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The field of regenerative medicine is well underway, with many emerging biopharmaceutical enterprises focusing on numerous disease indications. With this competition comes the need to diversify target disease indications, as well as generate more compelling data for both regulators and payers. Additionally, developing physician-centric stem cell administration procedures during clinical trials appears to position the therapy for wide adoption and utilization post-approval. Further, getting to market first is critical, and regenerative medicine companies, such as Pluristem, have taken unique regulatory pathways to advance their therapies. In this interview, Yaky Yanay, CEO of Pluristem, will elaborate on his experience and the strategies Pluristem implemented in regenerative medicine clinical trials.

Moe Alsumidaie: As a regenerative medicine company, what regulatory pathways are you pursuing and what challenges did you experience when setting up the studies using placenta-derived stem cells?

 We have been one of the first companies that engaged with the FDA for improving real allogeneic cell therapy products. A key step is informing the FDA that this is not a stem cell product-these are adherentstromal cells, which do not differentiate or replace patient cells; the mechanism of action is an endocrine/paracrine effect. Ten years ago, regulators had some concerns about potential homogeneity issues and how cellular products functioned. I’m glad to say, a decade afterwards, the FDA stands behind cell therapy. Regulatory agencies use terms like cell therapy, regenerative medicine, not “stem cells”, which is good.

MA: You are developing a therapy for protection from acute radiation syndrome before exposure takes place. As the study cannot be performed in humans, how do you conduct this trial, and does it have an equivalent to Phase I through Phase III in human subjects?

 We are developing a product for acute radiation syndrome with the NIH, the DoD, and in part in Japan with Fukushima’s university and hospital. We received special designation from the FDA called the Animal Rule. When you cannot run clinical studies for medical and ethical reasons, as in exposure to radiation or certain chemicals, the FDA allows you to do efficacy studies on animals. You have to prove efficacy in small animal and large animal studies-mostly non-human primates-and you have to see the efficacy and a very detailed mechanism of action. The bar is much higher than in usual clinical studies, where you either meet the primary endpoint or not. Here, you need to put much effort into basic science. The Phase I equivalent is the small animal study, and the Phase II equivalent is a pilot study in a large animal model, as the pivotal study on a large animal model. They will also ask for safety in humans, so in parallel, we are conducting a Phase I study treating hematological disorders, like patients who have bone marrow deficiencies after transplantation. This is part of our strategy, across our pipeline we target indications using unique regulatory programs that will allow us fast-tracking and to get quickly to market with a relatively small number of patients.

MA: Is there a particular reason why you are pursuing that? Do you intentionally target indications with a limit on human trials? What are the limitations on normal pathways such that you chose to use this other pathway?

 It started the other way around. We found that the cells are very efficient countermeasures for radiation. If you inject the cells post-exposure to a high level of radiation, instead of 30% survival in the placebo, we saw close to 100% survival in the treated group. In these cases, when you cannot do clinical studies in the locations of nuclear catastrophes, the FDA developed this special pathway.

MA: In your human clinical trials, many things can go awry. What operational and logistical challenges did you experience with your study’s design and how did you overcome those challenges?

 One of our main goals, from the beginning, was to have a harmonized protocol between the FDA and the European Medicines Agency (EMA) because this is new technology, and we want to make sure that both regulators will comply with what we suggest. Luckily, we found a protocol that both of them agreed on for our Phase III studies. We invested time in developing the capability to manufacture high-quality cells with batch-to-batch consistency. However, with cell products, you must ensure that the cells can be administered simply. You do not want medical teams to spend too much time on a very complicated procedure; otherwise, they are not going to use it. So, we designed cells in a vial; the physician just has to thaw them and inject them. The medical team are the clients in this case, and you have to design the product that will work for them. We even built a thawing device to easily replace thawing in a water bath.

MA: You have turned this into something that we call physician-centric: the design of the product matches the site’s operations, so it is easier to administer with fewer mistakes or issues. Please elaborate on this.

 It is the philosophical approach of, where do you see the product ending? Many companies think that they are done with manufacturing their product once it leaves the facility. At Pluristem, we understand that we can say that we completed the product only when it is injected into the patient’s body. We need to take full control of each of our parameters until then. Manufacturing is critical, and we are using our 3D bioreactor technology-the most advanced technology that will give us full control over the manufacturing process to get the same cells every time. We also developed cold chain logistics with our partners Fisher BioServices to make sure that it is fully controlled and monitored. Through the physicians, we worked with patients to understand what they need: how many injections to use, injection volume, what patients can tolerate. So we check all of these parameters to make it simple for the medical team.

MA: Please discuss your clinical trial outsourcing model.

 At Pluristem, we do not use CROs for Phase I or Phase IIa trials. We have a full-blown clinical operational team that runs the studies so the organization is trained to understand what needs to be done. Moreover, when you work with CROs for Phase IIb or Phase III, you need to know what to ask and their key performance indicators. In addition to our full clinical operational team, we also have a quality system and quality personnel that work closely with the CROs. You have to be at the sites, meet the physicians, listen to the coordinator, see what is going on. These are your patients, not the CRO’s patients.

MA: From a clinical development strategy standpoint, how do you maximize the results of your data through clinical research, and can you apply the data gain from failed studies to advance studies in other disease indications that you are pursuing?

 I prefer to apply data from successful studies. From very early, Phase I, we collected more data than needed. It cost us more, but it gave us a much broader understanding of what we see. Moreover, we can apply what we saw in future studies. We also make sure that we understand how the mechanism of action looks and if we need to change something in the design for future studies. We apply this now in Phase III studies. There are no shortcuts here.

MA: Does this data help when you apply for payer coverage?

