The rush is on to develop new therapies and preventives to combat the lethal Ebola outbreak, a process that has been stymied by difficulties in testing compounds for deadly diseases and the reluctance of both public and private entities to invest heavily in a field with uncertain demand. Treatments for Ebola have been low on the priority lists for international and national health agencies, as efforts to combat malaria, tuberculosis, and other widespread diseases have absorbed more attention and resources. 

That has changed as Ebola has sickened and killed thousands. The World Health Organization (WHO) and public and private research programs have shifted funds to preclinical and clinical trials of promising Ebola treatments and vaccines, encouraged by WHO's decision in August that it is ethical to use unproven therapies to help contain the spreading outbreak. WHO further addressed research priorities at a "consultation" with public health officials and leaders of the biomedical research community in Geneva last month. Executives from large vaccine makers and small biotech firms joined with leaders of the infectious disease research community to consider the challenges in conducting clinical trials and collecting data from ill patients.  

Some 200 experts agreed to support Phase I safety studies despite limited preclinical data. The group noted the need for flexibility in requiring ethics committee reviews and in assessing risks and benefits. Harmonized data requirements are important for results from expanded access programs to be compared to support eventual registration.  

A stated goal is to minimize bias in evaluating the effect of an intervention without randomized placebo controlled trials; alternative protocols may involve randomizing patients to two different experimental therapies or to offer "usual care" to individuals not willing to be randomized, who could then provide a control group. Meeting participants also agreed that a safety monitoring board should be established to evaluate data from all interventions and that protocols should address informed consent and community concerns. 

Regulatory authorities are collaborating on these issues through WHO's International Coalition of Medicines Regulatory Authorities (ICMRA) and adopting flexible approaches to facilitate access to treatment. The FDA, for example, has authorized use of a not-yet-approved Ebola diagnostic in West Africa. The agency also permitted Tekmira Pharmaceuticals to treat infected patients with its experimental treatment by converting a "full clinical hold" to a "partial hold" on a Phase I trial; that allows use of the therapy for emergency care—but not by healthy volunteers due to concerns about a possibly serious side effect.  

A main goal of researchers and regulators is to facilitate the launch of human trials on treatments exhibiting safety and immune response in primate studies. GlaxoSmithKline's Okairos unit (Basel, Switzerland) recently obtained FDA approval for Phase I testing of a vaccine developed with the National Institute of Allergy & Infectious Disease (NIAID). Small trials have begun in the U.S. and are planned for the UK, Gambia, and Mali with support from a $4.6 million grant from the Wellcome Trust and UK health agencies. 

FDA has also approved Phase I trials of a vaccine developed by NewLink Genetics' in Iowa, which utilizes a vaccine platform licensed from the Public Health Agency of Canada and developed with funding from the Department of Defense (DOD). Further testing is planned for North America, Europe, and Africa. Similarly, Johnson & Johnson is planning preclinical testing of an Ebola vaccine developed by its Crucell vaccines unit in collaboration with NIAID and Bavarian Nordic. This monovalent vaccine combines vaccine platforms developed by the two companies.  

WHO and research sponsors also anticipate clinical trials on several broad-spectrum antivirals that indicate potential effectiveness against Ebola. The WHO consultation examined several candidates, including a small molecule injectable treatment for hemorrhagic fever viruses from BioCryst Pharmaceuticals. A promising therapy is favipiravir, an oral tablet developed by Japan's Fujifilm as an influenza treatment. Fujifilm has engaged Boston-based MediVector to conduct Phase III trials in the U.S. for that indication, and the company now plans broader testing against Ebola and other viruses.  

Most discussed is the ZMapp monoclonal antibody cocktail from Mapp Biopharmaceutical, which made headlines with the recovery of two infected U.S. health workers following ZMapp administration. HHS' Biological Advanced Research and Development Authority (BARDA) recently awarded a $25 million contract to Mapp to further ZMapp testing and production. 

Clinical trials on these and other therapies may be supported by a BARDA-funded network of five clinical research organizations, launched last year to design and conduct clinical studies needed to develop drugs, vaccines, and diagnostic tests to protect against public health emergencies. BARDA Centers for Innovation in Advanced Development and Manufacturing, moreover, may help provide clinical supplies for initial trials and products for broader distribution, if appropriate. 

Articles

News

The rush is on to develop new therapies and vaccines to combat the lethal outbreak.

Ebola Research Requires Flexibility by Sponsors, Regulators

 "Open integration" has been a primary objective of technology and collaboration adoption for more than five years. Recent research from the Tufts Center for the Study of Drug Development (Tufts CSDD) indicates that the clinical research enterprise is far from achieving this objective.  			

Time-savings, lower cost, and increased efficiency have been the promises of integrated technologies and multi-functional alliances. Ideally, open integration should leverage the benefits of advanced collaborative planning; standardized, compatible, and interoperable systems; accessible and transparent data and information; shared governance, risk, and operating practices; dedicated staffing and reduced numbers of sponsor staff overseeing execution. 

During the past five years, pharmaceutical and biotechnology companies have moved to revise and restructure their operating models and introduce new internal mechanisms to facilitate the adoption of open integration. It is estimated that at this time more than 90% of major sponsor companies and 70% of mid-sized companies have entered into at least one integrated alliance with a contract research organization (CRO). But the promise of open integration remains elusive.

The results of several studies published in 2011 and 2012 provided early indications of the challenges in implementing integrated alliances. A study among 89 sponsor companies conducted by the Avoca Group noted that approximately one-third of sponsors found that their integrated alliances were falling well short of performance and cost-saving expectations and nearly half of sponsors did not believe that their strategic relationships would ever achieve the intended outcome. That same study found that one-out-of-five sponsors had already terminated an integrated alliance despite the high cost and labor-intensive investment required to do so.   

A study conducted by Vantage Partners among 81 sponsor company representatives and 88 CRO company representatives found that nearly half of integrated relationships were unable to establish a collaborative working style, and failed to align expectations and capabilities. One-third of sponsor organizations reported that their strategic alliances had not delivered expected cost and time savings. Nearly 60% of CRO companies reported that their sponsor partners were unable to work collaboratively.  

As part of a broader study, in 2012 Tufts CSDD assessed the frequency of change orders in studies for which the majority of their budgets were allocated to contract service providers. Tufts CSDD hypothesized that change orders—formal, written changes to the original scope of work agreement—would occur less frequently under integrated alliances because the parties share planning and governance, and offer the CRO partner more operating autonomy. The study results showed no difference in the frequency of change orders between traditional transactional relationships and integrated alliances. 

