour de force” and the report “a wonderful paper.” He said the whole-genome approach seemed likely to yield important information about other types of cancer as well as leukemia.

While scientists have debated the validity of sequencing the whole cancer genome, the study was possible due to recent advances in technology that have made it easier and cheaper to analyze 100 million DNA snippets.

Dr. Richard K. Wilson, director of Washington University’s Genome Sequencing Center and the senior author of the study, sees a bright future for DNA sequencing. “That’s personalized genomics, personalized medicine in a box,” he said. “It’s holy grail sort of stuff, but I think it’s not out of the realm of possibility.”

Dr. Wilson said he hoped that in 5 to 20 years, DNA sequencing for cancer patients would consist of dropping a spot of blood onto a chip that slides into a desktop computer that produces a report suggesting which drugs will work best for each patient.

Some feel that this study signals a change in the oncology drug development landscape. If personalized medicine for oncology becomes a reality, it could signal the end of the “one-size-fits-all” oncology blockbuster drug. Patient survival rates should increase, because cancer patients and oncologists will have a greater selection of drugs and more data to predict efficacy.

The real change will be in the drug development process: Biotech and pharma will need to create more varieties of drugs that affect different genomes. Efficacy rates should improve, but each drug will treat far fewer patients. Clinical trials will be smaller and faster, as many of the drugs should receive FDA Fast Track and/or Orphan Drug status.

That puts quite a burden on oncology drug developers. Not only do they need to shoulder the additional costs of creating more drugs (that will produce lower revenues per drug), but they will also have to create more efficient trial designs to handle the larger number of smaller, quicker trials for each drug.

One way to accomplish this is to run phase I and/or phase II trials in parallel instead of running multiple separate trials. For a deeper discussion of this strategy, check out Dr. Daniel Von Hoff’s 'The Complete Phase Ib' Insider Abstract.

But the biotech and pharma industries will adapt. If the personalized genomic predictions are correct, the burden will be worth it when powerful treatments are developed to match common genomes.

Excellent cancer discussion on the Diane Rehm show

Yesterday morning’s Diane Rehm Show on NPR featured an excellent, detailed discussion about cancer and genomics research in terms that are very understandable for patients, families, and the general population.  Diane’s guest, Dr. Bernadine Healy, is the health editor of U.S. News & World Report, the former director of the National Institute of Health, the former director of the American Red Cross, and the author of “Living Time:  Faith and Facts to Transform Your Cancer Journey.”

In the opening of the “New Approaches to Treating Cancer” segment, Dr. Healy, a cardiologist, touches on her own personal journey with cancer; she was diagnosed with a malignant brain tumor on Valentine’s Day 1999.  “One of the sad things about cancer is that so often it hits in the prime of life,” she explains.  “Virtually everybody is touched by cancer, either directly themselves – about 40% of people – but also through their families.  Cancer is a family effort; it’s a family disease.”

They go on to discuss, in nontechnical terms, how the mapping of the human genome offers the possibility of a personalized approach to diagnosing and treating the disease, along with the latest developments in the war on cancer. 

If a family member or friend is learning about cancer, this segment is an excellent resource.  Here are several links you can share:

• You can listen to the broadcast via Windows Media Player or Realplayer here. 
• Download the MP3 here. 
• Subscribe to all of the shows via podcast here. 

Dan Von Hoff discusses "The Complete Phase Ib"

Medelis has published a free new downloadable abstract, "The Complete Phase Ib: An Approach to Getting to Phase II Faster," an interview with renowned oncology investigator Daniel D. Von Hoff, M.D. 

"The typical phase I approach is essentially serial drug development, which involves running multiple separate trials,” Dr. Von Hoff explains at the beginning of the interview.  "Each site at each trial adds a layer of time, cost, and management oversight. What I call 'the complete phase Ib' is a simple solution that essentially tests the various drug combinations in one phase Ib with multiple arms run in parallel.

"For example, assume you have good preclinical data on a single agent that may be more effective in combination with another agent—for example, a monoclonal antibody plus gemcitabine (GEMZAR®)," he explains. "Most Chief Medical Officers anticipate that the pivotal clinical trials will be standard therapy with or without the new drug, and they prepare for that eventuality by conducting a phase I trial of the combination. Typically, this involves launching five, six, or sometimes more combination phase I trials. Each trial has to be negotiated and managed separately, and each must have its own protocol, adding layer upon layer of cost and effort.

"The strategy I'm suggesting eliminates all these separate serial trials because it puts the combinations into one phase Ib trial."

Dr. Von Hoff offers a detailed look at this approach and the many benefits to sponsors, patients, and investigators, including:

• Patient accrual and treatment benefits
• How the approach can "rescue" patients
• Dosing strategies
• Logistical considerations
• Cost and timing considerations
• Effects on phase II studies
• Reactions from the FDA investigators, sponsors and patients

The abstract is the second in Medelis' "Peer Perspectives in Oncology" series.  In the first issue, "Patient Safety in Clinical Trials," Dr. James Gourzis discusses recent issues in patient safety and the role of sponsors, CROs, IRBs, DMCs and the FDA in ensuring patient safety in future clinical trials.

You can download each of the interviews here.  You’ll receive email notices when future issues are published as well.

FDA Commissioner Launches A Blog

FDA Commissioner Andy von Eschenbach has joined the blogosphere with a new weekly column, "Andy's Take," for the American public. 

In his inaugural post, he explains, "As Commissioner, I want to give you my take on some of the events about food and medical products that you have been hearing about in the news.

"I want to give you the inside story on some of the things that will soon be announced at the FDA so that you have my insights about why these initiatives are of such great importance to protecting and promoting your health," he continues.

So far, he has written about heparin, integrated medical products, and liquid dietary supplement products that contain hazardous levels of selenium.

The blog also offers audio versions of the posts, and you can sign up to receive new articles via email.

Patient safety abstract available for download

Medelis has just published “Patient Safety in Clinical Trials:  A Q&A with James T. Gourzis, M.D., Ph.D.” It’s the first abstract in “Peer Perspectives in Oncology,” a new Q&A series that brings together respected researchers to discuss issues that face Chief Medical Officers today: rising costs, optimum patient accrual, targeted therapeutics, patient safety, FDA regulations, efficacy, budgets, and timelines.

Patient safety has always been the industry’s focus during clinical trials. However, a recent spate of well-publicized patient safety issues has increased public scrutiny and the industry’s desire to improve study quality, resulting in larger, longer, more expensive trials.

In the piece, Dr. Gourzis discusses a variety of critical issues affecting patient safety:

• Factors that have launched patient safety to the forefront of public scrutiny, including the effects of increased reporting requirements
• What to look for when evaluating CRO excellence and commitment to patient safety
• Unique safety considerations in oncology trials and the ramifications of the rare toxicity
• Optimizing the role of the Data Monitoring Committee
• Budget decisions that support patient safety
• The evolution and future of FDA regulations

You can download the abstract here and sign up to receive future publications in the series as well.