Written Statement of Oren Cohen, MD, Senior Vice President and Global Head, Early Clinical Development Quintiles

October 9, 2014

Thank you for the opportunity to participate in this important dialogue on vaccines as part of the 21st Century Cures Initiative conversation.

My name is Dr. Oren Cohen; I am Senior Vice President and Global Head of Early Clinical Development at Quintiles. Headquartered in Durham, North Carolina, we are the world’s largest provider of biopharmaceutical development and commercialization services. 

About Quintiles

We have 30,000 employees globally, approximately 8,000 in the United States and more than 2,800 in North Carolina. Together, we deliver services in over 100 countries and are engaged every day in helping bring better medicines and vaccines to patients faster.

If you take a prescription medication, there is a very good chance that Quintiles helped develop or commercialize it, as Quintiles helped develop or commercialize all of 2013’s top-100 best-selling drugs on the market.  

Our company is known best for its management of clinical trials, helping pharma and biotech companies navigate the highly regulated environment of the multi-phase clinical development process. The studies we conduct and data we generate on behalf of our biopharma customers are what underpins the information you see on your medication bottles and the package inserts.

Vaccine Experience

On the topic of vaccines in particular, Quintiles has helped develop or commercialize all of 2013’s top 35 best selling Vaccine products. In the past five years, we’ve worked on more than 110 vaccine studies and registries, involving more than 250,000 subjects and nearly 4,000 investigative sites in 55 countries

In 2013, we received the Vaccine Industry Excellence (ViE) Award for Best Clinical Research Organization (CRO) at the World Vaccine Congress for the third straight year. We are one of five preferred product development providers for the Global Health Clinical Consortium (GHCC); this means we work with most of the major not-for-profit organizations engaged in vaccine research. We are also a team partner for the Department of Defense’s Medical Countermeasures Advanced Development and Manufacturing (MCM ADM) program and have supported a number of vaccine programs sponsored by the Department of Health and Human Services’ (HHS) Biomedical Advanced Research and Development Authority (BARDA) and the National Institutes of Health (NIH).

Our Perspective and Recommendations

The breadth and depth of our experience, as well as our role as a facilitator of the process, gives us a unique vantage point on where the challenges — and opportunities — are in the vaccine and drug development process. We are pleased to be part of this roundtable on improving the discovery, development and delivery cycle for vaccines. 

Vaccines are widely recognized as the most successful and cost effective approach to minimizing the incidence and prevalence of many infectious diseases. As scientific research pushes the boundaries of our understanding of disease pathogenesis, there are great opportunities to prevent and treat  infectious diseases that continue to plague the lesser developed world, but also for treating cancer, inflammatory diseases such as rheumatoid arthritis, diabetes and more. As our world grows ever more interconnected, emerging and re-emerging microbial threats are becoming the norm. Whether it is pandemic influenza or the threat of a global Ebola outbreak, the importance of vaccine research and development has never been more critical to global public health and security.

At issue today – how can the discovery, development and delivery of safe and effective vaccines be optimized to ensure these important advances most efficiently find their way to people who need them?  My remarks focus on three areas:

Process — Reducing clinical trial timelines by addressing inefficiencies and redundancies

Pathways — Establishing alternative regulatory pathways that adapt to scientific advances and minimize clinical development times across phases, while safely bringing needed vaccines to market sooner

Preparedness — Ensuring we are ready to take advantage of better technologies and methods inherent to the development of vaccines

Process

It is well documented that clinical trials are taking longer and are becoming more complex — and, thus, more expensive. Vaccine trials can be particularly challenging for a number of reasons, including the large sample size and longer duration needed in Phase III to show efficacy in preventing infection compared to natural incidence; the high bar for establishing safety in an otherwise healthy population; and rapid recruitment and data collection required, especially with influenza. The following are some pragmatic steps that could reduce unnecessary redundancies and inefficiencies in the process, particularly for vaccine development.

Ethics Committee/Institutional Review Board (IRB) Approval: One bottleneck that can be addressed is the ethics review, or IRB approval process (as it is called in the U.S.). IRB approval of a protocol must occur before a site, such as a hospital, doctor’s office or academic medical center, can be ‘opened’ and begin recruiting patients.

Our experience indicates that there is wide variability in the review timelines of among IRBs.  Some IRBs review a protocol within days, whereas others take weeks if not months to perform the same task.  While IRBs must have the time and experience to properly review protocols, the variability that is observed needlessly delays the initiation of studies.

The delays and resource costs become exponential when local IRB review is repeated for a multi-site project. For a 100-site study with two study protocol amendments, the identical protocol and amendments could be reviewed as many as 300 times (once by each site).  If these reviews were conducted swiftly, and with significant scientific and ethical rigor, such duplication, while inefficient, would not delay the initiation of studies.  However because of the observed variability of review-times, such duplication of efforts magnifies the existing inefficiencies of IRBs.

Recommendation: One approach would be for the Food & Drug Administration (FDA) to require sponsors, when seeking to develop a new product under the Breakthrough Designation, to agree to use only research sites that will either 1) accept mutual recognition for central IRB review of multi-site trials OR 2) commit to IRB review within a stipulated period of time, e.g., 30 days.  If a therapy is important and promising enough that the FDA gives it priority and agrees to move quickly, so should other parties engaged in the development project.

Electronic Source Data Capture: During the conduct of a clinical trial, one of the biggest drivers of time and costs is source data verification (SDV).  SDV is conducted by a study monitor who visits sites and checks that the information recorded in each patient’s trial record — called a case report form (CRF) — matches what was entered in the patient’s medical chart (the source). This transfer of information from one system to another, especially if either is paper-based, is prone to error, creates extra work for the site staff and necessitates intensive verification for accuracy. It also creates a lag in availability of data for aggregate review.