 We anticipated that collecting economic parameters is as important as clinical endpoints. In each study, we collect every possible economic parameter. Regenerative medicine is about the patient, but it is also about the system. If it is not able to reduce the healthcare cost, it will be challenging to implement, so this is the promise of what we do. We are going to impact the quality of life, we are going to regenerate patients’ ability to overcome chronic diseases, but we are also going to save much money for the system itself, and this is what we are targeting.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials

News

Yaky Yanay, CEO of Pluristem, will discuss his experience and the strategies Pluristem implemented in regenerative medicine clinical trials.

Regenerative Medicine Companies Pursue Unique Regulatory Pathways

In today’s competitive clinical trial environment, sponsors and contract research organizations (CROs) are under intense pressure to move drug candidates safely and efficiently through clinical trials. Adoption of a risk-based monitoring (RBM) approach can help enhance the safety and efficiency of clinical trials, while automating labor-intensive data analysis and improving data quality. As the FDA encourages drug developers to integrate digital technologies into the development process, biopharmaceutical companies are increasingly turning to automated clinical trial software solutions that incorporate RBM.

	Dynamics accelerating the trend toward RBM

	RBM has garnered attention among the clinical research community since the FDA published its industry guidance, “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring” in August 2014. In the intervening years, though, adoption has been slow and implementation has been challenging.

	With the recent update to the ICH Guidelines for Good Clinical Practice and the FDA’s draft guidance on “A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers,” which was published in April 2019, regulatory focus on RBM has intensified. In fact, RBM has emerged as the standard for clinical monitoring.

	Other factors are also accelerating the trend toward RBM. Industry-side emphasis on modernizing and optimizing the efficiency of clinical trials is driving digitization of the development process, from recruitment and data collection to adherence and data analysis. Further, the push toward precision medicine and biomarker-guided drug development has led to an increase in the volume and complexity of data generated by clinical trials. With nearly 80% of data scientist time spent collecting, cleaning, and organizing data sets, there is a strong demand for automated solutions.

	Overcoming five challenges of transitioning to RBM

	RBM technology is an automated solution that can help sponsors and CROs implement comprehensive monitoring strategies from a single platform with built-in workflows and advanced analytic capabilities. As RBM software solutions evolve to keep pace with the rest of the clinical trial landscape, it can be overwhelming for sponsors and CROs to make the transition to RBM. Here, we’ve outlined five key challenges associated with adopting an RBM approach and how they can be addressed to ensure a smooth transition.

	Embracing the concept of RBM requires a shift in mindset from traditional monitoring, and drug developers may feel cautious of, or resistant to, this change. This may be due, in part, to uncertainty about how the FDA will respond to the use of RBM techniques. However, sponsors and CROs should also consider how regulatory agencies might respond if RBM modifications are not made. For companies who are uncomfortable making the shift to RBM, a useful exercise would be to evaluate the factors fueling that hesitation and figure out how to address them.

	Even for companies that are ready to transition to RBM, the change can be daunting and proactive change management is essential. The move toward an RBM approach requires change management related to people, process, and technology. Commitment at the leadership level, along with staff training and a clear understanding of each team member’s roles and responsibilities, helps ensure that RBM is incorporated into the DNA of both the company and the clinical trial.

	As the saying goes, if you fail to plan, you plan to fail. Implementation of an RBM approach requires proactive planning. Once an organization is ready to transition to RBM and key stakeholders have been identified, the following steps should be taken:

 What data and processes are critical to ensuring patient safety and study integrity?

 Identify, analyze, and prioritize risks, and then determine whether those risks need to be modified by implementing controls.

A comprehensive monitoring plan should focus on preventing or mitigating the most important or likely risks to critical data and processes.

	There are a growing number of RBM technologies available, but drug developers should keep in mind that features vary widely from software to software and many fall short of delivering the full benefits of RBM. Some RBM technologies only look at risk in isolation, without context or analysis. Others may be limited by their reliance on retrospective data, missing the critical capability to draw insight from emerging issues or placing undue emphasis on irrelevant historical information. An incomplete approach to identifying, managing, and analyzing risk introduces complexity and cost without adding value. Moreover, a system that fails to fully assess risk could also introduce a new risk: a false sense of security. Sponsors and CROs may mistakenly believe that they are utilizing RBM, without fully benefiting from all that RBM can offer.

	A comprehensive RBM technology approaches risk from all angles-operational, safety, and quality. The following are factors to consider when evaluating an RBM software platform:

 Check that the system allows users to identify and log critical data and processes relevant to the study. The system should also enable users to assess and characterize risk at study start-up and throughout the course of the study.

 Verify that the RBM technology has the ability to control and mitigate each of the risks identified through a variety of risk management strategies. These risk management strategies may be automated or manual. For example, can the software issue alerts when risks approach pre-defined thresholds and when safety or data quality is at risk of compromise?

Determine if the RBM technology allows for streamlined, centralized review of the risks detected through statistical models, intuitive data visualization, and the ability to drill down into the data (e.g., by geography, site, patient, or type). Ideally, the software should also give users the ability to act on and close out risks through automated workflows and ticketing functionality.

 Finally, confirm that the RBM software allows for regular and ongoing review and modification of risks. This helps sponsors and CROs ensure that risk management activities remain effective and take into account emerging knowledge and experience.

	RBM technology that delivers all of these capabilities can truly empower sponsors and CROs to conduct trial monitoring efficiently, while simultaneously enhancing patient safety and data quality.

	As clinical trials become more complex, RBM technologies have also become more sophisticated. Thoughtful implementation is the first step in unlocking the full value of RBM technology. However, there is no “one-size-fits-all” approach to RBM and implementation must be customized to the sponsor and the study.

