 When evaluating regions in which to expand clinical trials, oncology drug developers must take many factors into consideration, including patient enrollment potential, the region's standard of care, and a myriad of other direct and indirect costs that affect feasibility. Comparator arm drug access and reimbursement policies are other key components that pose a distinct set of challenges to sponsors and which are becoming increasingly important to consider as part of early clinical development planning. Between 2002 and 2007, 41% of all clinical trial sites used by U.S. companies were located outside the United States, so weighing these considerations has become a mainstay in the daily routine of clinical operations professionals.

Due to the limited amount of published data on clinical trial comparator arm reimbursement in Canada, the purpose of this article is to shed some light on the topic so that sponsors can make more informed decisions when evaluating the region as a possible option for geographic expansion. 

Once an oncology clinical investigative compound progresses beyond the Phase I setting, it is subjected to a study design that includes its application either in combination with or compared to a drug that is deemed, by clinical guidelines, to be the safest and most effective in treating a particular cancer indication.  

These comparator drugs, or standard of care, are the benchmark against which new experimental drugs are evaluated. The FDA has published guidelines to support the choice of comparator arm drugs for clinical trials, but this does not address the sponsor's responsibility in assessing a drug's availability, establishing a procurement mechanism, and managing its cost.

  These issues, although administrative in nature, are critical steps that must be skillfully executed to ensure timely execution and return on investment of any clinical drug development program. 

While there appears to be a wide variation from one year to the next in terms of the industry's average annual spend on comparator arm drugs, 11 large pharmaceutical companies reported that their average spend between 2009-2011 represented half of their overall clinical supply budget, or $25 million USD.

  In an attempt to contain these costs, sponsors have traditionally adhered to a strategy of maintaining their early phase trials within the United States whenever feasible, and the reason is clear.

With 85% of Americans having private healthcare insurance to help reimburse the cost of comparator arm drugs, this was once an effective cost containment strategy

; however, it's a different reality today. The Personalized Medicine Coalition reports that 60% of early phase trials now use defined biomarkers and are, thereby, classified as personalized medicine. This distinction has changed the drug development landscape significantly.

  Under this classification, the inclusion criteria for these trials are extremely selective, leading to a low incidence of a specific patient population and, hence, the need to look abroad for patients. This challenge, coupled with the fact that today's costly breakthrough biomarker-enabled medicines will be tomorrow's comparator drugs, means that the cost of conducting oncology trials is set to skyrocket. Sponsors will be under even greater pressure to execute a well thought-out international site selection strategy.   

Canada has some strong cards to play as a prospective region for the expansion of both early and late phase oncology trials. Cancer treatments tend to vary widely from one region to the next, as well as within any one particular region, making it difficult for sponsors to implement a U.S. protocol in other countries.

  In Canada, however, the standard of care for cancer patients is somewhat consistent across the country due to its universal healthcare system. In terms of clinical guidelines and best practices, Canada's approaches to cancer treatment are often similar to those in the United States. Therefore, a protocol designed to reflect treatment standards in North America would likely be a good fit for Canada.  

A combination of the universal healthcare system and the fact that Canada's population is located predominately around urban centers, means most Canadian patients are treated in publicly funded teaching institutions located in large metropolitan cities. This trait facilitates rapid site selection and may result in enhanced patient enrollment. Finally, coupled with its geographic proximity to the United States, Canada boasts excellent clinical data quality and a standardized clinical trial agreement (CTA) designed to accelerate the study start-up process.  Despite the potential advantages, U.S. sponsors, especially smaller biotechnology companies, may have reservations about coming to Canada simply because they are unfamiliar with the region's drug availability and reimbursement landscape.  

A brief explanation of the process may be helpful in better understanding a dynamic and sometimes complex regulatory environment. First, the Therapeutic Drug Directorate at Health Canada must approve the drug's use based on its safety and efficacy profile. Next, the Patented Medicine Prices Review Board, an independent, federally funded agency, decides whether the drug's proposed pricing is reasonable when compared to other benchmark countries. Finally, the decision to fund a drug on provincial formularies falls within the jurisdiction of each of the 10 provinces and three territories after receiving a recommendation from the Pan-Canadian Oncology Drug Review (pCODR).  

Created in 2007, the pCODR operates as a collaborative health technology review and advisory body, acting on behalf of all participating provincial and territorial jurisdictions, except Quebec, which has its own oncology review agency. With the intent to ensure that public funds are invested wisely, pCODR accomplishes its mandate to support sound reimbursement decision-making based on rigorous review of clinical and economic evidence leading to the most beneficial patient outcomes. While taking the pCODR's recommendations into consideration, each member province also reviews drug reimbursement applications according to its own policies and formulary practices before rendering a final decision on reimbursement listing and scope of coverage. In essence, pCODR provides a strong influence in creating uniformity of cancer care treatments across all Canadian jurisdictions.  

With respect to trial comparator arm reimbursement of formulary drugs, the landscape is also changing. Canadian provinces were once very lenient in issuing reimbursement in support of clinical research. While there is still a strong commitment to advance these efforts for improved health outcomes, provinces have adopted a more stringent reimbursement approach to contain rising healthcare costs. This includes an initiative to publish guidelines on the subject. To date, only two provinces have an official policy, while the province of Ontario has one that is currently in draft format. The policies outline the principles, criteria, and process related to the reimbursement of publicly funded cancer drugs when patients participate in trials as part of their therapy.  

As per Ontario's draft policy, The Ontario Public Drug Programs and Cancer Care Ontario will consider all requests for the reimbursement of publicly funded cancer drugs within the context of trials where the drug is being used within the approved indication.