Tufts CSDD conducted its most recent study in the spring and summer of 2014. Nine major and mid-sized pharmaceutical companies—each having had a minimum of three years since implementing one or more integrated alliances—provided data on contract service usage for 43 individual Phase II and III clinical studies. For each study, companies indicated whether internal staff or CROs had provided functional support and the relationship model used (e.g., transactional, functional service provider, and integrated alliance).  

Participating companies also provided study performance (e.g., start-up time, cycle time, enrollment rates) and quality data (e.g., queries per thousand clinical data points collected; number of protocol violations; number of change orders) for each individual study to determine if the outsourcing relationship model used had a measurable impact.   

The results of the study indicate that sponsor companies are using a variety of outsourcing relationship models to support their studies, mixing and matching the use of internal staff, and utilizing traditional transactional relationships, functional service, and integrated alliances simultaneously. Although each sponsor company had entered into one or more integrated alliances at least three years ago, in no instance did a single CRO manage all functional areas supporting an individual Phase II or III study. The results also showed that sponsor companies vary the types of outsourcing relationship models that they use inconsistently, on a study-by-study basis.   

Despite the investment and effort required to identify, select, and integrate their outsourcing relationships, sponsor companies choose to keep all options on the table.   

Lastly, with two exceptions, no statistically significant differences in performance and quality were observed between the types of outsourcing relationship used. The number of screen failure rates was higher, and the frequency of protocol amendments was lower, among studies managed by integrated alliances. This suggests that upfront planning and established site relationships supported by these alliances may be contributing factors. No observed differences in cycle time and cost measures, however, indicate that pharmaceutical and biotechnology company inability to successfully implement integrated alliances is creating operating friction and inefficiency. 

A study soon to be published by Tufts CSDD found similar results with respect to technology adoption. Despite efforts to implement a variety of technology solutions during the past five years, sponsor and CRO companies participating in the study showed high levels of disparate—and often incompatible—systems use across functional areas. In another Tufts CSDD study, described in a past Clinical Trial Insights column, of nearly 300 approved drugs, those that were developed under a collaborative or shared innovation model (e.g., in-licensing, co-development, merger or acquisition) took 20% longer—an additional 14.8 median months from clinical testing to approval—than drugs whose development program was not shared. 

Avoca and Vantage Partners concluded that the primary causes of relationship failure include a long-established culture of mistrust in vendors and service providers and poor communication. The long-held view that CROs are commodity service providers that must be carefully policed and to which some information cannot be shared, is hard to change. The failure to achieve buy-in from senior staff and affiliates and the setting of unreasonable expectations were also cited as factors contributing to relationship failures.  

Tufts CSDD found that similar conditions played a role in the most recent study findings. In addition, legacy activity contributed to implementation challenges as sponsors were frequently compelled to entertain entrenched relationship preferences and approaches simultaneously while new models were being implemented.   

The size and scale of many sponsor organizations is also a key factor. Highly fragmented companies, many deeply involved in integrating recent mergers and acquisitions, often must accommodate inconsistent practices across functions to ensure that the demanding workload is completed.   

A number of sponsor organizations also point to the disruptive nature of internal and collaborative partner turnover—a relatively common occurrence. When key staff leaves the partnership—particularly those involved in critical operating roles and in ensuring consistent practices—old habits and novel approaches fill the vacuum.  

A highly risky and demanding operating environment also plays a major role. Aversion to risk entices sponsor company staff to hedge their bets by maintaining multiple contract service providers under a variety of sourcing models. 

The conceptual promise of integration remains compelling but it appears to be beyond reach in the near term. Many organizations believe that continuous improvement and refinement in their outsourcing models and technology adoption will help realize the benefits of integration. Some of these improvements focus on facilitating higher levels of operating interdependence where internal staff and their many collaborative partners acknowledge and support clearly defined and delineated roles and responsibilities without necessarily aiming for broad-based systems integration, and consistently shared practices and procedures.  

But in the absence of widespread, clear successes and measured return on investment, sponsor organizations and their CRO partners may lose patience. It will become harder to implement refinements and take remedial steps as levels of organizational resistance and fatigue grow. A mix-and-match approach compromises the promise of integrated alliances and reinforces the need to simultaneously accommodate multiple, inconsistent relationship models.   

 MBA, is the Director of Sponsored Research at  the Tufts CSDD and  Chairman of CISCRP, both  in Boston, MA, e-mail: 

CTI Insights

Research shows that the potential of integrated alliances remains elusive in the near term.

Is 'Open Integration' Beyond Our Reach?

The FDA has shown an increased sensitivity to the sedating and impairing effects of drugs. Since 2013, the agency has issued warnings or taken action on dosage recommendations across the therapeutic spectrum, ranging from approved hypnotics (e.g., Ambien, Lunesta) to over-the-counter antihistamines. The focus has mainly been on driving safety.  

Drugs that stimulate or depress CNS functioning have the potential to impact driving safety. As new drugs enter the approval process, the FDA is increasingly requesting an assessment of the their potential to impair driving. In the past, the focus was on drugs that target CNS function such as hypnotics and antidepressants. It is now recognized that drugs whose primary therapeutic activity is not CNS, such as antihistamines and antispasmodics, can also impair driving. We are awaiting guidelines from the FDA that will lay out the standards for conducting the studies needed to evaluate if a drug impairs driving. How can pharmaceutical manufacturers prepare for this new guidance? 

Obviously, drugs known to produce somnolence will be required to undergo a thorough assessment of their potential to impair driving. However, it is also critical to assess drugs that impair attentional abilities such as concentration, divided attention, or selective attention. Drugs that interfere with psychomotor speed or coordination are a cause for concern, too, as well as those that impair executive functions (e.g., judgment, planning). Unfortunately, we can't rely on self-reported sedation to identify those drugs that can potentially impair driving performance.  

The recommendations of the National Highway Transportation Safety Administration (NHTSA) panel evaluating drug impaired driving (

http://www.nhtsa.gov/staticfiles/nti/pdf/811438.pdf

) are likely to be a model for FDA guidance. The protocol identifies the essential driving ability domains (cognitive and psychomotor) and identifies tests for assessing these domains. The report discusses the role of standardized cognitive and psychomotor tests, driving simulation, and over-the-road driving tests.  

