Michael Rosenblatt, M.D.

March 2016

How Can We Deliver Life-Enhancing Medicine Faster and Responsibly?

A “moonshot” to cure cancer – that’s how U.S. Vice President Joseph Biden describes his call to generate a decade’s worth of progress in R&D over the next five years to tackle one of the world’s biggest killers. It’s an inspiring and ambitious call to action, and one that can be achieved given the unprecedented recent progress in cancer research. Unfortunately, this may not be true for other diseases crying for attention.

The issue of how we can create and deliver medicines to patients more quickly is a hot topic everywhere in healthcare today. Last summer, when the World Health Organization (WHO) held its first ministerial conference on dementia, many of the sessions focused on improving research and delivering treatments faster.1 Even within the cancer community, the American Society for Clinical Oncology (ASCO) plans to hold at least two headline educational roundtables on expedited clinical trial designs at this year’s annual meeting.2,3 Faster R&D was also the central theme of a panel I was honored to participate in at the recent Partnering for Cures Conference.

Like many of my colleagues, I welcome the growing interest in this subject. Lives are at stake. The real question is how can we shrink R&D timelines without sacrificing what we must learn about the safety profile of a new treatment? We need to speed up R&D, but we must do so responsibly.

Tradeoffs Accompany Speed
In any discussion about the benefits of hastening the delivery of medicine, we cannot lose sight of patient safety. This must be our number one concern.

Today, it is possible to determine the general efficacy profile of a compound, at least with regard to ‘proof of concept,’ with relatively small numbers of patients and in relatively short order. Safety, however, is a different story: assessing safety typically requires experience with larger sets of patients and longer durations of exposure. This means that any system for developing medicines faster may inherently skew our understanding about the overall profile of a medicine – characterizing efficacy before safety if not done thoughtfully. This has huge implications for society as a whole. It means we will need to determine the level of patient risk that we as a society are willing to tolerate. It means we will need to focus on "benefit/risk" – the key issue in all of medicine. And we will need to educate patients, the public and the media to think along these lines.

What makes this challenging is that individual patient perspectives will ultimately decide how we address that issue – the idea of “tolerable risk” is very personal. A single cancer patient, for example, may be willing to accept a level of risk that a government agency deems unacceptable for the general population. The same holds true for an individual suffering chronic pain or another debilitating condition who may be willing to tolerate side-effects and assume potential risks of medication if, on balance, it makes life more productive or joyful.

I believe we can better address this complex question if we re-frame the discussion around the concept of “risk/risk,” rather than the traditional parameters of “benefit/risk.” The benefit/risk paradigm stems from the original charter of the U.S. Food and Drug Administration (FDA). The FDA is chartered by an act of Congress to provide approval for “safe and effective” products for the American population. In my opinion, this charge not only potentially paints a misleading picture of medicine, but it creates an impossible expectation if viewed simplistically. There are no fully “safe” medicines – all medicines have side-effects.

So “risk/risk” more accurately describes the paradigm. As medical professionals committed to patient interest, we are always weighing two types of risk: the risk of a disease condition and its natural history if left untreated, versus the risk of potential adverse experiences from a treatment.

Speeding R&D means we may need to make trade-offs and think differently. If we decide to speed research in areas of urgent patient need, we might have to accept a different level of risk as a society – and we are going to have to inform the medical community and fully brief the public about its many implications. What does it mean to weigh risk against risk? How do we reconcile the need to authorize treatments for large populations with the need to keep decision making about individual benefit/risk squarely inside the doctor-patient relationship? These differing perspectives will come into sharp focus as we drive for greater efficiencies in the process of drug development and approval.

Transformation in Progress
When we look to establish the efficacy and safety of any new medicine, clinical trials are, of course, the gold standard. But that process – plus the steps leading up to them – can be painfully long.

Yes, we’ve recently been able to reduce the R&D timetable for new medicines in fields like cancer. But, on average, the time to complete clinical trials for new medicines has increased from 8.5 years to more than 10 years. There are many impediments to speed. For new osteoporosis medicines, for example, we study double the number of patients in double the number of countries compared to the 1990s. Medicines for many chronic conditions now demand large outcomes trials, which are expensive, complex and take more time to conduct. And payers expect to see increasing amounts of data as they seek to understand the value of a new medicine compared to other available treatments. All of this, of course, is fair and reasonable, but it also serves to slow down the process of making new medicines available to patients.

Barriers remain, but we can take lessons from the recent, unparalleled momentum in speeding cancer R&D, and from creative collaborations that are improving speed and efficiency across research. Some basic learnings include the following:

Learn and adapt – This new era of cancer discovery is driven in part by a growing understanding of the biology of what drives tumor cells and what the body does to keep such growth in check. Knowing more about the genetics and pathways of the disease and about the response of the microenvironment in which cancer grows allows scientists to design approaches to cancer that were only dreamed about just a decade ago.

These insights have helped inspire an unprecedented effort to reengineer the clinical trial design process known as “I-Spy2 (http://ispy2.org/) .” It includes the FDA, the National Institutes of Health (NIH) and the National Cancer Institute (NCI). It is an “adaptive trial,” meaning that it allows us to learn as we go and to use data from early trial participants to guide treatment decisions for patients who enter the same trial later.