	The process of implementation involves requirements gathering, planning, and testing, and should cover five key areas:

 Ensure the scope aligns with the needs of the end user(s) and includes clear definitions of roles and responsibilities. Sponsors may benefit from starting with a pilot of the technology, which allows them to familiarize themselves with the implementation process, test the system, and validate internal processes on a small scale.

 Review existing procedures and plans, and update them or create new processes, if necessary. This is also an opportunity to document how issues identified by the system will be escalated internally.

 Document how the sponsor will communicate with both the technology vendor and the end user(s).

 This is an area many sponsors overlook. Perform UAT at both the system level and the study-specific level to ensure seamless integration.

 Outline not only how success and value will be measured, but also how these metrics will be communicated to all stakeholders.

	The key stakeholders driving the transition to RBM will come from multiple departments within an organization, from clinical operations, data management, and safety, to IT, training, statistics, and regulatory. Typically, the implementation team will include the following stakeholders:

 These are the people who will own and drive the implementation process.

 These are the stakeholders who will make decisions on how the RBM technology is implemented.

 These are the people who have the right background and skillset to advise on the implementation that makes the most sense for a particular study.

 These are the stakeholders who will be utilizing the RBM technology during the course of a clinical trial. Considering the needs and requirements of end users in the early stages of implementation ensures that the system is being set up in a way that is most useful, efficient, and cost-effective post-implementation.

Given the cross-functional, multi-disciplinary team required for a successful RBM implementation, some sponsors and CROs may have resource or knowledge gaps within their organizations. For companies that are considering integrating RBM into their organizations, there are a variety of external resources, ranging from online training to risk/quality management consultants and RBM software vendors, that can help them navigate the decisions needed for a successful RBM technology implementation.

	Taking advantage of the benefits of RBM technology

	A common misconception is that primary goals of RBM are to reduce source document verification (SDV) and decrease the frequency of on-site monitoring visits. In reality, RBM is part of a broader trend toward risk-based quality management, which encompasses the entire ecosystem of processes sponsors put in place to identify, assess, control, communicate, and review the risks associated with a clinical trial. Within this larger context, RBM technology is software that:

		Provides visibility into an entire study, allowing stakeholders to manage and mitigate risks, and provides a clear audit trail.

		Enables consistent communication across the entire team.

		Provides ongoing oversight of patients, sites, and the study as a whole to facilitate informed decision-making (e.g., percentage of SDV required, frequency of on-site monitoring visits, safety, site performance, etc.).

	Implementation of RBM has the potential to bring a number of measurable benefits:

 Some RBM technologies utilize machine learning to alert stakeholders and decision-makers about potential risks that may have been overlooked during trial set-up. By analyzing data collected during the trial on a prospective basis, these technologies can identify patterns and anomalies.

Improved patient safety and data quality.

 RBM technology provides notifications when issues are identified at the patient-, site-, or study-level. By continuously tracking trend information and making actionable data readily available, RBM technology enables sponsors and CROs to take corrective action in a timely fashion, improving both patient safety and data quality.

 Apart from investigator fees, clinical monitoring is the largest driver of clinical trial costs, accounting for over 60% of study-related labor costs. With RBM analytics, on-site visits are triggered by study-specific risk thresholds-rather than being performed on a pre-defined schedule-which may lead to reduced, but more effective, on-site monitoring.

 Data cleaning at the end of a study can be extremely time-consuming. Implemented correctly, RBM can help shorten the timelines for evaluating study data. RBM technology evaluates data on an ongoing basis, which can help reduce the time from the end of the study to the reporting of study results.

 Regulatory agencies are demanding more robust assurances of patient safety and data quality. Drug developers who leverage an RBM technology with traceability and audit capabilities are well-equipped to meet current and emerging regulatory requirements.

	With a combination of proactive planning and the right people, processes, and technology, sponsors and CROs can minimize the growing pains associated with RBM implementation. Investing time in getting an RBM technology implementation right enables drug developers to leverage this automated solution to manage risk, facilitate communication, and get the insights they need to make informed decisions, all at their fingertips.

 is Risk-Based Monitoring Senior Product Specialist, Remarque Systems; 

 is Risk-Based Monitoring Product Specialist, Remarque Systems

Feature Articles

Methods sponsors and CROs can use to minimize the growing pains associated with RBM implementation.

Tackling the Challenges of Transitioning to RBM

The surge in new drugs gaining FDA approval based on small, early clinical studies and fast-track reviews has raised concerns about patients being exposed to unsafe therapies with limited benefits. At the same time, patient advocates complain that FDA testing requirements and lengthy review process delays access to potentially life-saving remedies. A main point of agreement is that products approved based on preliminary evidence should be priced much lower than the usual steep launch prices, until further research can document long-term efficacy and safety.

	Certainly, FDA is expediting the development and review of most innovative therapies, including many new cancer drugs and therapies for rare diseases that often are approved based on clinical trials with very few enrollees. In 2018, FDA’s Center for Drug Evaluation and Research (CDER) provided priority review for 43 of 59 novel new drugs; of the total, 14 had breakthrough therapy status, and 24 benefited from fast-track designation. 

CDER’s annual report on new drug approvals

 for 2018 celebrates its success in speeding many important medicines through the regulatory and review process with greater efficiency and predictability to support innovation and respond to patient demands.