For many years, studies were conducted in Europe using an instrumented car on an active highway. This method was effective for measuring weaving but failed to provide a measure of other abilities essential to driving. This type of over-the-road testing appears likely to be eclipsed by driving simulation as demand for driving studies increases. 

Historically, driving simulator studies conducted at a limited number of research sites employed a single driving simulator that used custom software and driving scenarios unique to that site. These simulators had not undergone the software validation or data validation required for a regulatory study.   

Advanced driving simulators, however, provide realism and driver immersion, along with a standardized and validated platform for testing drug-impaired driving. CRC MiniSim, for example, uses a standardized chassis with a full-size car seat, steering wheel, and pedals. The driving scene is presented on three monitors, roughly the size of a car windshield. Driving scenarios have been validated with respect to their sensitivity to the effects of drugs and alcohol. In order to conduct multicenter clinical trials, a fleet of these simulators have been developed and deployed to sites in the U.S., Canada, and Europe. For example, our group recently completed a study employing nine of these simulators in a protocol that tested the acute and steady-state effects of a potentially sedating medication at multiple doses, compared to placebo and an active control.  

The technology and methodology is now available to meet the expected regulatory demands for assessing the potential for drugs to impair driving. Pharmaceutical companies can begin to prepare for upcoming FDA guidance on evaluation of drug-impaired driving. 

 President, Cognitive Research Corporation. E-mail: 

A Closing Thought

The technology necessary to meet the expected regulatory demands for assessing drug-impaired driving has emerged.

Cognitive Guidance for Clinical Drug Trials

The five-yearly changing of the guard among senior European Union officials is approaching, and this time around it will be more than just a few new names and fresh faces. The president of the new European Commission, Jean-Claude Juncker, plans to shake things up during his mandate—and pharmaceuticals will be one of the policy areas to feel the wind of change.  

Juncker, a former prime minister of Luxembourg, has won the role of Commission president after a bizarre and byzantine selection process that did neither him nor the European Union (EU) much credit. But there he is, and he is determined to use his position to inject some new dynamism into the EU and to remedy some of the sclerosis that has overtaken it in recent years. As a center-right politician, there is a distinctly pro-business tone to his approach—which will bring some relief to drug companies, but which is already provoking dismay among consumer groups. 

One of Juncker's planned modifications, announced in early September but still subject to approval by the European Parliament before the new Commission can take office on its scheduled date of Nov. 1, is to put a former health minister in charge of the health portfolio. Vytenis Andriukaitis, a surgeon by profession, has been Lithuania's health minister since 2011. He won praise for his chairmanship of the EU health ministers during his country's turn in the EU presidency in the second half of last year—including for his management of a compromise on the clinical trials regulation, and for raising the profile of health policy in the EU with a major conference in Vilnius. 

That has already pleased some of the European health lobbies. It is a long time since a health commissioner has had any professional involvement in health. And it is probably the first time that a health commissioner has actually wanted the job: traditionally, health is not a portfolio that candidate commissioners fight to obtain, but Andriukaitis had already indicated his interest in doing the job. 

In his instructions to Andriukaitis, Juncker is realistic about what can be accomplished as far as European health policy. He notes that in the area of human health, the role of the Commission is "limited," and "the specific exclusion of national health policy and of the management of health services illustrate the importance of respecting the rules on subsidiarity and proportionality"—in other words, no EU rules on things that can be better dealt with at national level. "At the same time," says Juncker, "the EU can clearly help member states address the challenge of increased calls on health services and more complex technological choices at a time of intense pressure on public finances."  

But the pro-business approach is clearly seen in Juncker's plan to shift responsibility for drugs out of the health commissioner's domain and put it under the commissioner in charge of industry affairs. In a reshuffle of the Commission's operational departments, Juncker is to remove the task of regulating drugs and medical devices from the health directorate general, and put it, instead, into the directorate general responsible for industry and the internal market. The European consumer organization, BEUC, immediately condemned the shift. "With this change, the European Commission sends the signal that economic interests come before those of patients," said BEUC's health expert, Ilaria Passarani. 

Pharmaceuticals and medical devices will now become part of the fief of Elzbieta Bienkowska, the 50-year-old former Polish infrastructure minister, who Juncker has designated as commissioner for the internal market, industry, entrepreneurship, and smaller firms.  

Juncker is determined to maximize the beneficial impact of the single market. In the same vein, he counsels against excessive regulatory intervention. "To support innovation and competitiveness, we must not come with too prescriptive and too detailed recommendations." He is particularly attentive to the needs of smaller firms. The avoidance of unnecessary red tape is essential, he says. 

The European Federation of Pharmaceutical Industries and Associations has welcomed the new structure. It claims that the outcome owes much to its own urgings: "The president of the Commission has taken on our views and put together all units that are relevant for our business in Europe"—units that were, stresses EFPIA, previously spread over distinct departments responsible for health and consumer affairs, internal market, and enterprise. Juncker's business-friendly tone is also discernible—indeed trumpeted—in his approach to research. Carlos Moedas, who was until recently the secretary of state in the Portugese prime minister's office, has been named as the next commissioner for research, science, and innovation. Juncker has told him to promote "the international excellence of the EU's research and science" and strengthen research capacities and innovation strategies across all the member states. 

View from Brussels

Reshuffling to heavily impact life sciences policy in Europe.

All Change for Pharma at the European Commission

The European Forum for Good Clinical Practice (EFGCP) and MedTech Europe have established a Medical Technology Working Party to promote collaboration and dialogue between all stakeholders on the specific aspects of clinical standards. Setting effective ethical and quality standards for medical technology is critical to ensuring that patients have access to safe and effective treatment, according to a joint statement. The group will strive to  ensure these standards are broadly accepted and reliably introduced in the diverse medical technology landscape. 

"Historically, the clinical development debate has focused on pharmaceuticals," said EFGCP Chair Ingrid Klingmann, MD. "But it's important that we have a deeper conversation about issues that need to be considered when setting standards for the medical technology sector." 

The working group will initially organize a joint workshop on "Mitigating Risks in the Lifecycle of Medical Devices: Options and Challenges in the Medical Device Legislation." The workshop, to be held Dec. 4 in Brussels, will bring together patients, national competent authorities, ethics committees, lab technicians, healthcare professionals, industry representatives, and European regulatory authorities with the aim of finding consensus on key topics of interest and potential policy recommendations. 