  While meeting other select criteria that run parallel to GCP/ICH guidelines, the study must not incur any deferred or incremental costs to the provincial public health system. Although the remaining provinces do not have an official policy, they regulate reimbursement activities according to a similar set of unofficial guidelines. Exceptions may apply to protocols bearing a particularly compelling scientific hypothesis. Since oncology is a highly dynamic therapeutic area, it is plausible that a study design may include a comparator arm drug that has only recently been approved by the FDA, but that has not yet been reviewed by Health Canada or listed on the provincial formulary for an approved indication. In such a case, the provincial policies do not apply.  

It is also possible that the comparator arm drug is not a newly approved drug by the FDA, but rather a drug that has never been filed and approved in Canada. In either case, sponsors may file a Clinical Trial Application with Health Canada, the equivalent of a U.S. investigational new drug (IND) application, but they must obtain comparator arm information submitted to the FDA. If the comparator arm is part of a head-to-head study design, then obtaining the required information will likely be difficult due to competitive concerns of the comparator drug manufacturer. On the other hand, if the drug is used in combination with the research compound, then the process of obtaining the required information should be fairly easy since there are no real competitive concerns.  Clearly, in either case, the sponsor would be obliged to obtain the drug from a U.S. source, such as a drug wholesaler, or from a collaborative non-profit organization, such as TransCelerate BioPharma Inc. TransCelerate's Clinical Trial Comparator Network has created a new model for comparator drug distribution by enabling direct shipment between participating companies.  

In cases where the comparator arm is not reimbursed by public healthcare but the drug is licensed for use and is available within Canada, the sponsor may direct the institution to procure the drug from a local wholesaler or directly from a drug manufacturer and then invoice them. Comparatively, patented drug prices in Canada average between 35% and 45% lower than those in the United States.

  As such, although the sponsor would have to assume the comparator drug cost, it would be less than the U.S. market price. Over time, the Pan-Canadian Pricing Alliance (PCPA), established in 2010, may further mitigate the impact of patented drug prices. PCPA is a purchasing-oriented collaborative with the goal of achieving economies of scale and lowering drug acquisition costs by facilitating the centralized buying of drugs in bulk by provincial governments.

  By contrast, U.S. laws still prohibit Medicare or Medicaid from negotiating drug prices.   

Finally, and perhaps of greatest importance, one must consider the institution's individual needs and preferences. Having a sponsor cover the cost of the comparator arm provides great value to the institutions because it presents an opportunity for them to investigate and advance standard of care for their patients in a safe and cost-neutral manner regardless of the formulary or reimbursement environment.

One thing is certain, the rise of personalized medicine will force sponsors to start thinking about regional expansion much earlier than was previously required. Once clinical trial development is expanded beyond the United States, sponsors should evaluate whether it makes economic sense to absorb the costs of the comparator arm drug when weighing the risks versus the benefits of a particular region.  

Opportunities for reimbursement do exist in Canada, but the environment is much more restrictive today than in the past due to sustained public policy on implementing provincial healthcare cost containment measures. But even if a comparator arm drug will not be covered, there are other factors to consider, such as accessibility of patients and investigator interest, which may outweigh the drug costs.  

Regardless of drug reimbursement potential, the cardinal rule for successful patient recruitment continues to be focusing on opening trials at the right institutions, because high recruitment and quick study start-up often trump the costs associated with paying for the comparator arm drug. To get this right requires a strategic and careful case-by-case analysis of all country-specific issues that could either derail or speed up enrollment for a particular trial.  

is President and Co-Founder of Scimega Research Inc. She can be reached at 

1. Tufts Center for the Study of Drug Development, 2007 Report.  

2. FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf

3. M.J. Lamberti, T. Walsh, and K. Getz, "Tracking Trial Cost Drivers: The Impact of Comparator Arm Drugs and Co-Therapies," 

4. C. Bredin, M. Eliasziw, and R. Syme, "Drug Cost Avoidance Resulting from Cancer Clinical Trials," 

5. Obamacare Facts, Where Americans Get Health Coverage, 

http://obamacarefacts.com/howdoes-obamacare-work.php

7. L. Aberg, B. Albrecht, and T. Rudolph, "How Health Systems Can Improve Value in Cancer Care," McKinsey Healthcare Systems and Services, 12, 43, (2012), 

http://www.mckinsey.com/Search.aspx?q=How%20health%20systems%20can%20improve%20value%20in%20cancer%20care

8. Cancer Care Ontario/Action Cancer Ontario, "Policy On Cancer Drug Reimbursement Within the Context of Clinical Trials," draft for consultation purposes (2013). 

9. V. Paris and E. Docteur, "Pharmaceutical Pricing and Reimbursement Policies in Canada," OECD Health Working Papers, 52, (2007), 

10. W. Dempster, A. Blanchard, and J. Chambers, "Will a Pan-Canadian Approach to Drug Purchasing Save the Provinces Money?," I

11. J.S. Hoch and M. Sabharwal, "Informing Canada's Cancer Drug Funding Decisions With Scientific Evidence and Patient Perspectives: The Pan-Canadian Oncology Drug Review," 

Articles

Feature Article

Examining a region's comparator reimbursement climate to better inform trial expansion decisions.

Oncology Trial Comparator Drug Reimbursement: A Canadian Perspective

 (Needham, MA) announced the addition of 

, MD, as Advisory Board Chairman. Guerra has been in the global biopharmaceutical industry for more than 30 years, including 24 years at Merck & Co.  

 (Dublin, Ireland) announced the appointment of 

 PhD, as Director of Metabolic Research. Based in ICON's Clinical Pharmacology Unit in San Antonio, TX. Elahi will lead ICON's early phase glucose clamping programs globally.  

 (Camberley, UK) announced the appointment of two senior executives to its team. 

, PhD, has joined as Vice President, Clinical Development, Oncology. 

