Category: Clinical Research Trends

New draft guidance has just been issued by the US Food and Drug Administration (FDA), which aims to make it easier for medical device companies to rely on data obtained from clinical studies conducted outside the United States (conveniently termed ‘OUS’ studies by the FDA).  Naturally, this is provided that those studies are conducted to appropriate federal standards.

The draft guidance document (1) is closely related to a rule proposed by FDA back in February 2013 (2), which proposed a requirement that all clinical studies conducted outside the US in support of a device application comply with US regulations on good clinical practice (GCP).

The goal, regulators explained, was to promote consistency in the trials whilst assuring that human subjects participating in the trials were given adequate protection. The FDA now accepts data from foreign-conducted clinical studies meeting requirements of code of Federal Regulations 21 CFR 812-14.  This states that the data must be scientifically valid and must have been collected in accordance with the ethical guidelines of the Declaration of Helsinki or local laws (whichever offers stronger protection to research subjects).

These data are most commonly used in support of an application that includes data from the US, but the FDA encourages sponsors to discuss plans with them if the application will be “based solely on foreign clinical data”. Those requirements are less stringent than required for clinical trials conducted within the US, which are held to various US-specific regulations (e.g. 21 CFR 56 for IRBs and 21 CFR 50 for informed consent).

In this newest draft FDA guidance, the change regulators need to account for is that medical device trials are becoming increasingly global.  They say that the number of IDE applications and submissions for marketing authorization supported by ‘OUS clinical trials’ has increased in recent years and it is likely to continue increasing in the future.  They also say that this increasing globalization of clinical trials presents challenges to both US and foreign regulators. Among the challenges are constraints in resources that have an impact the number of foreign clinical site inspections and unnecessary duplication of clinical studies and administrative burdens.

Another proposed change acknowledges Section 1123 the FDA Safety and Innovation Act (FDASIA) of 2012,  Here, the FDA was required to accept data from clinical investigations conducted outside the US as long as the data were collected according to acceptable good clinical practice. While the FDA said it had a “longstanding” approach to accepting these types of data, FDASIA served to codify the practice into law and called on the FDA to clarify the processes by which the data could be accepted.

Thus an Either/Or Approach is indicated in its guidance document. Either a company’s clinical trials conducted outside the US meet federal human subject protection requirements exactly, or they meet local standards, which a company must show are either equal to or greater than US requirements for human protection under the Declaration of Helsinki (1983 version). In addition, the FDA’s guidance addressed what it calls “valid scientific evidence” – this is evidence from what the FDA defines as “well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts and reports of significant human experience with a marketed device.” Should the FDA determine that the OUS data constitute valid scientific evidence, under its code 21 CFR 860.7, then the OUS data can be used to support clearance or approval of the application, say the FDA. Sponsors intending to initiate or rely on an already-conducted OUS data should “seek input from the relevant Center for Devices and Radiological Health (CDRH) or Center for Biologics Evaluation and Research (CBER) review division at the earliest stage possible using the Pre-Submission process,” it adds.

Given all this, one might ask what factors sponsors should take into account when assessing whether they can rely on data obtained from studies conducted in countries other than the US. The FDA says that there are three main considerations:

• Are there differences in clinical conditions which might affect the standard of care afforded to a patient?
• Are there differences in the populations being studied, which might preclude the data from being extrapolated to US patients?
• Are there differences in regulatory requirements which might cause the study to fail to meet US requirements?

If readers require further insight into these considerations, seven examples are given in the 15 page draft document (1) of issues that can arise when using clinical data from device studies collected OUS to support FDA regulatory decisions. How the FDA and sponsors may seek to resolve such issues and the likely review outcomes are also mentioned.

Clearly from all this, medical device companies or other researchers aiming to conduct important or pivotal studies in countries other than (or in addition to) the US wanting FDA-standard data – and, in certain areas of the globe, there are considerable advantages in ease of set up, speed of recruitment as well as significant cost benefits without any sacrifice in data quality – should use a reputable Clinical Research Organisation well versed in all regulatory issues with well GCP-trained sites to ensure that all appropriate study standards meet or exceed those of the FDA and other regulatory bodies.

These new guidelines are currently published as a draft for the time being, with the FDA accepting comments until 20 July this year.

1. ‘Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States’ http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/UCM443133.pdf?source=govdelivery&utm_medium= email&utm _ source = govdelivery
2. ‘Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices’
   https://www.federalregister.gov/articles/2013/02/25/2013-04201/human-subject-protection-acceptance-of-data-from-clinical-studies-for-medical-devices

It is well known in the clinical trial industry that the start-up phase of clinical studies can be very challenging. It is at this stage of development that clinical trials must lay the groundwork for success, and good intelligence gathering must be integrated into every aspect of strategy, from site identification to patient enrollment.