Meanwhile, EFGCP has revealed more details about the theme of its upcoming annual meeting in Brussels on Jan. 27-28, 2015. Delegates will discuss the inherent tensions between confidentiality and transparency in health research, and the organizers aim to provide a description and report on data protection arrangements in research across the EU through an ethics survey. They also want to encourage debate on a draft statement about the secondary use of data in research and on how the EFGCP's report and recommendations will be provided to those involved in the legislative process. 

These two key questions will be addressed: How do we improve health without betraying confidentiality within current and upcoming EU regulations? What is the price of maintaining confidentiality for patients in health research?  

Many advances in healthcare are founded on the use of personal data, such as medical records; without access to the data, medical progress would be seriously impeded, organizers of the 2015 annual conference said. 

A Medical Technology Working Party is established to promote collaboration and dialogue on the specific aspects of clinical standards.

Europe Unveils Plan to Standardize Clinical Development

Maintaining health and safety of patients is a primary objective when conducting any form of research. With the research arena becoming increasingly complicated, maintaining oversight over patients' safety is more critical than ever. In order to assist in this effort, data monitoring committees (DMCs) have been created in order to monitor data in an independent, organized, unbiased, and real-time manner.  

A data monitoring committee (also known as a data safety monitoring board, or DSMB) is a committee comprised of independent experts who are gathered to advise a research organization during the conduct of a clinical trial or trials. DMCs were created in the 1960s, to evaluate the patient and community impact of marketed products in longer running government trials. The use of such committees made its way to the private, mainstream pharmaceutical industry about a decade later. Throughout the 2000s, with economic markets as well as patient populations changing, drug companies began to produce more targeted trial designs, many of which had special or higher-risk patient populations targeted to obtain more rapid product approval. As part of this evolution, DMCs have not only become a more regular part of clinical programs, but their use is also in earlier phases of clinical development.  

While all global regulations require the ongoing safety monitoring of clinical trials, currently, no concise guidance exists describing how, when, and why to use a DMC. The emphasis on appropriately incorporating DMCs into a clinical program often leaves sponsors with questions concerning creation and implementation of these committees, therefore expertise (internal or consultant) is crucial for success. 

The recommendations within the industry on when to use a DMC includes research studies where: 					

There is a randomized trial (or set of trials) with a large study population conducted over a relatively long period of time

The trial is intended to provide definitive information about effectiveness and/or safety of a medical intervention

Prior data suggests that the intervention being studied has potential to induce potentially unacceptable toxicity

The trial is evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety and effectiveness implications

It would be ethically important for the trial to stop early if the primary question addressed has been answered, even if secondary questions or complete safety data were not yet fully addressed

If two or more of these questions are noted to be applicable, a DMC is indicated. If fewer than two apply, a DMC may not be indicated; however, there is nothing to contraindicate implementation of a committee under any circumstances.  

When implemented, the DMC has three fundamental priorities: protecting and ensuring the safety of study participants, preserving the integrity and credibility of the trial and its results, and also facilitating the timely dissemination of reliable clinical findings to the broader community. 

A committee is composed of a panel of three to nine independent experts (key opinion leaders, statisticians, scientific experts, etc.), with expertise relevant to the product and drug indication. An uneven number of committee members should always be maintained so that a clear decision is made when voting occurs. Globally conducted trials should ensure that member selection allows for appropriate regional representation.  

For any sized pharmaceutical company, navigating the processes of the DMC meetings can be deceivingly difficult and costly, as all conflicts of interest and biases must be avoided with a complete appearance of transparency maintained. The operational process of a DMC is fairly standard and includes the following activities (listed in approximate order of completion): 

Selection of members requires execution of confidentiality agreements, review of medical or other qualifications, collection of active medical licenses, absence of sanctions and debarment, and anti-bribery and corruption checks, review of conflict of interest declarations, and if the previously noted checks are in favor of committee inclusion—implementation of consulting agreements. This process takes an average of about four months.  

Approximately two to three weeks prior to first patient initiation, an organization meeting is held, where key documents are reviewed, the draft DMC charter is reviewed and ratified, and the data shells and sample formats for data presentation are agreed-upon. Following the organizational meeting, final minutes are prepared, circulated, and approved. After the minutes are finalized and approved, the DMC charter is also updated, finalized, and distributed to all committee members. Once these organizational processes are complete, data review meetings are held over the course of the project according to the finalized DMC charter with all findings and recommendation documented and distributed. The flowchart in Figure 1 outlines this process for a typical DMC requiring three members.  

Three models are reviewed ahead, including the "DIY" model, and two different models of outsourcing (partial and full). With any of these models, careful consideration needs to be made to ensure the unblinded statistical team has no direct contact regarding the unblinded data with any member of the working project/blinded team. This philosophy needs to also be applied to manage the documentation of the meeting minutes for closed sessions as well as any recommendations. 

Do It Yourself (DIY) model/In-sourcing model 

In the "DIY" model, the sponsor provides all services, including locating and contracting committee members, drafting and finalizing committee charter, meeting logistics and preparation, statistical analysis, meeting moderation, and all applicable documentation. This model gives sponsors full control over timelines and provision of data, and allows them complete oversight over staff and costs. When using this model, sponsors must take extra care to ensure that no bias or conflict of interest is introduced.  

In a partial outsourced model, the sponsors can internally handle all activities that would not come under scrutiny for transparency or bias issues. This includes completion of all of the member locations and on-boarding processes, including consulting agreements, drafting of charter, meeting logistics and preparation, open-meeting moderation, and provision of blinded statistical activities. All other activities, such as the unblinded statistical support activities and closed meeting moderation/documentation, would then be outsourced to a third-party vendor, such as with consultants or a CRO. With this partial outsourcing, the sponsor is less involved overall, which can produce some anxiety on the sponsor's side, especially when the sponsor is a small biotech company, for example. However, outsourcing is an ideal solution for medium-sized sponsors, because they may have difficulty providing sufficient resources to adequately staff separate blinded/unblinded and other support-team members required to avoid the potential bias and transparency issues. Larger sponsors may also benefit from an outsourced model, as it is financially beneficial to outsource a few resources when they are needed, reducing time and recruitment costs versus hiring and maintaining the full staff required for specialized committee support over longer periods of time.  

Fully outsourced models are typically handled by a CRO. This model can be practical and cost-effective; however, it does remove some of the control away from the sponsor. The CRO will provide a service, which includes providing the experienced, appropriate staff required to create and support a DMC for staff acquisition, meeting logistics, moderation, and documentation.  