 PhD, has joined as Executive Director, Clinical Development, Oncology. INC also announced the addition of 

 PhD, as Vice President, Clinical Pharmacology; and 

as Senior Vice President of its Global Consulting Unit.  

, MD, PhD, has joined its Clinical Development Services business as Vice President and Global Therapeutic Area Head of the expanded Cardiovascular, Metabolic, and Scientific Affaris leadership team. 

• Vetter Development Services USA, Inc.

, PhD, was elected to the board of the Illinois Biotechnology Industry Organization. 

 (Cambridge, MA) announced three new appointments to its global team. 

 join the company's US Business Development Team. 

, President of the Board of Directors of GlaxoSmithKline Biologicals, was welcomed as a member of the board.  

, (St. Petersburg, Russia) a Russia-based CRO, announced that 

, (Stevenage, England) a Quintiles company, announced the addition of 

, PhD, MBA, as their new Managing Director of European and Asian Operations. 

• The European Federation of Pharmaceutical Industries and Associations (EFPIA) 

 (Sawbridgeworth, UK) announced the appointment of 

• CTI Clinical Trial and Consulting Services (CTI)

 (Cincinnati, OH) announced the addition of 

 as Director, Global Safety and Pharmacovigilance. 

(Philadelphia, PA) announced that Philadelphia SmartCEO has recognized the company in its Future 50 Awards program. The program recognizes the region's fastest-growing mid-sized and large Blue Chip companies that have experienced outsized growth based on a combined three-year average of revenue and employee growth.  

• Pharmaceutical Product Development, LLC (PPD)

 (Wilmington, NC) announced the company was ranked among the top US businesses for employee learning and development by 

 magazine. The recognition marks the third consecutive ranking for PPD on the annual Training Top 125 list.  

 (Dallas, TX) announced that it took home the gold in the 2014 AVA Digital Awards competition of writing, design, and execution of its DACTracks digital marketing campaign.  

 (Madison, WI) announced that the Research Resonance Network received the Clinical Informatics News Best Practices Award in the category of Clinical Data Intelligence. The Research Resonance Network—which was developed through collaboration with research organizations and offers free tools for continuous improvement—was recognized for its standards-based approach to improving clinical research operations.  

 (Cincinnati, OH) was named Blue Ash Corporation of the Year by the Cincinnati USA Regional Chamber. The award recognizes outstanding companies in one of Cincinnati USA's most vibrant business communities. 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and People April 2014

The clinical trials community in Europe is working ever harder to get its message across to its key partner: patients. The second workshop of the European Patients' Academy on Therapeutic Innovation (EUPATI), entitled "Reaching a Public Audience on Medicines Development," was held in Warsaw, Poland, earlier this month. In addition, the BBC has released a free video about the risks and ethical aspects of clinical trials. 

The EUPATI workshop has been designed to draw on the group's social research work involving patients and citizens across Europe, as well as to hear views from patient advocates and the public and to provide details about successful examples of information sharing. EUPATI is funded by the Innovative Medicines Initiative (IMI), and aims to provide scientifically reliable, objective, and comprehensive information to patients on clinical research. The consortium's goal is to increase the capabilities of well-informed patients and patient organizations to be effective advocates in clinical research. 

In a separate initiative, trial organizers have participated in a video that should help reassure patients after continued fallout from the 2006 clinical trial disaster involving six healthy volunteers at Northwick Park Hospital in London. In the incident, volunteers were treated for organ failure after experiencing a serious reaction within hours of taking the anti-inflammatory drug, TGN1412.  

Such incidents are unlikely to happen again, according to experts quoted in a BBC article published last year. Things have changed, they said, since the release of the Duff Report, which was written in response to the Northwick Park trial. Among the changes is the U.K.'s Medicines and Health products Regulatory Agency (MHRA) now ensures that ethics committees look at preclinical data to decide whether the first dose given to humans is the right dose.  

The BBC video begins with a news report about the Northwick Park disaster, before discussing the clinical trial process. To view the video, visit 

http://www.bbc.co.uk/learningzone/clips/clinical-trials-regulation-and-ethics/1465.html

News

As pair of initiatives show, the clinical trials community in Europe is working harder to get its message across to its key partner: patients.

Europe Puts Renewed Emphasis on Patient Communication

 Physician participation in and patient access to cancer treatment clinical trials are key measures for delivery of quality cancer care.

  A recent Institute of Medicine (IOM) committee stated that the "therapies offered through cancer clinical trials should ideally be considered the preferred treatment choice for physicians and patients, if they are available" and recommended that all oncologists "strive to make participation in clinical trials a key component of clinical practice and to achieve high accrual rates of 10% or more."

  Despite these guidelines, current adult trial participation in the United States remains under 3%.

  Participation is even lower among patients who are from racial or ethnic minority groups, are age 65 or older, and/or live in rural areas.

  A number of studies have shown that cancer health disparities are due in large part to receipt of less-than-standard care.

  According to the IOM, increasing clinical trial participation among minority populations can address these persistent disparities.   

Although numerous challenges face the cancer clinical research system,

 most studies have focused on individual barriers to clinical trial participation, specifically barriers related to a lack of knowledge and underlying attitudes and beliefs among patients.

  What is often overlooked are accrual barriers related to ineffective operational procedures, such as inconsistent screening and approach.

Studies have found that only between 9% and 20% of cancer patients are told about the option of participating in an oncology trial.

  Even at major cancer centers, oncologists may not approach all eligible patients about participation,

  and patients from minority groups or who are age 65 or older are less likely to be approached, regardless of eligibility.

While accrual is a critical outcome, the metric of "pre-screening," defined as basic patient matching to cancer clinical trial requirements based at the very least on age, sex, cancer location, and stage can systematically flag patients for additional screening and/or make consistent offers for participation. Such systematic patient screening has been shown to increase clinical trial enrollment, and reduces the opportunity for bias.