	Even more limited evidence often supports approval of highly innovative cellular and gene therapies, as more cutting-edge treatments emerge designed to replace, repair, or inactivate a gene linked to a serious or fatal condition. The Office of Tissues and Advanced Therapies (OTAT) in FDA’s Center for Biologics Evaluation and Research (CBER) received more than 400 investigational new drug (IND) applications for cell and gene therapies in 2018, many qualifying as breakthroughs and for the Regenerative Medicine Advanced Therapies (RMATs) designation for products providing evidence of treating, modifying, or curing a serious or life-threatening condition. For such therapies, FDA offers sponsors extra assistance in developing innovative testing and production methods, expedited review, and flexibility in meeting regulatory requirements.

	The debate over increased FDA fast-tracking recently heated up with publication in 

article questioning the safety and efficacy of the growing volume of drugs

 benefiting from FDA accelerated approval. This examination of the impact of fast-track development and review follows the decision by Eli Lilly to halt marketing of its cancer drug, Lartruvo, in April due to data from a post-approval study indicating that the treatment does not prolong lives of advanced-sarcoma patients. FDA approved the drug in 2016 based on a small study that showed evidence of patients living longer with the drug.

	To many observers, this outcome, while disappointing, reflects how more expeditious drug development and approval programs are designed to work. Ellen Sigal, chair and founder of Friends of Cancer Research, 

 that FDA’s breakthrough program and other expedited initiatives reflect patient wishes to assume more risk in seeking remedies to urgent medical threats, and that delaying approval until a sponsor gains evidence that a therapy extends overall survival would deny potential cures to thousands.

	In fact, many new therapies receiving accelerated approval show evidence of serious side effects and carry strong warnings to limit use to patients with severe conditions and no alternative treatment options. In June, FDA approved a new use of Soliris injection from Alexion Pharmaceuticals to prevent serious visual impairment and paralysis in patients with certain antibodies linked to this condition. Due to possible fatal infections associated with intravenous use of the drug, FDA required restricted use and boxed warnings for this additional use. Another new drug benefiting from accelerated approval is Xpovio from Karyopharm Therapeutics. It’s available for adult patients with multiple myeloma, who relapse after treatment with at least four other therapies, and have no alternative treatment options available.

	For therapies approved based on limited testing, it is important for investigators to track adverse events closely and to examine fully how well surrogate endpoints predict real-world overall survival. While longer clinical trials and more confirmatory studies could provide additional evidence of a drug’s potential impact, such requirements would add to product costs and delay access to treatment. FDA and the research community need to ensure that sponsors follow up on initial accelerated approvals with additional studies to assess longer term benefits, despite difficulties in conducting clinical trials on already approved products. At the same time, there is growing support for compelling biopharma companies that benefit from expedited regulatory programs to limit prices on new products until post-approval studies confirm that the treatment has long-term benefits.

Patient advocates debate whether FDA approval on small, early clinical studies is too fast-tracked for efficacy and safety, or too slow due to long review processes.




Too Fast or Too Slow? Debate Intensifies over FDA Regulatory Requirements

Nonalcoholic steatohepatitis (NASH) is a form of nonalcoholic fatty liver disease (NAFLD) that remains largely unknown among the adult population in the U.S. In the coming years, however, the prevalence of this potentially deadly disease, which can lead to cirrhosis and even liver cancer, is expected to grow significantly. According to a 2018 study,

 instances of NASH in the U.S. are expected to increase 63% from 16.52 million to 27 million cases by 2030.

	The complications associated with NASH include cirrhosis and liver cancer, with an increased chance of dying from liver-related causes. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK3), studies have shown that people with NAFLD have a greater chance of developing cardiovascular disease-the most common cause of death among people with NAFLD or NASH.

	To highlight the seriousness of NASH, there currently exists no FDA-approved therapy to treat the disease. In the next five years, more than 60 sponsors

 will attempt to randomize nearly 30,000 NASH patients into clinical trials. So pharmaceutical companies face an uphill battle to both increase awareness of this disease and enroll tens of thousands of patients in NASH clinical trials.

	Of all of the challenges that sponsors face in enrolling patients into NASH studies, the biggest is lack of awareness of the disease, even among patients most at-risk-those with type 2 diabetes, obesity, and hypertension.

	Continuum Clinical conducted a survey of 1,014 adults in the U.S. and found only 2% were aware of NASH. A follow-up study of 450 adults with comorbidities associated with NASH revealed only 6% were aware of the disease.

	Continuum also found that 48% of at-risk Hispanic/Latino respondents were most concerned about liver disease versus 32% of the total population surveyed. In addition, Hispanic/Latino respondents were significantly more interested in learning about a hypothetical NASH clinical research study (62% versus 49% of the total population).

	In addition to low awareness of NASH, targeting patients for clinical trials is challenging because the disease doesn’t manifest itself in consistent, overt ways. Many times, patients with NASH are asymptomatic.

	It’s estimated that as many as 30 million Americans currently have NASH, but only 180,000 have been diagnosed. Given the average participation rate in clinical trials is around 15% of a given diagnosed population-and coupled with an 80% screen/fail rate in this condition-that means the 180,000 patients will translate into only 3,000 randomizations.

	The FDA currently requires sponsor protocols to confirm patients’ NASH diagnosis via an invasive and potentially dangerous liver biopsy.

	In order for progress to be made against this disease, pharmaceutical companies must find solutions to some of the problems posed earlier. Where are these organizations begin? How does a drug company reach out to consumers who aren’t aware of a disease that they may or may not have to enroll in a clinical trial that requires a liver biopsy for a diagnosis?

 in December, which urges the pharmaceutical industry to develop/validate better biomarkers for NASH diagnosis and progression. In many regards, getting over the biopsy hurdle rivals the lack of general awareness of NASH, which is why we believe it is important for pharmaceutical organizations to invest in innovations (e.g., a variety of imaging techniques) to allay this patient burden, and subsequently persuade the FDA with strong data to accept those innovations as suitable endpoint markers for clinical trials. To that end, many researchers are investigating such biomarkers that will be as predictive, if not more so, than invasive liver biopsies.