In this post I will discuss the some of the approaches to streamlining study start-up, and the new technologies that are being utilized, in order to achieve the greatest possible efficiency at this challenging phase of clinical trials design.

Workflow management

One aspect of the start-up phase that has evolved over recent years is the use of workflow management systems. This approach, involving the use of techniques such as CPM and Lean Six Sigma methodologies, allows study teams to improve their ability to manage key start-up steps, and to move away from an overreliance on simple data tracking. The aim of these systems is to create global visibility and promote better communication to create more seamless transitions between the different stages of study start-up.

Today, companies are building databases which enable CROs and sponsors better anticipate the future based on past project experience. In using this information, new protocols and products can be evaluated according to their overall design and composition. This more easily enables the prediction and therefore avoidance of risks that may occur along the same path.

However, the use of broad comparisons with past trials, even of a similar type and at the same phase, to predict a project timeline, is inadequate. For aspects of study start-up with high levels of complexity, it is vital that intelligence databases allow study teams to enter multiple unique parameters to generate the designs that are most likely to result in predictability around timelines.

Fundamental to the appropriate management of timelines is the ability to measure against baseline performances, and in order to establish realistic start-to-finish goal at the beginning of a project, key deliverables must be tracked against a baseline plan. While inevitable changes in circumstances, that alter a timeline, can be incorporated into a new projection, the initial baseline should always remain. This ensures that the appropriate data is available, and when delays occur and allows information gathering that will lead to swifter mitigation strategies, leading to greater timeline predictability.

Site selection

The identification of high performing sites and investigators is crucial for positive research outcomes. Choosing an appropriate site correlates with faster patient recruitment, and therefore success in reaching overall enrollment goals, superior data quality, fewer queries, and better patient retention.

However, the selection of poor clinical trials sites continues to be a problem, and it leads to an increase in the cost of clinical trials. Inappropriate site selection is principally due to lack of knowledge of relevant clinical investigators, and many sponsors predominantly rely on established connections with previously used sites, to find suitable investigators.

When recruiting sites, sponsors and CROs typically first identify regions in which the targeted patient population is more commonly located, and then determine whether the protocol is suitable. These initial assessments must be combined with information from regulatory intelligence databases to determine country and site feasibility. This should form the foundation when exploring locations to conduct trials.

Study start-up efficiency can also be improved by the use of enrollment modeling. This technology allows enrollment data, as well as intelligence regarding specific protocols, countries, and sites to be viewed in parallel. This enables study teams to predict the speed at which enrollment targets can be met using a set number of sites, and provides a means of measuring recruitment as the study progresses.

Technology

Over the past decade, there have been considerable advancements in global reporting systems and technologies for use in clinical development. This has gone some way to shift study teams’ workloads from the onerous tasks of compiling Excel spreadsheets, towards approaches that incorporate more real-time data and reporting. This has muerous advantages, such as enabling queries from regulators and ethical committees to sites in several countries to be shared worldwide, in real-time.

While digital methods of communication between investigators are becoming increasingly common, site implementation of web-based tools for the exchange of clinical document, remains slow. In 2011 a global survey found that traditional methods of communication, such as e-mail, fax, and courier, were the principal tools being used for the exchange of clinical trial documents in 73% of sites. [2] This is despite the fact that most investigators have access to tablets and smartphones.

It is the responsibility of CROs and sponsors to utilize these tools. Application of these technologies could be used, for example, to electronically distribute questionnaires, or predictable, pre-populated documents, to investigators. They could then be completed on a handheld device and signed with an electronic signature, helping to speed up the overall start-up process and reduce timelines.

Another area in which technology is affecting a more streamlined approach to study start-up, is through the use of online clinical document exchange portals. These can be used to simplify the task of tracking study start-up activities for several sites. Online portals enable the generation of reports, increasing the transparency of the status of a site’s progress. They also provide the capability to streamline communication, making for a clearer, user-friendly, and regulatory-compliant method for sites and sponsors to track and collaborate on operational data. Finally, these smart workflow technologies also make it easier for study teams to deliver real-time status updates to management, enabling the identification of bottlenecks and optimization of resources.

It is important to acknowledge that, as with the adoption of any new technology, the implementation of digital portal systems can be a challenge, requiring the creation of new SOPs, additional staff training, often at site already burdened with a heavy workload. However, it is vital that the clinical trial environment keeps pace with improving technologies, to manage competing demands, and to remain competitive and continue to increase efficiency.

Conclusion

New strategies and technologies, to streamline onerous and time-consuming start-up procedures, show potential. However, while the implementation of integrated data systems and digital document management remain uneven, challenges in estimating start-up timelines and identifying potential bottlenecks will continue. It is therefore essential that companies continue the process of collecting and compiling data, together with the use of appropriate systems to share that intelligence, in order to achieve ever-greater predictability in study start-up.