  Institutions conducting cancer clinical trials can improve accrual by adopting procedures to help ensure that 100% of patients are screened for trial eligibility prior to treatment discussion, and that ultimately, 100% of eligible patients are approached about participation.

Figure 1 illustrates a prototypical example of the pre-screening process, even though pre-screening may look different for every institution. In fact, many sites may experience additional challenges due to HIPAA or the local institutional review board (IRB). While HIPAA protects patients' protected information, most IRBs and privacy officers allow screening of medical records for the purpose of identifying patients that may benefit from participation in a clinical trial. The results of the screening are given to the treating physician, who then discusses the trial with the patient. While clinical trial teams may flag charts of the patients scheduled to be seen that day, it has been documented that at least 30% of accrual sites, if not more, have no systematic approach to screening patient charts for patient eligibility.

 This article will describe the experience of two cancer clinical trial sites and a national multi-site collaborative project—each of which address improvements in pre-screening to enhance accrual.  

Example 1: Meharry Medical College clinical trials office

Located in Nashville, Tenn., Meharry Medical College (MMC) incorporated Nashville General Hospital from its original downtown location onto its campus in 1998 to facilitate continuation of the city hospital. Two years later, the research team formed at MMC under an NCI U54 Partnership grant allowing for implementation of clinical trials operations at the site. Finally, in 2003, MMC was awarded a Minority Based Community Clinical Oncology Program (MBCCOP) grant. The site serves a significant African-American population in North Nashville and the institution predominantly serves medically underserved patients. 

The clinical trial team at MMC began by exploring some of the barriers faced by the patient population as it related to cancer care as well as clinical trial participation. Some of the major observations from this assessment included things such as frequency of missed appointments/poor follow-up, missed communication (i.e., how physicians and patients learned of the pathology results), missed rides and transportation, lack of insurance, and the need for ensuring patient comprehension about cancer and their care. 

Early on, the research team recognized the need to identify every patient that was entering its system. This was challenging considering the various entry points for patients throughout the healthcare system. The clinical trials office (CTO) established a protocol to have all pathology reports sent to the office in order to track each diagnosis of cancer and to let the ordering physician know when a report indicates cancer. In addition, the cancer committee requested that every patient coming through the system would be screened for a cancer clinical trial as standard policy. Screening involves not only matching for disease type and stage but whether the trial is applicable for the particular patient. The information is entered into a database for review at weekly research team meetings. Team members review progress through the system and arrange appointments and referrals as needed for diagnostic workup and staging. The patient is navigated through the system using a nurse navigator and a research nurse.   

Physicians are advised if a clinical trial is available and informed of plans developed by CTO to address obstacles such as transportation for related medical visits or medications; this is seen as an important way to further support physicians in their ability to offer a trial to the patient during initial treatment discussion. CTO staff monitor whether the patient is ultimately placed onto a study. The option of clinical trial participation is offered during initial treatment discussion. Patients can receive clinical trial care in their usual care facility and it is not offered as another option after the treatment discussion has occurred. 

 As published in detail in the literature elsewhere

  and briefly summarized below, using this approach, in a four-year period, MMC went from a 10% accrual rate to 22% (see Table 1). The overall accrual rate is calculated by number of patients on a study divided by number of new patients in the clinic (154/15=10%). When evaluated in the context of patients for whom there were studies available for their disease and stage and were offered trials (32), the actual accrual rate for patients who enrolled (15) was even higher (32/15=47%), demonstrating that minority patients would be just as willing to participate in cancer clinical trials when presented as a quality care option.  

The most common reason (67%) patients did not join a study had to do with physical status, such as the presence of co-morbidities, laboratory abnormalities, and performance status; less than 10% refused participation on a particular study (see Table 2).  

Over a seven-year period, MMC has sustained its 21% overall accrual rate and actual accrual rate (patients with a study available) at more than 65%. Accrual was particularly successful in cancer control and prevention trials, with solid improvement in the accrual rate among treatment trials as well. The proportion of patients enrolled to studies also reflected the overall demographics of patients seen at MMC. 

The Meharry experience strongly suggests that racial/ethnic minority and underinsured patients are willing to participate in cancer clinical trials. Ensuring success requires a team approach and case management (navigation) strategies, along with taking a proactive rather than reactive approach to address screening needs. The pre-screening process also presented an opportunity to examine the extent of patients that they did not have available studies for and to take into consideration when to modify the site's future research portfolio to meet this need. 

Example 2: Vanderbilt Ingram Cancer Center clinical trials shared resource

The Vanderbilt Ingram Cancer Center (VICC) sees over 5,500 new cancer diagnoses annually. More than 600 patients participate and are active in therapeutic studies each year. VICC has more than 250 protocols available for adult patients. Its Clinical Trials Shared Resource (CTSR) is organized by disease site teams, with each team led by a physician and manager and a team of nurses, regulatory and data coordinators, and other research support staff. 

Patients enter into the VICC system through a variety of methods, including direct referrals; the access center, which is a call center for appointments; external referrals; self-referrals; and the Clinical Trial Information Program (CTIP). In existence at VICC for more than 15 years, the program is staffed by registered nurses who screen for clinical trial eligibility. 

In the last two years, the CTIP began to proactively screen patient records for trial eligibility. A list of new patients is generated from the electronic medical record (EMR) daily. The screener reviews this list and looks at any additional records available to assess whether there is a study for the disease site and stage and whether the patient is eligible based on known information. An email is then sent to the physician indicating that the patient may be eligible for a clinical trial or is not eligible. A follow-up is conducted by CTIP to determine the outcome for the patient. 