	This long-term solution doesn’t help the number of trials that are enrolling today, however. Addressing the gap between the diagnosed patient population and the number of patients who will be needed to fill these trials requires implementing a robust patient recruitment program.

Sponsors with designs on this therapeutic area could consider increased investment in developing unbranded disease awareness campaigns alongside patient advocacy groups; the National Liver Foundation has begun to implement such an educational campaign on its own. In addition to these education efforts, incorporating fundamental disease education into clinical trial recruitment outreach materials is critical. This is unusual but not unheard of-Continuum has in the past successfully included institutional review board (IRB)-approved education information for an unaware patient audience for a different chronic disease campaign.

	In conjunction with a broad-based disease education plan, smart web development-for example, a site that funnels disease-aware or diagnosed patients to a different landing page than unaware or undiagnosed patients-will be necessary to motivate potential patients to complete study screening.

	Specific to this are materials that target patient demographics that are disproportionately affected by NASH or NAFLD, such as Hispanic and Latino patients. Directly engaging patients locally through educational and community events is critical to connect with those individuals both before and after diagnosis. Community-level engagement, especially important to populations typically underrepresented in clinical research, will ensure NASH patients receive education and information at the right time in their journey and can make recruitment campaigns more effective.

	Despite the potentially enormous patient population, the challenges industry will face in enrolling clinical trials are daunting and unique. NASH patients are diverse, both ethnically and in their diagnostic pathway. The only way to successfully achieve the required trial enrollment numbers is to be strategic, creative, and thorough in planning both for recruitment and retention.

		Li Q, Dhyani M, Grajo JR, Sirlin C, Samir AE. Current status of imaging in nonalcoholic fatty liver disease. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767767/

https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts

https://clinicaltrials.gov/ct2/results?cond=NASH&term=&type=Intr&rslt=&recrs=b&recrs=a&recrs=d&age_v=&age=1&gndr=&intr=&titles=&outc=&spons=&lead=&id=&cntry=&state=&city=&dist=&locn=&phase=1&phase=2&fund=2&strd_s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&lupd_s=&lupd_e=&sort=

https://www.raps.org/news-and-articles/news-articles/2018/12/fda-issues-draft-guidance-on-nash-drug-development

, PhD, is the Senior Scientific Director, Continuum Clinical

Addressing the current hurdles and potential solutions in nonalcoholic steatohepatitis awareness and clinical trial enrollment.

Challenges Emerge from Low NASH Awareness

At DIA in June, I moderated an executive roundtable for Parexel, which the CRO sponsored around the topic of patient centricity. Specifically titled, “Collaborate to Innovate for Patient Centricity in Pharma,” it wasn’t just about patient-centric clinical trials-we discussed numerous opportunities and challenges around patient centricity in all of pharma. But Parexel did share some very compelling data on research it has conducted on the business case that supports patient-centric clinical trial designs. I’m itching to share the whole roundtable information, but I have to wait for the final article approvals. Also, the roundtable was conducted under our sister brand 

, so you’ll be seeing that info come out under its branding. But suffice to say...the discussion was good, and the article will be great. Here are some highlights:

 Once the industry embraced the terminology of patient centricity in clinical trials, it’s been hard to shake the plans, the pilots, and the progress forward. But true ROI? Measurable results? That’s been a bit harder to quantify. Until now. Parexel shared data it had amassed, which include the following:

	Patient-centric trials recruit twice as many participants (533) compared to non-innovative trials (271)-and in almost half the time.

	Patient-centric trials in the U.S., the EU, China, and Japan took half the time to recruit 100 participants compared to other geographies (2.6 months vs 5.3 months).

	Patient-centric trials in the selected geographies also recruited twice as many participants (819) compared to other geographies (377).

Patient-Centric Relationship to Product Launch.

 For clinical trialists, this statistic may not be why you want a patient-centric trial. You may want it because it’s good for recruitment, enrollment, diversity, and retention. But, at the end of the day, patient-centric trials help pay for drug development 

a potential product launch. Drugs that include patient-centric designs were 19% more likely to be launched. And, in the real world, the product adoption rate was 13.7%.

	To compare, three other innovations included adaptive design, precision medicine trials, and real-world data trials. Their likelihood of launch increased 13%, 10%, and 21%, respectively, while their adoption rate post-launch affected positively .6%, 5.2%, and .3%, respectively.

 There was considerable discussion around the table about that nature of patient-centric and patient engagement ownership within an organization, as well as the fragmented external forward movement within industry. That pharma tends to work in “pilot mode,” where a budget for an idea or implementation is very short term, and very focused. Once completed, there is no continuity. Another barrier is that the budget lies in different departments, without a centralized accountability, and patient engagement is often not a built-in, upfront approach to clinical trials, but instead becomes an add-on item.

	Because of these very different internal challenges, external collaborations almost get lost in the discussion, but patient advocates are pushing every day to get their voices heard.

From the Editor

A look at the opportunities and challenges around patient-centric trials and patient centricity in pharma.


Zeroing in on Real Patient-Centric Metrics

	The implications for clinical trials of the UK’s departure from the European Union received further attention in late June as the prospects rose of a “no-deal” Brexit scenario. The UK parliament’s committee on exiting the EU heard prominent figures from the British healthcare and research community spell out the heightened risks in this new and more dangerous phase of the Brexit saga. Unlike two years ago, when the concerns were how drug development and supply would be affected by a managed exit from the EU, the country now faces being pulled out without any sort of deal at all, as a result of the dogmatic approach of both the contenders for leadership of the UK government. The consequences of such a fracture will affect the rest of Europe as well.