References:

1. Schimanski, M. Kieronski, “Streamline and improve study start-up,” Applied Clinical Trials, Vol. 22, Number 9, September 2013.
2. Bio-IT World, “IntraLinks Survey Highlights Need for e-Clinical Document Exchange Tools,” (2011), http://www.bio-itworld.com/news/06/14/2011/IntraLinks-survey-need-clinical-document-exchange.html.

At Clinical Accelerator we conduct many of our trials in Central and Eastern Europe, and it’s important to us that we monitor the latest data coming for our countries of operation. We’re pleased to see that, based on recent statistics, Poland is keeping up with some of the biggest players in the world of clinical trials.

While Poland cannot currently equal, in terms of numbers, the clinical trials conducted in Germany, France or United Kingdom, it has a thriving and growing clinical trials industry, which continues to attract investments from many sponsors worldwide.

Data from ClinicalTrials.gov shows that there are currently 3782 studies registered in Poland (1). This is an eight-fold increase on 2009 numbers when only 469 trials were registered (2).

What is attracting sponsors to conduct trials in Poland?

There are a number of factors that make Poland an attractive location to undertake clinical trials (2), including:

• A large population of prospective patients
• Effective patient recruitment and retention
• High quality of data and adherence to Good Clinical Practice.

Estimates from October 2010, show that the clinical trials industry in Poland is worth at least 860 millions PLN (3).

The influence of clinical research on Polish society

The clinical research industry influences Polish society in many ways. It brings innovative healthcare to Poland, allowing patients to learn more about their diseases and gain access to the latest treatments and therapies. Participation in clinical studies enables medical personnel to improve their skills, broaden their knowledge and keep up-to-date with the latest technologies and discoveries.

The dynamic development of a clinical trials industry in Poland has stimulated the process of administrative and legal change in the country, furthering the changes which began with Poland’s admission to the EU. Hopefully, the up coming European Union regulations on clinical trials will accelerate development in Poland’s administrative procedures, allowing for higher quality international trials. This is a chance for Poland to become an even more important center of studies in Central & Eastern Europe (CEE) region.

Poland leads the way in clinical trials across Central & Eastern Europe

According to a 2010 analysis by Pricewaterhouse Coopers and Infarma.pl, Poland is the leading CEE country in conducting clinical trails (3). Not only is it the country in which phase III studies are most likely to be registered, but also phase IV and even phase I and II trials. Furthermore, it is predicted that the number of phase I and II clinical trials performed in Poland will increase over the coming years.

Poland already benefits from dedicated clinical trials centers with experienced personnel, which are considered to be essential for clinical trials in the early phases of study. It is therefore unsurprising that data from the Office for Registration of Medicinal Product, Medical Devices and Biocidal Products shows an increase in the number of early phases trials registered in Poland (3).

Patient recruitment in Poland

As previously mentioned, clinical trials conducted in Poland profit from high rates of patient recruitment (3). Some of the factors associated with the healthcare system in Poland which contribute to these excellent enrollment rates:

• Detailed diagnostic and medical examination (with costs are covered by study budget) are provided for all patients.
• Clinical trials provide access to life or health saving therapies free of charge, providing a strong motivation for patients to participate in trials.
• Clinical trials provide an opportunity for patients to gain access to innovative otherwise unavailable treatments.
• Medical personnel are highly qualified, with excellent clinical trials experience
• The rates of compliance to study procedures are equal to, if not higher than, those found in Western Europe or USA (3).

Poland continues to play an important role in the clinical trials industry in CEE. The country’s administrative experience and membership in the EU unifies and simplifies procedures of registering and conducting trials. Whilst the swift recruitment of appropriate patient populations and high quality data output provide an attractive enticement to sponsors.

References:

• http://clinicaltrials.gov/ct2/results?cntry1=EU%3APL
• http://www.badaniaklinicznewpolsce.pl/badania-kliniczne-w-polsce/badania-kliniczne-w-polsce/polska-w-porownaniu-z-innymi-krajami/
• http://infarma.pl/fileadmin/badania_kliniczne_raport/Badania%20kliniczne%20w%20Polsce%202010.pdf

A “finding” – what does it mean?

In a clinical trial language a finding is usually referred to a numerical result of an analysis for a specific outcome, for example a relative risk (1). In proper understanding of research it is crucial to have some additional background information consisting of four key elements: methodological context, population context, a result for each outcome and interpretation (1). It has to be known how the trial was conducted and what was the hypothesis, to whom the results of the trial can be applied, what were the results for each outcome, and what are probable answers to the questions asked (1).

Where a “finding” can be found?