When done internally, companies often use highly paid staff (i.e., statisticians) to do non-scientific work, such as member onboarding, contracts, meeting logistics/preparation, and various documentation. The CRO has the ability to use more appropriate level staff (i.e., a nurse or high-level administrative support) for these tasks that not only ensures quality, but also cost-effectiveness. This model is ideal for any sized sponsor because it is able to easily avoid any appearance of bias or non-transparency, as well as being assured that the sponsor can review and provide input at any stage of the project or be guided by the CRO experts on the regulations, processes, and requirements. Care does need to be taken when selecting whom or where to outsource, as a team with experience is needed not only for efficiency gains, but also avoidance of errors—which are always costly at some level. If the wrong outsourced team is consulted, miscommunication and bias can be accidentally introduced, or an improperly assembled DMC could be put in place.  

For the average pharmaceutical company, each DMC managed would require a minimum of six staff members, plus committee members. The six staff members include: one member of procurement/contracts to perform the location of members and onboarding/qualification process; two statisticians (one blinded, one unblinded); two programmers (one blinded, one unblinded); and one for administrative support. Based on average internal cost for these resources, combined with DMC member fees and travel and logistical costs, the average DMC using these staff members could cost about $800,000. Considering these assumptions, outsourcing DMC services can create a significant cost savings based on the following: 					

Each internal member only provides work for the amount of meetings required—there is no fear of conflict of interest

Sponsors pay only for the work required—which means only portions of staff are used and billed for the project—versus having to hire and train an entire team of resources internally

Outsourcing allows the use of the appropriate level of staff 

There are three sourcing options to be considered when implementing a DSM: full in-sourcing, partial outsourcing, and complete outsourcing of work. There can be incremental level of cost savings with the various levels of outsourcing. It may also be possible that additional savings can be made for any model with the use of the same committee (and management teams) during programs (eliminating many onboarding or other start-up processes). These three models will, therefore, provide sponsors with viable options for implementing DMCs on any project, thus enhancing the monitoring of patient safety during their trials. 

, RN, MSN, is Director, Drug Safety, ICON Clinical Research, email: 

, RN, BSN,  is Senior Drug Safety Manager, ICON Clinical Research, email: 

Ellenbeg, S, Fleming T, DeMets D. "Data Monitoring Committees in Clinical Trials, A Practical Perspective." West Sussex, England: Wiley; 200. 

Herson, J. "Data and Safety Monitoring Committees in Clinical Trials." Boca Raton, FL: Chapman and Hall; 2009.  

Slutsky, A.S. and J.V. Lavery (2004). "Data Safety and Monitoring Boards." 

Institute of Translation Health Sciences. Data Safety Monitoring Boards (DSMBs). Web site. 

National Institute of Dental and Craniofacial Research. "Data and Safety Monitoring Board (DSMB) Guidelines." Web site. 

http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/DSMBGuidelines.htm

NIH Guide: NIH Policy for Data and Safety Monitoring. NIH Web site/ 

http://grants.nih.gov/grants/guide/notice-files/not98-084.html

The Research Subject Advocate (RSA) Program. A Guide to Data and Safety Monitoring Boards (DSMB). Web site. 

http://www.utmb.edu/gcrc/aboutus/RAS/RSA.dsmb.htm

Feature Article

Exploring sourcing model options for appropriate incorporation of DMCs into a clinical program.

Implementation and Usage of Data Monitoring Committees

The percentage of registered clinical trials being conducted at investigative sites outside of the U.S. continues to rise. According to data provided by 

 on the distribution of locations for all trials registered on the website, 45% reside in non-U.S. geographies.  

			The U.S., of course, continues to be the most active location for clinical research by size, with the country still home to 40% of all registered studies in the world. Six percent, or 10,572, of those trials in the http://ClinicalTrials.gov/ database  have sites located in the U.S. as well as other global regions. 

As of Sept. 23, a href="http://www.ClinicalTrials.gov" target="_blank" rel="nofollow">http://ClinicalTrials.gov/ included entries on 175,249 studies, with locations in 187 countries.      

The distribution of locations for all trials registered on ClinicalTrials.gov.

Placement of Trials Increasingly Dispersed

ACT cover

Unlike classic drugs, which have relatively simple molecular sizes and structures (typically up to 300 Da), biologics are large molecules (up to 270,000 Da) with highly complex three-dimensional tertiary structures.

  To help put the magnitude of this difference into context, the chemical structures of aspirin, a small classic drug with a molecular weight of 180 Da, and Humira®, a novel biologic with a molecular weight of approximately 148,000 Da, are presented in Figure 1.  

Although classic drugs such as aspirin are usually easily characterized using sensitive analytical methods, biologics are created using genetically modified cell lines, and often undergo significant post-translational modifications (such as glycosylation), which can give rise to considerable heterogeneity. Consequently, producing an exact replica of an existing biologic is an almost impossible task. 

The first patented biologics were recombinant versions of endogenous human proteins, such as insulin, in the 1980s, followed by more complex products, such as monoclonal antibodies, in the late 1990s.

  Since biologics were first introduced, sales have grown considerably year-on-year, and by 2011 global sales had reached approximately 142 billion USD (equivalent to 19% of the global biopharmaceutical market), with more than a third of this (37.6%) attributed to the top 10 biologics.

 However, the period of exclusivity for these top 10 biologics is fast approaching, with a "patent cliff" anticipated between now and 2019 (see Figure 2).  

This patent cliff creates an enormous opportunity to develop generic versions of biologics. Advances in technology have led to higher production yields, reduced production times, and lower costs, while the global recession has significantly increased the pressure on national governments to drive down the cost of health provision;

  and, perhaps most significantly, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have both introduced regulatory pathways for the review and approval of "generic" biologics,

  thus paving the way to market for what have become widely known as "biosimilars." 

Guidelines for the approval of biosimilars were first developed by the EMA during 2005 to 2006, with the first biosimilar approved in the EU in 2006 (Omnitrope®, a somatropin biosimilar). Since the approval of Omnitrope®, a further 19 biosimilars have been approved by the EMA for use in the EU, as of January 2014.

; however, two of these approvals have subsequently been withdrawn—one for filgrastim in April 2011 (Filgrastim Ratiopharm®) and one for somatropin in May 2012 (Valtropin®)—leaving a total of 18 biosimilars currently approved for use in the EU. 