	Steve Bates, chief executive of the UK’s BioIndustry Association, told the committee unambiguously that, “a disorderly no-deal Brexit will negatively impact patients, public health, and the life science sector.” Vivienne Stern, of Universities UK International, described it as, “a creeping horror that something that we thought might happen by accident might actually now be the deliberate policy of government. That sounds to us like a very bad idea.”

	Dr Beth Thompson, head of UK and EU policy at the Wellcome Trust, warned that, “even with the best preparation, no deal will leave a vacuum in the UK’s relationship with our biggest research partner. That is untenable and cannot be allowed to happen.” And Professor Tim Wheeler, international director of UK Research and Innovation (which includes among other bodies the Medicines Research Council), said a no-deal scenario, “will be a significant short-term shock to the research and innovation system in the UK-to the people in and the funding for that system.”

	Bates identified “a big lack of clarity” about future operations for clinical trials and clinical trials databases. He pointed out to the committee that clinical trial data flows to and from a number of clinical trial sites within the EU, particularly in trials for rare disease treatments. He expressed concerns about future UK access to the new database that will be established by the new clinical trials regulation. Wheeler added that for him, “the main areas of risk” are in clinical trials support.

	One of the central issues is how far the UK would be considered-in a no-deal Brexit-to meet the requirements of what the EU terms “data adequacy.” This is the basis for the exchange of personal data across borders, and the expectation had been that a EU-UK deal would be agreed in a way that provided for such a recognition. A no-deal Brexit imperils that. Wheeler recounted how the Medical Research Council has been working with its clinical trials unit at King’s College London, “to try to prepare together for the situation where the data adequacy issues have to be negotiated post-exit.” He said it was his understanding that it would require negotiations on a case-by-case basis-individual contract by individual contract.

	Thompson added that this, “is not just something that the UK can do unilaterally. There has to be a negotiation with the EU partner.” This is made all the more difficult because if a UK researcher wants personal data from the EU, the burden would be on the EU researcher to negotiate the specific terms of an individual contract. “That is a real challenge,” she said. Thompson underlined the point, “The challenge if we leave with no deal is that immediately, as a third country, the UK won’t have an arrangement in place to enable the free flow of data between the UK and the EU. At the moment, because we are a member state, we have that free flow.”

	The data gap that a no-deal Brexit would create would be similarly problematic for pharmacovigilance, Bates also explained. It is important that pharmacovigilance data can continue to be shared, he insisted, “That is about patient safety data.” At present, this is handled through the European Medicines Agency’s (EMA) centralized system. “If there were to be a no-deal Brexit, the data flows would stop and the UK judgment could not be based on information that would have formerly come from regulators outside the UK,” Bates said. At the same time, the UK data would not be available to Europeans. As a result, for patients everywhere, “the ability and the speed to be able to make a determination if there are any concerns would be significantly compromised.”

	The outlook from the experts called by the committee was equally gloomy on research in general. As Thompson put it, “No deal will fracture our relationship with the EU in a way that is going to be very difficult to come back from. The kind of agreement that we would need on research for the future, in terms of the movement of people and researchers, research regulation and also funding, will be very difficult to achieve, if not impossible, in a no-deal scenario.”

	She added that from Wellcome’s own statistics, “We have seen a 20% drop in early career researchers applying for our funding schemes in the last year. That has been consistent. The Wellcome Sanger Institute saw nearly a 50% drop in applications from EU nationals for their PhD studentships in 2017.”

	Somber reflections indeed as Boris Johnson and Jeremy Hunt vie for the support of that tiny proportion of the UK population that will make the choice of the next head of the UK government-the 160,000 members of the Conservative party, most of whom have little interest in and even less knowledge about the intricacies and vulnerability of medicines research and development, and many of whom have declared themselves in favor of a no-deal Brexit.

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

The consequences UK faces after being pulled out of the EU without any healthcare and research deal may affect all of Europe.





The Growing Threat to Clinical Trials and Research in a Fracturing Europe

While the field of gene transfer has been active and evolving over the past 30 years, there are only a handful of products that have recently become approved gene therapies. Most product developers believe that gene transfer is now at a tipping point, but realize it will require a close coupling between the accumulating scientific knowledge and the therapeutic target product development expertise to generate approved gene therapies at an increasingly rapid rate. Although it is an inaccurate term (nothing is a therapy until it has market approval), gene therapy has become a ubiquitous term to refer to gene transfer products and the more recently discovered gene editing (e.g., CRISPR) products in development.

	Gene transfer products are meant to treat diseases resulting from lack of a gene’s functional protein product. The gene addition can be accomplished either by 

(vectors and other delivery vehicles) or 

(manipulation of a patient’s own cells and reinfusion) techniques. Both 

 gene addition techniques are currently at the forefront of science, which explains the paucity of marketing applications that have been submitted, let alone approved, in recent years.  Gene editing products in development are meant to alter the existing gene, thereby conferring efficacy and not add a new functional copy of the gene; but none of these have been approved as of yet.

	Over the last several years, gene therapy technologies and products have primarily been developed by biotechnology companies, academic laboratories, and government laboratories as large pharmaceutical firms have evolved to marketing and sales companies by divesting themselves of a great number of research scientists and licensing in these technologies from other entities. However, few academic or government organizations are experienced with the entire product development process, including bringing a product to market. Therefore, there must be a coordinated effort and close collaboration between academia/government and biotech development talent to access both scientific and product development knowledge required for a program to be successful.