In the case of vaccine trials, which generally involve healthy volunteers, there is great opportunity to use eSource Data Capture. The investigator enters the patient visit data once, directly into the electronic CRF, which is then considered ‘the source’ and does not require the additional verification step.

Quintiles sees the January 2012 “FDA Guidance on Electronic Source Data in Clinical Investigations” and subsequent efforts to promote eSource Data Capture (January 2014 webinar) as welcome steps, as we estimate the use of eSource Data Capture in vaccine trials could save time and costs by up to 15-20%. 

However, many study sponsors are reluctant to adopt new technologies and approaches that affect data and could later be called into question by regulators. In fact, a recent qualitative study we conducted showed sponsor reluctance to believe regulators would accept 100% eSource data for vaccine studies.

Recommendation: Congress could encourage adoption of eSource Data Capture by requiring its use in federally funded or supported studies for vaccines. This would have the downstream effect of giving industry confidence of FDA acceptance of eSource Data. Additionally, FDA should continue to encourage eSource Data Capture and could be asked to report to Congress annually on the progress made toward the overall use of electronic data capture in clinical trials, as well as consistency of FDA audit findings results with the spirit of the guidance.

Data Standardization: Standardization of clinical trial protocols and data collection requirements would help reduce the repetitive activities that happen across trials and be particularly helpful in trials requiring the patient volume and quick data turnaround that vaccine trials do.  Clinical Research Forms and supporting systems are often recreated for different studies, and use different terms and abbreviations for even the most common measurements such as blood pressure. Among the private sector initiatives, the Clinical Data Interchange Standards Consortium (CDISC), a group Quintiles helped found, has recently created data standards for use in a number of therapeutic areas.

Recommendation: Congress can make a difference by encouraging or requiring the NIH, FDA, Patient-Centered Outcomes Research Institute (PCORI) and other government-sponsored research initiatives to use a common set of data standards, such as those created by CDISC.

Regulatory Pathways

Today’s technologies and science offer the potential to address both old and new disease threats while keeping vaccines safe and accelerating access in ways not envisioned  by the “Gold Standard” three-phase randomized clinical trial (RCT) model that has been in place for more than 50 years.  Quintiles supports the adoption of Alternative Development Pathways alternatives to the traditional three-phase model to speed the introduction of vaccines and other promising therapies to address unmet medical needs for serious or life-threatening conditions.   An example of this is the Adaptive Licensing approach that the European Medicines Agency (EMA) is now piloting.

One approach would allow for an accelerated ‘conditional’ approval of a new vaccine based on pre-registration studies in smaller populations that meet rigorous, pre-defined safety and short-term efficacy standards, followed by robust, well-conducted and scientifically valid post-marketing registries and observational studies to ensure safe use and confirm effectiveness over time. In our experience, this combination augments what can be seen in pre-registration studies and can serve as an effective way to balance addressing urgent patient need, while protecting against risks only uncovered in larger studies.   

Such an approach would be consistent with a cooperative agreement grant announced by the FDA’s Center for Biologics Evaluation and Research (CBER) and the World Health Organization (WHO) in 2012 regarding the development of new vaccines, which said, “There is increased interest in finding innovative study designs that optimize allocation of study participants between late phase clinical trials and post-marketing safety studies, changes that could lead to more rapid access to lifesaving vaccines while still obtaining the data necessary to ensure vaccine safety before universal use. ” 

Recommendation: With regard to new vaccines and drugs to address serious and life-threatening diseases, Congress should encourage the FDA to consider alternative development pathways similar to the Adaptive Licensing approach that the European Medicines Agency is now piloting.

Preparedness

Preparedness is a cornerstone of public health. This includes not only being ready to respond to today’s threats, but also looking to the future. Particularly, it includes spurring on discovery and development of better approaches to preventing and addressing known and unknown public health threats. 

In that light, we offer two recommendations on what Congress could do to foster these developments and encourage the FDA to be prepared from a regulatory perspective for new ways of developing vaccines. 

Sharing of Precompetitive Data: With the various complexities and the high-risk/low-reward paradigm in vaccine development, collaboration and careful use of resources are critical. To that end, it would be helpful if precompetitive data of no direct commercial value — including placebo data, safety and other data related to vaccines that have failed, are no longer being developed, or are off patent— could be made available for such uses as earlier validation of targets, methods, tools and biomarkers, and modeling and simulation of trial outcomes or sample size.

The FDA has done some work to encourage companies to submit genomic data associated with their early development programs to add to the general body of knowledge; a similar model would be helpful for vaccine development.

Recommendation: FDA could encourage companies to share precompetitive data from studies of failed products, including studies incorporating new virus vectors, biomarkers, etc.  More data would allow for earlier and less duplicative validation of additional tools that would help advance all engaged in vaccine development.

Adoption of new technology:  As we will surely hear in the Roundtable, and as we’ve seen at Quintiles in development programs and in our Phase I clinics, there are many new approaches to vaccine development. Novel molecular targets and exciting developments in nanotechnology, adjuvants, mucosal delivery and recombinant vectors hold promise to deliver highly effective vaccines, potentially requiring only a single immunization.  

Conclusion

On behalf of Quintiles, thank you again for the opportunity to be part of this important event. I will be more than happy to expand upon any of these recommendations, and look forward to your questions and our further participation in the 21st Century Cures Initiative.

1. http://csdd.tufts.edu/files/uploads/Outlook-2013.pdf

2. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057755

3. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000601.jsp&mid=WC0b01ac05807d58ce