Although the route to market for classic generics is well defined, and has been successfully applied to many drugs over the years—typically a small number of studies in healthy volunteers are sufficient to prove physiochemical and pharmacokinetic (PK) equivalence—the corresponding route to market for biosimilars is relatively new and considerably more complex. Comparative PK and pharmacodynamic (PD) studies are essential; efficacy trials are usually also required, the safety profile must be well defined, and immunogenicity must always be investigated. Ahead we focus on some of the key issues affecting PK studies used to support biosimilar drug applications: 

The most common study designs associated with standard bioequivalence studies are crossover designs, with a relatively small number of subjects receiving both test and reference drugs in separate treatment periods (in a randomized fashion), with a short wash-out period between each period. However, using crossover designs in the development of biosimilars can often prove to be difficult for a number of reasons: for example, biologics tend to have much longer half-lives than classic drugs, therefore, a crossover approach is generally not practical (as the required wash-out period is often prohibitively long), and the potential for biologics to illicit an immune response can also limit the use of crossover studies (if a patient was to develop an immune response in the first period of a crossover study, the patient's ability to participate in the second treatment period would be compromised). 

To negate these issues, it is common to use parallel designs when conducting biosimilar studies; only one treatment period is required for each subject, removing the need for a wash-out period, and the potential knock-on effect caused by an immune response is also limited. However, it is important to note that parallel designs are not without issues of their own: large sample sizes are often required to ensure that there is sufficient statistical power to prove biosimilarity, and, as treatment differences are estimated between subjects (rather than within subjects), it is important to stratify treatment groups by certain covariates (i.e., age, weight, and sex) to avoid potential imbalances in baseline characteristics between treatment groups. 

Recent examples of successful Phase I biosimilar studies include Remsima®

—both Remicade® (infliximab) biosimilars—which were approved by the EMA in 2013. To investigate the PK of these biosimilars, randomized, double-blind, multi-center, parallel-group studies were carried out using a large sample size of 250 patients (125 per treatment group).

  The biosimilar and innovator biologics were subsequently shown to be comparable by demonstrating that the 90% confidence intervals for the key PK endpoints (AUC and Cmax) were within the bioequivalence limits (0.80, 1.25).

While large parallel-design studies such as these are often required in early phase PK comparability studies, it is perhaps worth noting that this is not always the case; all studies should be based on the PK and PD characteristics of the comparator, or reference, biologic. Indeed, Grastofil® (approved in 2013)

  —both Neupogen® (filgrastim) biosimilars—have recently been approved for use by the EMA following completion of a series of Phase I cross-over trials: one for Grastofil® (using 35 patients), and two for Nivestim® (using 44 and 48 patients, respectively). In these instances, crossover studies were possible as the terminal half-life of Neupogen®, the comparator biologic, is in the region of three hours, which is considerably shorter than the half-life associated with most biologics (thus compatible with a crossover approach). However, this is not typically the case. Of the top 10 biologics listed in Figure 2, only two have half-lives which are not measured in days, Novolog® and Lantus®, which are insulin-based biologics and have short half-lives in the region of one to three hours; the other eight have half-lives ranging from approximately 3 days (Enbrel®, Lucentis®, Neulasta®) up to 50 or 62 days (Avastin® and Rituxan®, respectively). Therefore, the use of crossover studies in the development of biosimilars for most of the top 10 biologics is likely to be impractical. 

In classic bioequivalence studies, PK equivalence is demonstrated using bioequivalence limits of (0.80, 1.25); the test and reference products considered to be equivalent if the 90% confidence interval of the ratio of geometric least squares means lies entirely within (0.80, 1.25).

  There are currently no such limits defined for biosimilars; indeed, the EMA guidance on similar biological medicinal products

 currently states that "The acceptance range to conclude clinical comparability with respect to any pharmacokinetic parameter should be based on clinical judgement, taking into consideration all available efficacy and safety information on the reference and test products. Hence, the criteria used in standard clinical comparability studies, initially developed for chemically derived, orally administered products may not be appropriate and the clinical comparability limits should be defined and justified prior to conducting the study." Therefore, might it be possible to justify wider acceptance limits? 

A review of the clinical development of the 20 biosimilars which have (at some stage) been approved for use in the EU prior to January 2014

 would suggest not. Of the 20 approved biosimilars, at least 19 applied bioequivalence limits (0.80, 1.25) as the key criteria for establishing PK comparability at some stage of their clinical development (the approach used for Somatropin Biopartners® is unclear, based on the European Public Assessment Report

). In some instances (e.g., Retacrit® and Silapo®) the limits were applied post-hoc (perhaps following regulatory advice), and in one instance (Valtropin®) a wider limit (0.70, 1.43) was used for Cmax. This is a common approach used in standard bioequivalence studies when comparing highly variable drugs.

  Therefore, in the absence of acceptance criteria specific to biosimilars, adhering to the guideline on investigation of bioequivalence

Due to their nature (recombinant proteins, some with non-human origins) and a complex manufacturing process that often results in impurities, biologics have the potential to illicit an immune response. Indeed, nearly all biologics induce anti-drug antibodies (ADA); however, the incidence of ADAs differs widely among products and between individuals.

  ADA may have no clinical significance; however, high levels can interfere with the PK and PD properties of the drug (e.g., increasing clearance, and thus reducing the extent of systemic exposure and desired effect of the drug). It is, therefore, important to have an assay in place to test for the presence of ADA at suitable intervals during the study, so that subjects who illicit an immune response can be identified and the impact assessed.   

As defined in a recent guideline issued by the EMA, "differences that could have an advantage as regards safety (for instance, lower levels of impurities or lower immunogenicity) should be explained, but may not preclude biosimilarity."

   While differences in immune response for a true biosimilar seem unlikely, equivalence in immune response cannot be assumed and is an integral part of the PK assessment; indeed, care needs to be taken when dealing with subjects who develop an immune response. One approach, which has been ratified by the EMA and FDA in one of our recent studies, is to perform a secondary analysis which incorporates ADA titer results as a covariate. Although the statistician may find it tempting to include terms for ADA and ADA with treatment interaction in the primary analysis—so that estimates of difference can be constructed separately for each sub-population, and averaged over both—since ADA is not a truly independent covariate, the overall estimate may be misinterpreted. In particular, an overall treatment difference would balance for similar levels of ADA response in each treatment, when it would be more appropriate to reflect the relative problems with immune response, and not correct for an imbalance. Thus, assessing the effect of ADA as a secondary analysis ensures that the ADA issue is addressed, without compromising the validity of the primary analysis. 