	Updated FDA guidances provide clarity and require more information 

	While gene therapy products provide potential for exciting breakthroughs, they are also extremely complex to develop for the market. This complexity has prompted the FDA to recently release additional guidances to help move these products forward. Early FDA gene therapy guidances include traditional investigational new drug (IND) requirements and Phase I good manufacturing practice (GMP) guidance. Two of the six 2018 gene therapy guidances are related to requirements for long-term follow-up monitoring and other clinical study design considerations, as well as chemistry and manufacturing and controls (CMC) procedures and practices to ensure safety. This is not surprising inasmuch as regulators have been concerned about the safety of gene therapy products from the inception of this field due to the lack of complete understanding of the science surrounding these products.

Considering there is no track record for the administration of these products, companies should be aware of these guidances and budget for extensive follow-up (e.g., five years) for their clinical study subjects and potentially even the patients treated with their product after it is approved to determine the eventual safety profile and durability of the therapeutic effect. As far as manufacturing concerns go, new cellular-mediated gene therapy products will require many different materials during the course of their journey-from the harvesting from the patient or donor, through manipulation and testing, and into the patient. Hence, a comprehensive list of the materials used in the process and a description of their quality and suitability must be included in the regulatory submissions.

	Since most gene therapy products are targeted for life-threatening or serious orphan diseases with unmet medical needs, the clinical plan will, in all likelihood, be expedited relative to the traditional clinical plan for a product intended to treat more conventional diseases. This acceleration requires early and more frequent interaction with regulatory authorities to ensure agreement on such things as 1.) novel clinical endpoints that convincingly demonstrate clinical benefit; 2.) biomarkers or other endpoints that could potentially be used as surrogate clinical endpoints; 3.) collection of data reflecting the natural history of the disease from the literature, real-world evidence, or via the conduct of a 

 natural history clinical study; and 4.) patient-reported outcomes focusing on quality of life metrics that matter to the patients or their caregivers, all of which can contribute to the totality of the data regulators will integrate to ultimately reach their decision on marketing approval.

	One of the main takeaways from the updated FDA guidance is the need for a strategic CMC development plan, because if the product cannot be manufactured safely, then clinical studies will inevitably be delayed. For gene therapy products, CMC work often ends up being a rate limiting step in preparing for the initial IND as well as the eventual marketing application submission of a gene therapy product.

	A comprehensive CMC plan is also important because the FDA places a greater emphasis on the quality portion of the submission for gene therapy products than for traditional therapies. In a 2018 interview with former FDA Commissioner Scott Gottlieb, he stated, “that for most standard drugs, traditionally 80% of the review process is focused on clinical aspects and only 20% on quality or is CMC related. For gene therapy products, those numbers are reversed.” From this, sponsors and CROs can be sure that the CMC modules in their submission must be comprehensive to obtain regulatory approval.

	Consider an INTERACT/pre-pre-IND meeting

	Some products need to be discussed early with the FDA so that sponsors have buy-in from FDA on their proposed development plans. If eligible, sponsors should take the opportunity to sit down with the FDA in an INTERACT meeting (aka, Initial Targeted Engagement for Regulatory Advice on CBER products; previously known colloquially as a pre-pre-IND meeting). This interaction is used to educate the FDA about the sponsor’s product and familiarize the agency with the science behind it and help FDA understand the rationale behind their integrated product development plan. These meetings also can be crucial in helping obtain agreement for the preclinical program. Additionally, sponsors should use the INTERACT meeting to get clarification on CMC aspects related to specifications, controls, as well as what steps they want to see in terms of the manufacturing process.

	In summary, the only way to move some of these gene-based products forward quickly is with more FDA interaction than is usually recommended for developing products. The guidances issued thus far are not sufficient to enable a company to make much development progress without interacting with the FDA. By asking the correct questions at regulatory meetings and listening carefully so product sponsors may coalesce bits and pieces of information, the FDA has learned from other gene therapy sponsors that have submitted INDs and bioligics license applications (BLAs) for gene therapy products. The FDA is unable to breach confidentiality with product sponsors, but they will comment much more intelligently as a result of its experience with many of these products.

	When one looks at the remarkable efficacy that some gene therapy products are providing, it also makes sense for the agency to prioritize and expedite gene therapy guidances and help sponsors develop treatments that can make a difference. However, if a company’s development team comprises individuals who both understand the science supporting these novel products and are experienced with the guidances and regulatory precedents established for previous product approvals in these or similar indications, a gene therapy program may ultimately make it to market.

, PhD, is Senior Vice President, R&D, Rho Inc.

Navigating the many complexities in clinical trials, manufacturing, and regulatory interaction in moving gene therapies from development to market.



The Gene Therapy Product Development Process

The adoption of using electronic systems in clinical research has been like watching a slow-moving train on a cross-country tour. Over the past 20 years, many technologies have been delivered with varying adoption rates. This underwhelming response came despite strong recommendations from FDA, European Medicines Agency (EMA), and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) regulators that encouraged adopting systems such as electronic source records.

 that in the most recent inspection metrics by UK’s Medicines & Healthcare Products Regulatory Agency (MHRA), record keeping represented the single greatest category of major findings. He further reported that FDA’s Bioresearch Monitoring Program (BIMO) metrics for FY2016 showed inadequate record keeping as the most common deficiency at investigator sites. Cocciardi further described the investigator site file (ISF) as a poorly controlled and growing risk for sponsors and investigators.

	For over 10 years, we have used an electronic Investigator site file (eISF) in addition to an electronic trial master file (eTMF). We have adopted special processes for access control, generating certified copies of documents collected in paper such as informed consents, subject source records, file structure, and archiving.