 Using one team as an example of VICC's screening efforts (see Table 3), between December 2011 and June 2012, of the 692 cases seen, 123 were screened as eligible for trials, with 10 going on to enroll in a study. Among those patients who did not enroll, 74 did not meet the eligibility criteria, 20 declined participation, and eight were due to "physician choice." It was particularly helpful to follow-up on the latter data group to help determine what the nature of any potential concerns were, so they could be addressed. 

Among the key lessons learned to date with the VICC experience has been a greater appreciation of the varied reasons why patients do not enroll in clinical trials. While some of the barriers may be patient-related, many have to do with availability of studies that match the patient population, study design, and eligibility criteria, whether the patient was appropriately screened, and equally as important, if the patient was actually offered the option of participating in the trial by the physician. Taking these factors into account, strategies to increase clinical trial patient accrual must include: 					

Identifying all potential patients before treatment options have been presented

Tracking reasons for going on or not going on clinical trials

Increasing communication about available trials, optimally in the community prior to a patient's diagnosis

Having a plan to overcome barriers such as transportation, housing, and extra costs

Example 3: Five sites participating in ENACCT's National Cancer Clinical Trials Pilot Breakthrough Collaborative

Founded as a national non-profit organization in 2004, the Education Network to Advance Cancer Clinical Trials (ENACCT) focuses exclusively on identifying, implementing, and evaluating innovative community-centered approaches to cancer clinical trials education. ENACCT's National Cancer Clinical Trials Pilot Breakthrough Collaborative was the first-ever national effort to identify best practices for recruitment, accrual, and retention through a systematic, proven quality improvement process.   

ENACCT selected five community oncology practices to test and implement specific changes in organizational practices. The goal was to identify practical, patient-centered approaches to significantly improve the accrual of eligible patients to cancer clinical trials, with a particular focus on patients from ethnic and racial minority groups and those age 65 and older (see descriptions of the five oncology practice teams below, and read more about the teams at 

http://www.enacct.org/our-programs/national-learning-collaborative

One of the important quality improvement measures the pilot focused on was the implementation of new pre-screening/screening processes prior to physician consultation. Measures related to pre-screening are described in Table 4.  

Developed a process for consistent screening of all new patients for clinical trial eligibility using a computer program allowing for the printing of the daily schedule, which identifies all new patients. As a quality assurance method, this list is checked again at the end of the day for no-shows and cancellations.

Began investigating new trials that more appropriately meet their patients' diagnoses and comorbidities.

Increased tracking of data and statistics regarding the number of patients seen, how many were potentially eligible, and how many were approached, in order to better illuminate processes and areas that may need improvement.

Standardized communication with physicians regarding eligible patients, including asking physicians to indicate why (or why not) a patient was offered a trial.

Implemented a rotating assignment of pre-screening patient charts to individual oncology research nurses to improve efficiency and reduce redundancy.

Created a process that ensured screening of new patients who were initially missed by the research department when they were called and seen on the same day. Medical assistants were tasked with alerting the research department to newly added patients. A staff member from the research department would then inform the physician of pertinent open clinical trials.

Established a quarterly competition and awarded prizes to teams with the highest total screening, enrollment, and highest increases in percent and number enrolled.

Over the ten-month period of the pilot, reported changes by the sites as a result of the collaborative included: 					

Improvements in the capture of race and ethnicity data, which is providing direction for developing better referral relationships to increase patient diversity 

Improvements in processes for screening and assessing trial match to new patients and informing assessment of the viability of opening new trials

Enhanced documentation of pre-screening and offer rates to identify system gaps and ways to increase these rates

ENACCT's pilot collaborative showed that a proven quality improvement framework, never before applied to the cancer clinical research setting, was both feasible and able to generate meaningful improvements in organizational processes and procedures as it relates to pre-screening/screening. Given the short duration of the pilot, there was limited ability to measure changes to accrual within the timeframe. However, it is anticipated that over time, these changes will increase cancer clinical trial accrual rates, in particular among ethnic minorities and the elderly. Based on the invaluable lessons learned, ENACCT is currently developing a second-generation learning collaborative to test further changes. 

The integration of pre-screening all patients for eligibility in oncology studies.

Making a Difference in Cancer Trials Accrual

The landscape of oncology drug discovery is constantly changing. Are researchers this year still discussing the same trends as 2013? Crown Bioscience analyzed the last three years of publications and presentations at the American Association for Cancer Research's (AACR) annual meetings, as well as the AACR/European Organisation for Research and Treatment of Cancer (EORTC) Molecular Targets and Cancer Therapeutics conferences to search for potential trends.  

The first group of keywords analyzed related to the main solid cancer types. Table 1 shows the relative frequency of keywords among the main cancer types in 2013. Table 2 illustrates the change in frequency of keywords between 2011 and 2013, as a percentage change compared to the overall number of presentations each year. Across the spectrum of cancer types, there does not appear to be a dramatic change in the frequency of publications around each cancer type. The dip in prostate numbers at the 2013 EORTC compared to previous years, while interesting, may just be an outlier.  

The second group of keywords analyzed for frequency were the hematological cancer types (Table 3). Change in frequency of keywords between 2011-2013 was also analyzed (Table 4). Considering the low frequency with which hematological keywords are mentioned, there does not appear to be a significant change in numbers.  

The analysis so far does not show any dramatic shifts in areas of interest for research. However, when examining the frequency in the use of terms, which relate to the informal feedback received from scientific and business development teams, some important trends emerge. A common theme of 2013 was the focus on cancer resistance, whether mechanistic or looking for pharmacological approaches against resistance. In the last two years, the relative frequency with which resistance has been mentioned at AACR has increased by 22%. The use of the terms "tumor microenvironment" and  "epithelial-mesenchymal transition" have also increased by 19%.