According to World Medical Association’s statement of principles for medical research involving people, every investigator running a clinical trial should register it and report its results (2). It is crucial for keeping medical information up to date (2).  There are several platforms provided for registration of clinical trials and reporting their results. To register a trial, the details should be submitted directly to any of the Primary Registries of the WHO Registry Network or an International Committee of Medical Journal Editors (ICMJE) approved registry. List of registries is available on the WHO website on International Clinical Trials Registry Platform (ICTRP) (3). It is only necessary for a trial to be registered once (in one registry) (3). The world’s largest register is clinicaltrials.gov which accepts registration from anywhere in the world (2). Although the registration of clinical trial is highly recommended immediately when the clinical trial begins, in some cases it is possible to register a trial retrospectively.

Publish or not publish?

Researchers who decide to embark on a clinical trial commit themselves to report the findings in accordance with ethical principles (1). However, it has been estimated that half of all completed clinical trials are never published in academic journals (4). Additionally, it is twice more likely to publish a trial with positive results than others (4). The problem of not publishing the results of clinical studies applies to industry trials, non-industry trials, international trials, trials at all stages of drug development, and to clinical trials of all sizes (4). When results are published, they are not always complete, what may lead to potentially biased view of the trial and its results (1).

Selective reporting of the results impacts informed health-care decisions of both healthcare practitioners and patients (1). A process leading to more transparent reporting of findings of clinical studies has already begun (1). The value of making clinical trial results publicly available, whether they are positive or negative, is more than of purely administrative benefit. It is not only ethical but also practical, because it helps avoid duplicating studies (1). Additionally, knowledge of specific finding has a great influence on people trying to choose between alternative interventions (1). Not publishing results, both positive and negative, can lead to serious consequences such as bad treatment decisions and missed opportunities for good medicine (2). In the United States, the public disclosure of clinical trial results is required by the US FDA Amendment Act 2007 (2). It puts study sponsors under an obligation of posting results of the trial on clinicaltrial.gov within a year of the completion of the trial. This obligation refers to all trials with at least one site in the US (2). In European Union, a similar tendency is observed.  Posting results of clinical trials on EudraCT is mandatory since the 21st July, 2014 (8). Study sponsors are obliged to post results within 6 or 12 months since the end of their trials, depending on the type of the trial concerned (8). For trials that ended before July 21^st, 2014, sponsors will have to post results retrospectively (8).

A negative result?

In the context of clinical trials the concept of “negative” result is often misnomer (5). A trial with negative results is often a study that for various reasons fails to show effectiveness in a certain indication or use (5). A negative result is rarely understood as an unexpected or unwanted harm for patients from the drug or medical device being tested (5). There are different reasons for failure of the trial, including insufficient statistical power of the study, inappropriate choice of route, dose or frequency of administration of the study drug (5). Negative result of a study can be caused by lack of effectiveness of the drug investigated (5). To substitute the term “negative” result, it would be more appropriate to use the word “unsuccessful” or “inconclusive” (5). Perception of the term “negative” applied to clinical trials is often inappropriately pejorative (5). A negative result of a trial is not always a proof of any actual harm. It may serve as a clue in which direction future trials should turn to look for potential benefits (5). Additionally, blocking the publication of a “negative” result could be a way in which pharmaceutical companies try to exaggerate the benefits of their products (5). Most clinical trials that are “negative” or inconclusive are also less attractive to journal editors, reviewers and medical practitioners (5). It has been observed that negative results do not make riveting reading (6). Chris Williams, M.D., coordinator of the Cochrane Cancer Network, Oxford, England said that “there is a strong link between failure to publish and a study being negative” (6). The initiative has been undertaken to create a journal that will accept publication based on the quality of clinical trial instead the newsworthiness of the results (6). It is considered to become a source for meta-analysis and overall view to what happened to disappearing trials (6). This open-access journal is called “Journal of Negative Results in Biomedicine”. (6).

Publishing “negative” results of clinical trials, even those with properly planned methodology and execution, is a reminder that understanding limitations of clinical trials is essential to discover which therapies simply work and which do not (5). The publication of the results can be enhanced, for example through ensuring at the very beginning of the trial, in the contracts, that results will be published regardless of whether they are satisfactory (4). Additionally, Ethical Committees or Health Research Authorities could commit to insisting on publishing the results of clinical trials and to checking that no study results are being withheld (4).

Summary

Publishing negative results of clinical trials with background information opens an opportunity to avoid possible mistakes in designing other prospective trials.  It creates a basis for modifications of trial design that leads to new answers and new possibilities in medicine. Publishing the results is simply being fair with patients who participated in the research, experienced inconvenience and sometimes risk, in the belief that their participation will improve understanding of which treatment works best (4). There are strong arguments for publishing “negative” results of clinical trials as well as positive, because what is negative now, can bring future success.