One additional consideration that should be taken into account when evaluating suitable ADA blood sampling times concerns the presence drug. High levels of drug can interfere with ADA assays, therefore, it is good practice to test for ADA levels at time points where drug levels are expected to be at their lowest (e.g., at the end of the PK sampling period following a single dose).  

In the future, the exact nature of statistical assessments to be performed in terms of ADA activity may be dictated by regulators; however, until this topic has been investigated further and authorities clarify how best to deal with the PK analysis of ADA positive subjects as standard, it is imperative that this issue is not overlooked. 

Whereas bioequivalence studies are typically limited to the area under the concentration-time curve (AUC) and maximum concentration (Cmax) as measures of the overall extent of systemic exposure and rate of absorption, respectively, elimination characteristics must also be considered when comparing biologics due to their long half-lives and potential to develop immune responses. Indeed, current EMA guidelines state that "the design of comparative PK studies should not necessarily mimic that of the standard "clinical comparability" design  (CHMP/EWP/QWP/1401/98), since similarity in terms of absorption/bioavailability is not the only parameter of  interest. In fact, differences in elimination characteristics between products, e.g. clearance and elimination half-life, should be explored."

In this context, it is important to note that, to fully characterize elimination kinetics in biosimilarity studies, the sampling schedule guidelines associated with equivalence (or clinical comparability) studies should still be applied: i.e., "The sampling schedule should also cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUC(0-t) covers at least 80% of AUC(0-8). At least three to four samples are needed during the terminal log-linear phase in order to reliably estimate the terminal rate constant, which is needed for a reliable estimate of AUC(0-8)."

  Thus, the last sampling time point may be many weeks or even months after dosing. 

Although there have been significant advances in the manufacture and production of biologics in recent years, the process is still considerably more complex than the chemical synthesis of classic drugs, and often results in impurities. Whereas "the assayed content of the batch used as test product should not differ [by] more than 5% from that of the batch used as reference product"

  in bioequivalence studies (unless otherwise justified), it may not be possible to meet this criteria for biologics; therefore, the total protein content of the test and reference drugs need to be considered when assessing biosimilarity.  

The importance of this issue is perhaps best illustrated by referencing a recent study performed to compare the PK of Retacrit®, a biosimilar, to that of Eprex®, an innovator biologic.

  This study highlighted differences in the amount and type of glycoforms between the biosimilar and the reference drug, which is to be anticipated given the different production processes. More notably, however, Eprex comprised more total protein (μg/mL) than Retacrit, which appeared to contribute to the potency (IU/mL) of Eprex being 10% higher than labelled. The EMA accepted that the PK of Eprex and Retacrit were comparable, based on introducing a correction factor to allow for the difference in protein content. Once this was taken into account, the comparison of PK parameters was well within the defined equivalence margins. 

We have recently encountered an issue in a Phase I study whereby the FDA would not accept the use of an European Economic Area (EEA)-licensed drug as a reference, and similarly, the EMA would not accept the sole use of a U.S.-licensed reference. As the ultimate aim was to license the biosimilar in both the EU and the U.S., both regulatory agencies advised that it would be necessary to include two reference drugs in the study, and conduct a three-way comparison between the test drug, the US-licensed drug, and the EEA-licensed product. Should similarity be proven for all three treatments in the Phase I studies, subsequent Phase II and III trials may then be limited to just one reference. 

This is in line with the recent EMA guideline on Similar Biological Medicinal Products, which states that "...with the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an applicant to compare the biosimilar in certain clinical studies and 

non-clinical studies with a non-EEA authorized comparator (i.e., a non-EEA authorized version of the reference medicinal product), which will need to be authorized by a regulatory authority with similar scientific and regulatory standards as EMA (i.e., ICH countries). In addition, it will be the applicant's responsibility to establish that the comparator authorized outside the EEA is representative of the reference product authorised in the EEA."

It is difficult to believe that this will always be a requirement for biosimilar studies; perhaps the stance of the EMA and FDA will soften as more biosimilars come to market and the difference between EU and U.S. versions of the same drug are better characterized. However, until then, the inclusion of multiple reference drugs, at least in pivotal Phase I studies, may be essential. 

Although this article focuses primarily on the PK characteristics of biosimilars, the importance of investigating to support these early-phase PK studies should not be overlooked. PD markers should also be assessed and compared to the innovator biologic; indeed, comparative PK and PD studies are essential for biosimilar approval. In certain cases, where the PK and PD properties of the reference drug are well defined, and at least one PD marker is accepted as a surrogate marker for efficacy, comparative PK/PD studies alone might be sufficient to demonstrate clinical comparability; however, efficacy trials are usually also required. In addition, the nature, seriousness, and incidence of all adverse events must be well defined, to ensure that there are no safety concerns associated with the biosimilar, and immunogenicity must always be investigated, as anti-drug antibodies can alter both the PK and PD effect.  

There are a number of characteristics of biologics that set them apart from traditional generic drugs, as summarized in Table 1. These characteristics make the route to market for biosimilars more complex than it may at first seem, with differences in study design between bioequivalence and biosimilarity studies.  

Due to their long half-lives and the potential to illicit an immune response, biologics may not be compatible with simple crossover designs; therefore, parallel study designs are often utilized. Acceptance limits for the 90% CI of the ratio of PK parameters must be predefined and approved by regulators; although traditional equivalence limits of (0.80, 1.25) tend to remain favorable. Anti-drug antibodies have the potential to affect pharmacokinetic characteristics and should, therefore, be measured and their impact considered. Unlike standard equivalence studies, the assessment of comparability must extend beyond absorption (Cmax) and overall exposure (AUC), with half-lives (t1/2) and clearance (CL) also investigated. Furthermore, the relative protein content of the test and reference drugs needs to be considered, with a suitable correction factor applied, if necessary. In addition, region-specific versions of reference drugs may exist in some instances (e.g., Humira®); therefore, if the intention is to ultimately license the new biosimilar across multiple regions, it may be necessary to incorporate more than one reference drug in at least one bridging study. 