	Despite the myriad of benefits for adopting an eISF, sponsors cite the following issues for not adopting an eISF:

		Does an eISF that the sonsor pays for, but where the site has full control to upload and download documents, meet the regulatory requirements for an ISF?

		Can you store documents with protected health information (PHI) in an eISF?

	To assist in answering these questions, I provided the information and posed these questions to the FDA Office of Good Clinical Practice (GCP) concerning use of an eISF as follows:

	We use a cloud-based file solution configured using an existing electronic file sharing system. We have confirmed that the system meets 21 CFR Part 11 using our processes and the system’s features. We have configured this file system to be used to maintain the site’s regulatory documents in addition to the sponsor’s eTMF. These folders align with the DIA reference model for the eTMF.

		The folders have role-based access. Personal identifying information (e.g., certified copies of informed consents and investigator assessment of clinical significance on lab reports) is maintained in folders that are only accessible by the site staff, monitors, and auditors as stated in the informed consent.

		The file system is configured, tested, and user roles administered by the CRO. Only users with specific roles and at specific sites can access an individual site’s eISF.

		Site users, such as principal investigator (PI), sub-investigators, study coordinators (SCs), and any other staff members identified by the site) are granted access to their site’s folders and documents after completing training.

		The site staff can upload and download any document in their site’s folders. These documents include the site’s regulatory documents and all reference documents and training materials that have been provided to the site.

		At the end of the trial, all site documents are archived as PDF documents and the site is provided with an archive of its site’s files.

		Once the site archive is completed, the documents are merged into the eTMF for archiving of the entire eTMF.

		During the study, duplicative documents are not collected and maintained separately in two different systems (eISF and eTMF). Documents, such as the signed 1572, financial disclosures, and protocol signature pages are maintained in each site’s eISF for the duration of the trial. The sponsor and CRO have access to the site’s eISF (excluding any documents with subject personal identifying information) so all documents are available-but it assures that there is only one version in the study files for both the eTMF and the eISF.

	The response we received from the FDA Office of Good Clinical Practice in 2016 was as follows: “Provided that your cloud-based file system meets 21 CFR part 11 controls (see 21 CFR 11.10 and 11.30) including the requirement that appropriate access controls be in place to limit access to authorized users (see 21 CFR 11.10(d)), we would find your approach acceptable for meeting FDA record keeping and record retention requirements (see 21 CFR 312.62).”

	We raised a second question to the FDA in April 2019 of whether documents with PHI can be maintained in the eISF and whether redaction was required.

	Our current approach is to add language in the subject’s informed consent stating that the study staff, monitors, clinical trial associates, and auditors can view the subject’s documents with PHI and personally identifiable information (PII). We document that the documents are stored in the cloud and an archive will be made and provided to the investigative site, but not the sponsor.

	We set up our eISF so that PHI/PII documents converted to certified electronic copies are managed in a separate workflow, including storage in files only accessible to the study staff (PI, SCs, regulatory), monitors, clinical trial associates (CTAs), and those performing QC (project manager and auditors).

	The company providing the eTMF/eISF will sign a business associate agreement and follow all the setup for HIPAA documents in the Amazon Cloud. The archive for the sites will include the PHI/PII certified documents. PHI/PII documents are not provided in the eTMF.

	Can you confirm that this process aligns with 21CFR Part 11, ICHE6R2, and HIPAA?

	The Office of GCP provided the following response:

	“We do not have specific requirements regarding the manner in which trial-related documents are stored. The applicant should ensure that the cloud service they use has the appropriate electronic safeguards on data security to ensure that these documents are only available to authorized users and that they cannot be modified or deleted within the record retention period.”

	Technology and process requirements for using an eISF with an eTMF

	We evaluated eTMF systems to determine if they could also be used for eISFs. Some companies said their system could not be used for eISFs. Others used workflows for converting documents to certified copies without an eSignature process, which is required in our processes. Other vendors were willing to work with us to implement our eISF process for automated management of eISFs. While automated systems are helpful for large trials and larger organizations, we have also implemented an eISF/eTMF solution with off-the-shelf software with electronic signatures and manual workflows.

	The changes in process needed to implement an eISF include five critical workflows:

		Modify file structure from DIA reference model so sites have all the files they need for managing the entire study, not just folder 5.0 in the DIA Reference manual, and provide a repository for all documents used routinely in the study (e.g., protocols, training materials, lab manuals).

		Certify documents as electronic copies based on 21CFR Part 11 requirements.

		Electronic signature workflow for documents, including start up documents, to enable collection and filing automatically.

		Managing documents with PHI so sites do not have to de-identify documents with markers ever again.

		Separate archiving process for sponsor and site files.

	Adopting an eISF benefits everyone involved in study conduct.

	Sites win because they save hours of time (e.g., printing documents for PI signature, scanning the documents for upload to eTMF, filing paper copies, copying documents multiple times), space in their facility, and long-term storage costs.

Sponsors win because they have full visibility into each site’s relevant regulatory documents-assuring they are always audit ready. Sponsors also win because the eTMF and eISF are completely aligned.

	CROs win because they no longer need to set up and print millions of copies of documents for regulatory binders, so start-up is faster and more efficient. CROs do not need to send CRAs to the research site to review documents, including informed consents (which can be converted to certified electronic copies and reviewed remotely). CROs can now identify missing documents more easily than by reviewing paper regulatory binders.

	Quality management teams wins because they can conduct audits remotely in a fraction of the time without travel, from anywhere in the world.

	Our environment wins because fewer flights and auto travel are needed and billions of pages paper are saved.

Exploring the use of electronic investigator site files for review of regulatory documents and informed consents.



Applied Clinical Trials-07-01-2019