References

(1)D Ghersi et al. 2008. Reporting the findings of clinical trials: a discussion paper. Biulettin of The World Health Organization. 86(6): 492-493

(2)http://www.alltrials.net//wp-content/uploads/2013/09/What-does-all-trials-registered-and-reported-mean.pdf

(3)http://www.who.int/ictrp/trial_reg/en/

(4) http://www.alltrials.net/wp-content/uploads/2013/01/Missing-trials-briefing-note.pdf

(5)http://www.forbes.com/sites/henrymiller/2013/04/03/what-we-learn-can-learn-from-negative-clinical-trials/

(6)http://www.jnrbm.com/about

(7) http://www.alltrials.net//wp-content/uploads/2013/01/letter-to-EMA-from-clinical-trial-participants-2013-Jan-18.pdf

(8) http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/06/news_detail_002127.jsp&mid=WC0b01ac058004d5c1

In the previous posts on barriers to recruiting patients for clinical trials, I addressed some of the problems that patients and clinicians face. In this final post, I will discuss some of the difficulties faced from a healthcare systems perspective, and ways in which these might be tackled.

Funding and coordination

Undoubtedly, the major barrier to healthcare organizations taking a more active role in clinical trials and recruitment of patients is funding and available human resources. This includes both limited resources at the level of healthcare facilities themselves, and a lack of funding for clinical trial research, especially from national research organizations.

Clinical trials often require a minimum number of patients to effectively assess the success of a treatment and therefore have to remain open and actively recruiting for long periods of time. This can be extremely expensive. Also, where funding is available, it still may not be sufficient to carry out clinical trials with designs that best test particular treatment modalities.

Another issue, connected to that of limited funding, is lack of resources for study coordination. It can be very difficult for healthcare organizations to identify patients that are eligible for clinical trials. Getting healthcare professionals working together to achieve patient recruitment targets is also a challenge. These issues are compounded if the facility has only a minimal infrastructure for clinical trials, or does not have a funded clinical trials coordinator.

In OncLive’s recent article, “Tackling Patient Recruitment Challenges in Clinical Trials”, Dr. Timothy Mullet, Chief, Section of General Thoracic Surgery at University of Kentucky College of Medicine, summarized the concerns, “Those in the ivory tower want us to take care of patients efficiently, and bill for it . . . there is just no way to justify the costs, so there has to be a commitment from the enterprise that they are willing to take a loss on it.”

Insurance

Issues regarding insurance can be another major hurdle for healthcare systems to overcome when recruiting patients for clinical trials. While some insurers may provide adequate coverage for standard care, many may be unwilling to cover care outside of their facilities, even if they do not have appropriate treatment options available to patients. Where patients are uninsured this can also be a barrier to participation in clinical trials. It is sometimes possible to find resources to support uninsured patients care, but this will often delay their treatment for several months.

Strategies for tackling funding

So, how can these barriers to recruitment be overcome? The experts interviewed by OncLive had a number of recommendations. One point that was emphasized was the necessity to hardwire clinical trials awareness and recruitment into healthcare systems.

In terms of tackling funding issues, the experts suggested that healthcare organizations approached legislative bodies for additional funding, as well as private foundations that might be interested in supporting clinical trials. In addition to this, organizations should consider supporting different types of clinical trials, from those supported by industry, which have sufficient funding of their own, to cooperative and investigator initiated ones.

Strategies for tackling coordination

As well as tackling questions of funding, it is essential for healthcare organizations to recognize the importance of clinical trials, by providing appropriate support, personnel, office space and resources, and thus enabling them to achieve their goals. Organizations should consider the support that their clinicians can provide and the systems capacity that they have, and only carry out trials which will be both cost effective, and can be conducted responsibly and with good clinical practice.

In terms of strategies for overcoming coordination challenges, OncLive’s panel of experts had a range of long-term practices that would hugely improve healthcare systems’ ability to effectively run clinical trials. For example, healthcare leaders can encourage recruitment by initiating a dialogue with patients and communities about clinical trials, leading to positive publicity and increased awareness.

Other suggestions included adopting new technologies such as electronic medical records, combining practices to create large networks, and devising methods of monitoring performance to assess whether trial targets are being met. One recommendation that met with universal support from OncLive’s experts was the designation of a dedicated clinical trials coordinator: someone who knows which trials are available and can explain to patients how participation in trials could be of benefit to them, acting to coordinate the whole process.

At Clinical Accelerator we believe that patient enrolment organizations can effectively intervene in situations when investigative sites experience lack of resources. Assisting sites with screening efforts, patient recruitment and retention, even embedding into sites’ structure external dedicated study co-ordinators directly employed by a patient enrolment organization can lead to significant improvement in site performance.

Clinical trials are good for patients

In this series of blog posts, I have discussed some of the major barriers to successful recruitment of patients to clinical trials. There are many potential approaches to overcoming these obstacles. However, communication has been demonstrated to be of paramount importance. The ultimate goal of clinical trials is to help patients and improve treatments. Getting this message across to everyone involved is key to improving recruitment.