More than 40 other terms and references to key mutations were reviewed, with most remaining surprisingly constant. One term, however, stood out: Patient-derived xenograft models (PDX). At 2013's AACR meeting, there was a seven-fold increase in the number of PDX references compared to the previous two years, and a nine-fold rise at the EORTC event. This points to an increasing trend in 2014 around the use of image-guided irradiation, which produces a concentrated and targeted treatment for cancer.

— Jean Pierre Wery, President, Crown Bioscience Inc.

When examining the frequency in use of keywords related to cancer research, some important trends emerge.

Analyzing 2013 Oncology Trends to Predict 2014 Directions

In early March, the European Commission granted conditional approval to Janssen Therapeutics' Sirturo (bedaquiline), for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients. Another new drug, Deltyba (delamanid), developed by the Japanese company Otsuka Pharmaceutical Co., has also been recommended for conditional approval by the European Medicines Agency (EMA). 

The recommendations are for only conditional approvals, since the products have completed testing only up to Phase IIb of clinical trials. In addition, the opinion specifies only second-line use, as part of combination therapy. Sirturo can be used only when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability, according to Janssen. Wim Parys, the company's head of R&D and global public health, said Janssen will now "continue to work with partners and relevant authorities to ensure Sirturo is used correctly and appropriately."  

This will be no mean feat. As the company says, "Under the provisions of the conditional approval, Janssen commits to support a Phase III study to further substantiate the benefit-risk for Sirturo and to define its optimal use, with regards to the number and types of agents that are needed in combination, and its optimal treatment duration." 

The challenge now—for Sirturo, and in due course for Deltyba—is to see how they can be constructively inserted into the combinations currently used to treat TB in a way that will shorten treatment duration or ease the side effects. In Europe, that is still far from obvious. There is a guideline from the EMA on clinical development of fixed combination medicinal products, issued in February 2009 by the Committee for Medicinal Products for Human Use (CHMP). But working out new treatment regimens for TB with new products is rather more complex than using fixed combinations.  

Last February, CHMP indicated that the guideline was under revision. The committee issued a concept paper on the need to revise the guideline, for a number of reasons, including updating it "to minimize reference to regulatory aspects (e.g., dossier requirements)," and to "update the scientific aspects of the guideline." That revision is still underway, and EMA sources say it is likely to take most of this year to reach any conclusion. Meanwhile, the attempts to identify the most appropriate regimens for the new TB medicines will have to move ahead in something of a void. 

The FDA has taken a more rapid path to this dilemma. In June 2013, the agency issued a guideline of its own. Noting that combination therapy "is an important treatment modality in many disease settings, including cancer, cardiovascular disease, and infectious diseases," FDA noted how "recent scientific advances have increased our understanding of the pathophysiological processes that underlie these and other complex diseases," and have in turn "provided further impetus to develop new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets." The rationale can be to improve treatment response, minimize development of resistance, or minimize adverse events.  

In settings in which combination therapy provides significant therapeutic advantages, the FDA document states, "There is growing interest in the development of combinations of new investigational drugs." And because "existing developmental and regulatory pathways focus primarily on assessment of the safety and effectiveness of a single new investigational drug acting alone, or in combination with a previously approved drug," FDA believes guidance is needed to assist sponsors in the codevelopment of two or more new investigational drugs.  

The FDA guidance is intended to describe a high-level, generally applicable approach to codevelopment of two or more new investigational drugs. It describes the criteria for determining when codevelopment is an appropriate option, makes recommendations about nonclinical and clinical development strategies, and addresses certain regulatory process issues. The guidance doesn't answer all the questions, but it is a start. 

It's not just one drug for TB that's needed. You need multiple compounds that work as cocktails that don't interact or have multiple adverse reactions," Dr. Evan Lee, VP of Eli Lilly's Global Health Programs and Access, told this columnist recently. "Collaboration helps in terms of generating that cocktail." 

Professor Frank Cobelens of the University of Amsterdam takes a similar view. He commented recently that companies may balk at the cost of extensive trials under current arrangements. The two new medicines will need to be field-tested in clinical trials that evaluate the efficacy and safety of drug regimens (e.g., combinations) rather than of individual drugs, and while industry is willing to invest in Phase III trials needed for licensing, drug companies for understandable reasons are reluctant to make the huge investments needed in such combination trials. 

"One major technical limitation is the lack of valid markers to predict treatment outcome," says Cobelens. "So that trials need to follow up patients for the entire duration of treatment plus another 12 months or so to see if patients relapse, making trial duration for a single patient at least 18 months for drug susceptible TB, and at least 36 months for MDR-TB." 

In addition, because new drug regimens need to be compared to current standard, requiring large numbers of patients to be evaluated across many sites, trials are expensive. This has been feasible for drug susceptible TB, but "it is a major challenge to do this for MDR-TB." In his view, "concerted efforts are needed to bring together trial capacity and funding in order to find out the drug combinations that are best used against MDR-TB." 

One approach pioneered—at present only as a theory—by campaigning group Médecins Sans Frontières (MSF) is to multiply the search for effective combinations by allowing wider access to candidate therapies. The group has recently sought—unsuccessfully— World Health Organization backing for a project that would test the theory. 

"TB must always be treated with a combination of drugs, but a lack of collaboration and transparency means that clinical trials to test these new drugs in the combinations needed will not be completed until years after these drugs are registered," says MSF in explaining its plan. "Many organizations working in the area of regimen development, including TB Alliance, UK's Medical Research Council (MRC), and RESIST-TB, have encountered obstacles caused by today's R&D framework, for example, in accessing new drug compounds for testing new treatment regimens."  

				MSF proposes the sharing of data, the pooling of intellectual property and "the creation of incentives for multiple actors to enter the R&D process in order to accelerate development timelines" by leveraging "as much existing capacity and expertise in TB as possible to foster greater collaboration between researchers."