When faced with the prospect of proving PK "equivalence" between a biosimilar and an innovator biologic, it may be natural to assume that standard bioequivalence study designs and analysis methods would be sufficient to meet the objectives of the study; after all, such study designs have been successfully employed for many years to bring generic drugs to market. However, due to various complexities of biologics, special consideration needs to be given to the study design (parallel versus cross-over), potential immunogenicity (anti-drug antibodies), elimination characteristics (half-life and clearance), and relative protein contents of the test and reference drugs before commencing the study. Furthermore, guidance should be sought from regulators to determine the most suitable acceptance limits to conclude clinical comparability, and to assess the potential benefits of using multiple region-specific reference drugs in pivotal early-phase clinical studies. Only then, with these factors fully and adequately addressed, can an investigator be confident that a biosimilar trial will be a success. 

 is Executive Vice President, Operations, Quanticate, email: 

1. Shellenkens, H. "When Biotech Proteins Go Off-Patent." T

2. Calo-Fernandez, B. Martinez-Hurtado J. L. "Biosimilars: Company Strategies to Capture Value from the Biologics Market."

3. EvaluatePharma. World Preview 2018 Embracing the Patent Cliff. Technical report, Evaluate Pharma, London, UK, 2012. 

4. EMA. Guideline on Similar Biological Medicinal Products. 2013 (draft). 

5. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-clinical and Clinical Issues. 2013. 

Proving a biosimilar's pharmacokinetic 'equivalence' requires adherence to several unique factors.

Demonstrating Biosimilarity: PK Considerations

 More attention is being paid to blood pressure (BP) effects in new chemical entities under development for non-hypertension indications, especially when these are not anticipated and not thoroughly defined during drug development. Concern by scientists, clinicians, and regulators centers around small-to-moderate effects that can contribute to cardiotoxicity in a therapy otherwise thought to have none. Scientific and regulatory efforts to raise awareness and better define approaches to assessment of BP during drug development were presented in a report published in March 2013 by the Cardiovascular Safety Research Consortium (CSRC), a collaboration between the FDA and multiple academic and drug development experts.

  While comprehensive in presenting the scope of the challenge and in providing an overall approach to evaluation of BP, specific proposals for the design of clinical trials were not made. 

This article presents a plan for a systematic approach to identifying BP effects during typical Phase I and Phase II trials. Most compounds will be able to be studied using this approach without additional dedicated trials and without additional subject enrollment. The outcome of this approach would likely not definitively exclude a small BP effect but, rather, would identify the presence of an important BP effect sufficiently early in drug development to define the need for additional testing. 

In general, it has been difficult to document the relationships between BP changes and cardiovascular (CV) events, particularly if these BP changes are modest in extent or occur only in a small proportion of treated patients. Clearly, a greater concern will exist with drugs that are intended to be administered chronically rather than for short term or occasional use. But beyond considerations for individual patients, there exists a public health issue: based on epidemiologic data, it can be argued that even small BP changes—if occurring in large cohorts of treated patients—might increase CV events across a community even if conventional safety studies do not detect an increased risk. 

There are many issues to be considered in defining potentially adverse BP effects of drugs used for non-hypertension indications. If BP increases are observed, are they likely to cause major CV events? Or are the increases a biomarker of some other mechanisms that could cause CV outcomes? For instance, non-steroidal anti-inflammatory drugs can cause increases in BP and are also associated with increased CV events. But it is not clear whether these increased event rates are due to the underlying disease (arthritis has been linked to increased CV risk), to the potential pro-thrombotic effects of these agents, or to the observed increase in BP.

Another example is the increased mortality observed with the anti-obesity agent, sibutramine. Even though there was an increase in BP in the definitive CV outcomes trial, SCOUT,

  that evaluated this agent, there was no evidence that patients with fatal events while taking this drug actually had increases in BP, compelling the investigators to speculate that other mechanisms were responsible. Perhaps the best direct evidence for BP elevations causing events has been with the vascular endothelial growth factor inhibitors used in cancer therapy: the sharp increases in BP that can be produced by these agents appear to have a direct connection to stroke events.

Systematic evaluation of blood pressure effects:  A working checklist 

From the perspective of adverse BP events, a checklist of questions, previously presented by one of the authors,

  can be applied to new drug development. The proposal in this article can reasonably only address questions 1 though 7 in the following list and summary, but allowing these to be defined will greatly aid in decisions for answering the others. 

 A direct BP-raising effect may occur almost immediately while the drug is in the circulation and thus could be readily detected in standard Phase I  trials or after a short period of repeated dosing, as in a Phase II trial. 

2. What is the incidence of this effect? 

In most cases, this calculation can best be determined during Phase II. For drugs with a low incidence of BP effects, it may be necessary to use Phase III, Phase IV, or even post-approval registry-type data to get an accurate estimate of incidence. 

3. What is the effect size and range of BP effects?

 This information is important for determining CV risk. Defining outliers at the high end of the range of BP changes obviously will be important for making estimates of potential event rates. 

Specifically, is there a dose at, and below which, the effect is not seen? Is there a dose where the incidence of this effect is unacceptably high? 

5. Do the drug's pharmacokinetic (PK) properties have a relationship to the BP effect?

 Is the timing of the change in BP or its amplitude predictable by knowing the drug's maximal concentration or other PK properties? 

6. Does the BP effect occur in relationship to the time of day of dosing? 

Is there a predictable time of day when the effect is seen? Could this be ameliorated by changing the time of day of dosing? Or is it an all-day effect seemingly unrelated to when the dosing is given? 

7. When does the BP effect occur in terms of the duration of the therapeutic regimen? 

BP changes may be immediate, or could occur after minutes, hours, days, weeks, or even months of treatment. Conversely, it might appear only after more prolonged chronic therapy. For example, an effect that depends on vascular remodeling might not even be observed during Phase III studies and might only be detected during long-term safety observations. 

8. Does the drug convert those with normal BPs into hypertensives or is the BP-raising effect seen mainly in those known to be hypertensive? 

This is a key question when a drug is being developed for chronic usage. The question assumes that patients with the circulatory changes that underlie hypertension might have a vasculature that is excessively responsive to potential BP-raising stimuli. 

9. Could the drug's BP-raising effect be due to interactions with antihypertensive drugs? 

For instance, it is believed that NSAIDs may have larger-than-average effects on BP in hypertensive patients receiving angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. 

10. Are there patient characteristics that are predictive of a BP effect?

A systematic approach for early identification of BP effects during development of new drugs.

Applied Clinical Trials-10-01-2014