References

Tackling Patient Recruitment Challenges in Clinical Trials – http://www.onclive.com/publications/oncology-live/2014/march-2014/tackling-patient-recruitment-challenges-in-clinical-trials/

In the second installment of the Clinical Accelerator “Barriers to recruitment” blog series, I will discuss the obstacles faced by clinicians when recruiting patients for clinical trials and suggest ways in which these can be overcome.

Clinical trials rely on healthcare professionals for the successful recruitment of patients, but lack of time can pose a huge barrier for clinicians. The requirement of clinicians to see large numbers of patients in a short space of time makes identifying appropriate patients for clinical trials a challenge.

Severe time pressures on healthcare professionals also make keeping up to date with the latest clinical trials difficult, adding a further hindrance to their ability to recruit patients. Even when a clinician manages to remain abreast of the latest trials, it can be hard to remember the specific enrollment criteria whilst in the process of caring for patients.

Another barrier to recruitment is fear amongst healthcare professionals: fear that patients might not receive the best treatment possible, or that physicians might lose their patients if they recommend participation in a clinical trial.

So how can the process be made easier for clinicians? One solution is for practices to employ a dedicated research nurse, clinical trials coordinator, or a clinical trials patient navigator whose role is to stay up to date with the latest trials.  He or she can advise physicians about those trials that are most relevant for their patients, and, just as importantly, talk with patients about what they involve.

Collaboration between researchers, nurses and physicians is also of vital importance to the success of clinical trial recruitment. Effective communication between these individuals will increase their knowledge and awareness of clinical trials and help to address any concerns. In a recent article in OncLive, a panel of clinical research experts and healthcare professionals noted that regular meetings between researchers and physicians are critical, providing a forum discuss the latest trials and any concerns or queries they might have.

Another key element to fostering successful collaborations between clinical trial practices and healthcare professionals is good communication and setting achievable targets. For example, regular communications from research organisation, such as newsletters listing current and ongoing trials, were noted as being particularly helpful for clinicians and nurses.

Practices could also consider setting individual or institution-wide goals for recruiting patients to clinical trials. Some experts have even suggested tying continuing medical education credits with trial recruitment.

Finally, focusing on the success stories and providing positive feedback is just as important, both for physicians and patients.

It is possible for well-organized clinical trial sites to implement all of these strategies. However, there is also a considerable place for patient enrolment organizations to assist the physicians with designing, planning and implementing all these or other applicable approaches. Busy investigators can outsource some of these tasks to professional patient enrolment managers or implement patient enrolment strategies as a collaborative effort with a patient enrolment organization.

In OncLive’s article, Sue Childress, Director of nursing at the Huntsman Cancer Institute at the University of Utah described her experiences with trial recruitment. “When we initially started phase I trials, the nurses were concerned that patients may not receive the best treatment possible,” she said. “After listening to their concerns and addressing them, now what I hear is that they are proud to work in a place that offers these trials. The patients don’t have to travel to Chicago or San Francisco.”

Her approach demonstrates the success that can be achieved in collaborations between clinical trials practices and healthcare professionals, with the appropriate support.

At Clinical Accelerator, we’re utilizing or encouraging all of these and many other general and project-specific strategies with our partner clinical sites. We’re firm believers that, with the correct communication and feedback mechanisms, the barriers to patient recruitment experienced by clinicians can be vastly reduced.

References

Tackling Patient Recruitment Challenges in Clinical Trials – http://www.onclive.com/publications/oncology-live/2014/march-2014/tackling-patient-recruitment-challenges-in-clinical-trials/

Here at Clinical Accelerator we know that one of the major sources of delay to clinical trails is achieving sufficient levels of patient recruitment. In the next three blog posts, I will discuss some of the barriers to enrollment and ways in which these problems can be tackled. This post will focus on how to minimize patient’s fears of taking part in clinical trials.

Communication and education: Tackling patient fear

In a recent article at OncLive¹, fear was described as one of the greatest barriers to patients and families taking part in cancer trials. In particular, patients fear being a “guinea pig” or receiving a placebo instead of treatment. Clinical trials can also be complicated and confusing for patients, leading them to turn down places in promising clinical studies because they do not understand the procedures or likely outcomes. Potential patients may believe that participation in clinical trials is a last resort, or that a drug already approved by the FDA (or by EMA in Europe) would be better than a drug that is not yet approved. Participation in clinical trials also impacts upon the patient’s families, and patients may pick a treatment option that they feel will be less of a burden for their families, rather than the right treatment for them.

So how can patients’ fears be assuaged, and recruitment into clinical trials be improved? Communication and education are key in overcoming the fear-based patient and family barriers to participation in clinical trials. Healthcare professionals play a vital role in patient recruitment and the way in which they provide information about clinical trials can reassure patients and their families, and increase clinical trial recruitment.