				MSF's Helle Aagaard says the current regulatory and economic system "results in drugs being brought to market individually, even though what we need for TB is new drug combinations and regimens." In her view, "The research collaboration required to bring new regimens to market will not take place without government-led policies and incentives in place to encourage it."			

Europe is also trying to solve the problem through a more scientific approach. The Innovative Medicines Initiative (IMI), a project funded by the European public-private partnership focused on early-stage research, is aiming to speed up the search for new, more effective combinations of treatments to tackle TB. "Current clinical trial methodologies make it very difficult to evaluate the optimal doses and combinations of drugs," says IMI. "Putting together a new, shorter treatment regimen could take a quarter of a century using today's methods." IMI, therefore, is running a project known as PreDiCT-TB, focused on tackling preclinical research barriers to the discovery and development of new TB drug combinations. It is exploring methods that can be more effective than the current trial-and-error method in which new drug candidates are developed and added to the existing regimen one by one. 

PreDicCT-TB is developing an integrated set of laboratory-based models that will provide data to indicate the most appropriate doses and combinations of drugs for patients. In addition, the project will generate a database of patient data from previous and on-going clinical trials, as a reference for evaluating the performance of combination anti-TB drug regimens in these newly developed laboratory models. Ultimately, the aim is that researchers will use the information generated by the novel models to design better clinical trials involving TB patients. 

However Europe goes about it, the need is clear for maximum speed as well as maximum efficiency. The latest data from the European Centre for Disease Control (ECDC) shows that multi-drug resistance poses a serious challenge in the attempt to eliminate TB across Europe.  

"The target of a declining five-year trend for MDR-TB was achieved by only seven of 21 reporting countries," says ECDC director Marc Sprenger. "Overall, Europe does not have a good track record."  

Only one in every three patients in the EU finishes MDR-TB treatment successfully. More than half either die, fail treatment, or default from treatment.  That should be a spur to action. 

is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

The advent of new drugs for tuberculosis is posing some interesting challenges for regulators in Europe.

Singular Approaches to Combination Trials

There is no denying that large contract research organizations (CROs) are increasing their share of the outsourced drug development market. Preferred provider lists are dominated by the large CROs and it seems every week brings a new announcement of a "strategic partnership" between a large pharmaceutical company and a large CRO. However, one thing ISR has learned over the years of measuring delivery quality and loyalty is that being viewed as the "leader" does not guarantee a CRO a spot among the most favored. Similarly, record sales generation does not always translate to ensuring the most loyal customer base. 

In ISR's new CRO Quality Benchmarking – Phase II/III Service Providers report, the data indicate the pendulum is swinging back toward the small or midsize CROs, at least from a delivery perspective (see chart below). 

ISR is not suggesting that the large CROs possess disloyal, disgruntled customers Some are, in fact, quite strong. But four of the top five loyalty ratings in this year's Benchmarking study belong to small or midsize CROs.   

The great news for study sponsors is they have choices. Whether the choice is driven by delivery quality, capabilities, relationship management, or something else, sponsors have viable options. 

Delivery Strength from Midsize CROs

Health policymakers, academic researchers, and regulators are clamoring for biomedical studies to fully examine how new drugs and medical products affect a broad spectrum of patient populations, including women, minorities, children, and older individuals with chronic diseases. Despite multiple FDA guidances and rules over the years advising sponsors to include all demographic groups in clinical trials, many subgroups remain underrepresented. A 2011 report from FDA found that African-Americans constitute 12% of the U.S. population, but make up only 5% of clinical trial participants; the disparity is even greater for Hispanics, which account for 16% of Americans, but only 1% of research subjects.  

One response from the Pharmaceutical Research and Manufacturers of America (PhRMA) is a collaboration with the National Minority Quality Forum to increase awareness and participation in clinical trials of minority populations.  

Meanwhile, FDA is developing an action plan for improving demographic subgroup data collection and analysis for regulated medical products, as required by the FDA Safety & Innovation Act of 2012 (FDASIA). As a first step, FDA issued a report last August on the subject. The study formed the basis of a public hearing on April 1 to hear from stakeholders on best approaches for encouraging subgroup enrollment in clinical trials and for capturing race and ethnicity data in studies. FDA is accepting comments on these issues until May 16 to help develop its plan for moving forward. 

Sex differences in drug response also raise questions about sufficient female enrollment in clinical trials. Last year, FDA lowered the dose for women of the sleep aid zolpidem. More recently, the agency turned down approval of a new drug, flibanserin, to treat low female sexual desire, calling for additional clinical trials to evaluate drug-drug interactions and drowsiness. Researchers at the Brigham and Women's Hospital in Boston recently issued a report calling for more women in clinical trials, especially for cardiovascular drugs, and to better assess how hormonal responses in women affect treatment for depression and Alzheimer's disease. The researchers urge FDA to require sponsors to include adequate numbers of women in clinical trials or clearly explain why not. 

Sandra Kweder, deputy director of the Office of New Drugs at the Center for Drug Evaluation and Research (CDER), noted in a recent blog post on 

 that the agency requires equal enrollment of men and women in most trials except where there is a known lack of response by one sex to certain treatment. And FDA-approved drug labels routinely discuss dose considerations or side effects related to patient age, health problems, and sex. 

Collecting information on drug response during pregnancy is even more challenging. An FDA public meeting in May will address methods for evaluating the safety of drugs and biological products during pregnancy, focusing on the design and implementation of pregnancy registries and other post-approval evaluation strategies. Issues related to response differences and dose selection based on age, ethnicity, pregnancy, and other factors was the topic of another FDA workshop on March 10. Experts from the agency and pharma companies discussed the uses of physiologically-based pharmacokinetic (PBPK) modeling in predicting drug-drug interactions and PK response for different patient groups.  