I-Spy2 contains a number of striking innovations. It is using biomarkers from individual patient tumors to determine eligibility and identify which treatment might be most effective for a specific patient. It includes a robust informatics system that allows data to be collected, verified and shared in real-time. It will enable researchers to simultaneously and rapidly screen up to 12 cancer drugs from multiple companies. The goal is to shave several years and hundreds of millions of dollars off the process of delivering effective cutting-edge treatments for breast cancer patients.

Other exciting advances in clinical trials include “basket trials,” newer trial designs that researchers, including those in our Merck oncology area have been using recently to test a variety of cancer types in one study, shortening timelines.

Talk early and often with regulators – Spurred by the shared calling to get promising therapies to patients sooner, research-driven companies and regulators are able to work more closely than ever to determine what kinds of data will be needed for approving new therapies. Expedited pathways have been around since the late 1980s, but the level of constructive dialogue around products deemed to warrant faster review has never been better. Of the 45 novel medications the FDA approved in 2015, 60 percent (27) were in one or more expedited categories (Fast Track (14), Breakthrough (10), Priority Review (24), and/or Accelerated Approval (6)). More than one quarter of all new medicines approved last year were cancer therapies.4,5

Collaborate at every stage – Some of the most exciting trends in speeding R&D involve collaborations across the healthcare ecosystem. These include many new and sometimes unexpected partnerships to advance cancer treatment, but also others that advocate ways to eliminate waste and boost overall efficiency in clinical trials and clinical research to benefit all patients.

One example is the Clinical Trials Transformation Initiative (CTTI) (http://www.ctti-clinicaltrials.org/) , co-founded by the FDA and Duke University almost 10 years ago. Today, CTTI has grown to more than 60 organizations: government agencies, patient advocates, professional societies, investigator groups and academic institutions from around the world. Among its official recommendations are tools and ideas to improve recruiting clinical trial participants, to engage with patient advocates, and to initiate new investigators into the clinical trial process and reduce investigator turnover.

Another notable group is the Alliance for Clinical Research Excellence and Safety (ACRES) (http://www.acresglobal.net/) . This partnership consists of an equally diverse and global alliance whose vision is an integrated, collaborative and global system of clinical research to improve what its president calls the “inefficient mess” of bringing safe and effective drugs to market.

These groups are recognized as advocates for change, leaders in identifying what we need to do better. Others have formed to take the lead in executing their recommendations.

Recognizing that responsibility, many in the biopharmaceutical industry are working together as part of a non-profit organization called TransCelerate (http://www.transceleratebiopharmainc.com/) . Since it was launched four years ago, TransCelerate has doubled its membership to include 20 of the world’s leading biopharmaceutical companies. It is working to transform the clinical trial process through 16 distinct initiatives. These include: improving the site investigator experience by eliminating training redundancies; enhancing the already strong progress made on sharing information by collaborating with a non-profit effort called “CDISC (http://www.cdisc.org/) ” that develops and supports global data standards; designing a new paradigm ("risk-based monitoring") to improve the safety and efficiency of clinical trial site oversight; and developing a common “site investigator platform” for interface between sponsors and sites.

In part, TransCelerate is an idea clearinghouse – gathering challenges and solutions that individual member companies have found are common, and then enhancing and packaging those insights for broad, voluntary adoption across industry. It is also catalyzing consensus among other stakeholders; last year, for example, it held working sessions with key government health agencies like the FDA, the European Medicines Agency and the Pharmaceutical and Medical Devices Agency in Japan.

One of the newest and most important areas where TransCelerate is engaged is e-informed consent for trial patients. Language in patient consent documents can be complex, cumbersome and intimidating, which contributes to the low participation and slow recruitment rates that bedevil many clinical trials and cause inefficiencies. TransCelerate is developing a solution called e-consent, a common approach for the electronic consenting of patients using simple language and interactive digital elements to help increase patients’ understanding of all aspects of a study, including tests they may undergo as participants. This also helps to improve regulatory compliance and reduce quality risks.

Promise and Challenge as We Move Forward
The initiatives I’ve reviewed here are beginning to pay dividends, but it is clear that we need to do more to deliver new inventions from our labs to the millions of patients desperately in need. The gratifying progress we’ve seen in cancer research can serve as both an inspiration and a resource for all of us committed to moving faster.

Yet as we move forward, we need to remind ourselves that making bigger strides in speeding the pathway for drug approval may mean a willingness to live with more potential risk as a society. With certain diseases like cancer, this is already part of the conversation. But, overall, given that safety must be our number one priority, we are facing an intrinsic tension that is not going away and that will challenge stakeholders across the entire healthcare community. In my opinion, this subject should be front and center as we move ahead.

I welcome your insights and perspectives.

Thank you and be well,

Michael Rosenblatt, M.D.
Executive Vice President and Chief Medical Officer
2000 Galloping Hill Road
Kenilworth, NJ 07033

1. http://www.who.int/mediacentre/events/meetings/2015/agenda-dementia.pdf?ua=1

2. http://am.asco.org/program-1

3. http://www.alz.org/documents_custom/071415_whcoa_statement.pdf

4. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302

5. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm474696



Michael Rosenblatt, M.D. Biography and CV (https://www.merckcmoviewpoints.com/include/RosenblattCV.pdf)

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