Communication strategies for healthcare professionals:

There are several strategies that health care professionals can follow to help assist when it comes to recruiting participants:

• Engage with patients, providing information about all the treatment options including clinical trials to patients and their families.
• Involve patients in the decision-making process
• Educate patients so that they know that clinical trials offer a type of treatment rather than a placebo.
• Designate a dedicated research nurse to explain the clinical trial options in depth.

Cynthia Davidson, APRN Clinical Operations Manager for the Center for Investigational Therapeutics (Phase I Trials) at the Huntsman Cancer Institute told OncLive, “It is important to provide one-on-one communication with the patient and family on all the treatment options. Spend the extra effort needed— however much time it may be—allowing the patients to have some control over their decisions.”

Choice of communication method: Targeting your patients’ needs

Various types of media can be effectively employed to educate and recruit patients to clinical trial studies. As has been previously discussed on the Clinical Accelerator blog (Patient recruitment: is social media the cure for this headache?), the use of social media, such as Facebook and Twitter, as well as online patient communities is becoming a new recruitment ground for clinical trials, and these are also ideal places to provide information and support to possible clinical trial candidates.

More traditional methods of communication can also be important, with advertisements and word of mouth providing an essential means of education to patients. For trials in which the recruitment of patients from minority groups is required, developing relationships within the community, providing specific outreach and education, is of particular importance.

It is also vital to have the ability to address any potential language barriers. Ensuring that participants who do not share their first language with the healthcare professionals feel confident that they understand the clinical trial process and can have any questions they have can be adequately addressed, is vital to recruitment.

Financial concerns

Another important barrier to patient participation in clinical trials are worries about the costs of taking part. Depending the country of residence, these costs might include travel, time off work, and the cost of procedures, particularly if the patient is uninsured. In the United States, The Affordable Healthcare for America Act (2014) should mitigate worries surrounding participation in clinical trials and insurance, as provides protection to those taking part. However, patients may still be concerned that there will be unexpected costs that are not covered by their insurance. Some patients have limited insurance plans with minimal out-of-network benefits, and many patients do not know the rights they have within their plans.

Strategies for addressing financial concerns

In OncLive’s recent interviews, six clinical trial experts gave this advice in helping to allay patients’ financial concerns (some of these are primarily applicable to the situation in the United States and some are universal):

• Connect patients to financial counsellors or social workers to identify resources.
• Set up patient assistance programs, in partnership with private foundations and coordinate with local hotels and businesses to help with travel expenses.
• Provide reimbursement from the trial for some travel expenses, including food, lodging, and transportation.
• Advocate for patients to insurance companies.
• Encourage patient participation in the Health Insurance Exchange Marketplace.

Patient-centric recruitment

For successful recruitment of patients to clinical trials studies, communicating with candidates in a way that gives them confidence that participation is the right choice for them is key. Be prepared to go the extra mile and spend the necessary time with patients and involve them with the decision making process.

References

Tackling Patient Recruitment Challenges in Clinical Trials – http://www.onclive.com/publications/oncology-live/2014/march-2014/tackling-patient-recruitment-challenges-in-clinical-trials/

There’s no doubt about it, a strong investment climate in BioPharma, biotech and other Life Science industries means more money for clinical trials. Here at Clinical Accelerator we keep a keen eye on market trends, and this August new data has been published on the health of venture capital investments in the biotechnology sector.

In the aftermath of the global financial crisis, we have seen some reduction of the investment appetite in the biotech sector and some misconceptions started to form about higher risks associated with such investments¹, with many investors preferring to put their capital into technology-related sectors, such as software, information technology and eCommerce.² However, the idea that returns in Life Science venture investing lag behind other venture capital sectors is beginning to lose credence, with data on venture returns showing that life science startups have out performed other sectors over the last decade³.

A comparison of data from the second quarter of this year showed that “U.S. venture capital funding for BioPharma companies jumped more than 25% by dollar value during the second quarter compared with the second three months of 2013.”⁴

This is undoubtedly due, in part, to the VCs capitalizing on increased exit opportunities, and particularly the initial public offerings (IPO) boom, which has seen healthcare IPOs dominate. A comparison of the first half of this year with 2013 showed Life Science companies raising $4.7 billion globally in 68 IPOs versus 66 in the whole of 2013⁵, and “according to IPO Scoop, 33 percent of the 288 market debuts have been healthcare companies”.⁶ The majority of biotech investment is in drugs for humans, at $1.4 billion, up 36% from the year-ago quarter.⁴

Greg Vlahos, life sciences partner at PwC, told the online news site GEN that the “IPO boom, and rising valuations give VCs more “liquidity” or assets that can be quickly converted to cash, allowing them to raise more money for investing in more companies.”