FDA also is taking steps to implement a broader Health and Human Services initiative to ensure that clinical trials include more individuals with multiple chronic conditions (MCCs). The program was launched in 2009 to encourage drug development programs to address "real world" health situations.  

An FDA-HHS study completed in August 2011 found that 71% of some 147 clinical studies submitted in market applications excluded patients with some psychiatric disorder; patients with a heart disorder were blocked from 66% of studies, and many trials ruled out patients with atherosclerosis or diabetes. Sponsors routinely institute such exclusions for fear such patients will drop out of trials or experience drug-drug interactions or negative results. 

In response, CDER issued an internal policy last December calling for inclusion of broad patient populations in clinical trials, particularly those with MCCs. The agency will use end-of-Phase-II meetings to check whether sponsors' planned studies include all appropriate patient groups, and that any exclusion criteria are appropriate and necessary. 

Robert Temple, deputy director of CDER for clinical science, explained at a January briefing that clinical trials should encourage broad participation of all subgroups in order to fully understand how a new drug may affect all potential users. Temple said that drugs tend to work similarly in most patients, but "if there are real differences in response among population subgroups, clinicians should know that."  

Despite guidances and rules advising sponsors to include all demographic groups in clinical trials, many subgroups remain underrepresented.

Pressure Grows for More Inclusive Clinical Trials

Drug development has always been a risky proposition. High failure rates combined with requirements for large and rising development investments have compelled major sponsors to pursue a variety of approaches to share innovation risk through collaboration, including joint development arrangements, in-licensing deals and mergers and acquisitions. Since 2008, sponsors have demonstrated a keen interest in establishing precompetitive alliances and five of the top 10 largest pharmaceutical companies have acquired and absorbed at least one major biopharmaceutical company (e.g., Genentech, Genzyme, Schering-Plough, Wyeth).  

M&A strategies represent the most extensive and costly collaborative approach, as fixed infrastructure, capabilities and the portfolio of intellectual property are transferred to the acquirer. In-licensing strategies represent a less extensive shared-risk approach because the licensor has incurred a partial development investment to advance a new molecular or biologic entity (e.g., the investment of capital and resources) before transferring the remaining development risk to the licensee. Co-development arrangements represent the most egalitarian arrangement as both parties share equally in the development risk.  

Although the impact of risk-sharing collaborations on success rates and spending has been assessed, until recently, the impact of these collaborations and the interruptions on drug development efficiency (e.g., development cycle time and regulatory review time) that they trigger has not been evaluated. This column shares the results of a recent analysis conducted by the Tufts Center for the Study of Drug Development (Tufts CSDD) and offers insight into an underlying challenge that sponsor companies face in establishing risk-sharing collaborations. Invariably, these collaborations are not yielding improvements in efficiency and speed, begging the question, "What can be done to drive better outcomes from risk-sharing partnerships?"  

This study compared development cycle and regulatory approval times of drugs developed by a single firm compared with those of drugs whose development had been interrupted by a collaborative or shared development arrangement. Regulatory approval histories—between 2000 and 2011—for 303 new molecular and biologic entities approved for marketing in the United States by the Food and Drug Administration (FDA) were analyzed. Clinical phase lengths were defined as the time from first human testing to new drug application (NDA) or biologics license application (BLA) submission.  

Tufts CSDD added a benchmarked adjustment factor to the total clinical phase length for drugs that had prior foreign testing before their investigative new drug (IND) filing. Approval phase was defined as the time from NDA/BLA submission to NDA/BLA approval. Total time is defined as the sum of the time from first human testing to NDA/BLA approval for marketing.  

To determine the type of risk-sharing arrangement established for each development program, Tufts CSDD reviewed publicly available drug pipeline databases and company-specific annual reports. A single firm included sponsor companies that developed a compound under its sole direction prior to its original regulatory submission for marketing approval. Risk-sharing collaborations included those compounds that were developed at least in part by a joint venture formed to develop the compound; those drugs for which a significant merger or acquisition occurred during their clinical development; those compounds being co-developed where either the sponsor or the other developer originated the compound; and those drugs that were licensed-in to a given company's portfolio during the clinical development period. Detailed development histories were compiled to categorize 289 of the 303 compounds. 

Frequency and impact of interrupted programs

Approximately half of all approved drugs between 2000 and 2011 had their clinical development activity interrupted by a licensing, co-development and joint venture arrangement, or by a merger or acquisition for which the originating company was absorbed by a larger firm. In-licensing was the most common collaborative approach, accounting for more than half (54%) of all interrupted programs. One-third of those programs were co-development arrangements.  

Tufts CSDD observed variation by therapeutic area. Analgesics/anesthetics, anti-infectives, central nervous system, gastrointestinal, and respiratory drugs had an incidence of interrupted development that exceeded 50%; AIDS, antiviral, antineoplastic, cardiovascular, endocrine, and immunologics were below 50%. Drugs targeting popular illnesses such as CNS and respiratory had particularly high incidences of interrupted programs at 65% and 60%, respectively. Antivirals had the lowest incidence with only one-in-four approved drugs experiencing a development interruption. 

Half of all drugs in clinical testing are interrupted by in-licensing, co-development, joint venture and M&A arrangements – and they are taking significantly more time to develop.

Applied Clinical Trials-04-01-2014

Oncology Trial Comparator Drug Reimbursement: A Canadian Perspective

Business and People April 2014

Europe Puts Renewed Emphasis on Patient Communication

Making a Difference in Cancer Trials Accrual

Analyzing 2013 Oncology Trends to Predict 2014 Directions

Singular Approaches to Combination Trials

Delivery Strength from Midsize CROs

Pressure Grows for More Inclusive Clinical Trials

Coming to Terms with Interrupted Drug Development Programs

The New Road of Cardio-Oncology in Clinical Development

ACT cover

Applied Clinical Trials Digital Edition April/May 2014