A recent article in Forbes² highlighted data from Correlation Ventures analysis of return distributions in VC financings of BioPharma. As the author Bruce Booth points out, this further supports “the thesis that BioPharma venture investing, in contrast to common perception, has actually outperformed most other non-biotech venture sectors at most of the percentiles of performance.”

The summarized data from Correlation Ventures provides a number of key observations. Firstly, CV data from 20,000 aggregate financings showed that returns of greater than 5x are higher in BioPharma than other sectors, with a rate of 11.5% versus 9.8% for other sectors. Given the size of the dataset this is almost certainly a real difference, and is also consistent with prior analysis at the company level. The data also shows that there are surprisingly similar frequencies of greater than 20x returns across BioPharma and other sectors, with figures suggesting that 1 out of 60 financings are reaching returns at these levels.

In his article, Mr Booth also noted that the CV dataset demonstrates that it is only when we look at returns greater than x50 that BioPharma begins to “numerically lag other venture sectors, where only 1-out-of-300 financings reach those return levels.” However, he went on comment that this was based on a “very small and noisy” dataset.

CV’s final major observation was that the rates of loss for BioPharma financings are lower those for the rest of venture capital, with 57% of BioPharma financings yielding returns lower than their invested capital versus 66% in other sectors. When looking at previous dollar weighted analysis, we see that the figures are even more favourable towards biotech. For example, Adam Street Partners data show a 36% loss ratio for biotech compared with 59% for the Internet.

“These data are further confirmation of the relative attractiveness of biotech venture capital in the asset class,” Mr Booth commented. He went on to say, “A recent report from Jon Norris at Silicon Valley Bank highlights the resurgence in returns in healthcare with over $12.5B in potential Limited Partnership (LP) distributions in 2013 alone.”

With strong mergers and acquisitions and IPOs through 2013 and 2014, and with the continuing demand for innovation from Big Pharma/Biotech, returns and LP perceptions of the sector have strengthened and are likely to continue to improve.

This is an excellent sign for the R&D industry that will surely lead to new investment. At Clinical Accelerator we are confident that this positive financial climate will create an environment in which more clinical trials can get underway.

References:

1. Life Sciences: The Rodney Dangerfield of Venture Capital (2011) – http://lifescivc.com/2011/07/life-sciences-the-rodney-dangerfield-of-venture-capital/
2. Data Insight: The Return Distribution Of BioPharma VC Financings (2014) – http://www.forbes.com/sites/brucebooth/2014/08/11/data-insight-the-return-distribution-of-biopharma-vc-financings/
3. Booth, B. L. and B. Salehizadeh (2011). “In defense of life sciences venture investing.” Nat Biotechnol 29(7): 579-583.
4. GEN News Highlights – VC Funding Revives with Market in Q2 (2014) – http://www.genengnews.com/gen-news-highlights/vc-funding-revives-with-market-in-q2/81250282/
5. Strong IPO Market for Life Sciences Companies Defines First Half of 2014 (2014) – http://www.cnbc.com/id/101807104#
6. Coelacanths And Other IPO Thoughts Before The Autumn Markets Return (2014) – http://www.xconomy.com/national/2014/08/26/coelacanths-and-other-ipo-thoughts-before-the-autumn-markets-return/

Transparency of data is paramount to scientific communities worldwide and a sine qua non for the unbiased technological advancement. This, naturally, also refers to scientific research in medicine. As we read on through the European Medicines Agency’s (EMA) mission and responsibilities, transparency comes as its integral and prominent feature. As part of its operations, the Agency is taking noticeable actions in order to address growing demand for the accessibility of data and results from clinical trials submitted as part of the marketing authorisation process.

A staggering response that followed the release of Policy 70 for public consultation in June 2013 reflects the interest of various stakeholders such as pharmaceutical industry, academia, patients and healthcare professionals, health-technology-assessment bodies, national medicines regulators, the members of the European Parliament, the European Ombudsman and European Commission in the availability of clinical data for further scientific scrutiny and reuse. Since the publication of the EMA previous policy on access to documents in November 2010 until April 2013 over 1.9 million pages containing clinical trial data were released in response to requests by patient organisation, pharmaceutical companies, healthcare professionals, academia, not-for-profit organisations, regulatory bodies and other individuals or institutions.

The Agency has long ago acknowledged potential gains for the public domain arising from open review and independent re-analyses of data after the medicinal product has been authorised. Availability of clinical trial data should lead to more efficient development of new therapies, bolster better-informed use of medicines, and facilitate verification of the regulatory authority’s decisions by third parties. However, concern remains regarding patient confidentiality, possible conflict of interests and independent analyses’ vulnerability to distortion as well as the risk of moving the research and drug development activities outside of the EU to avoid data sharing. In order to minimise these risks measures are taken ensuring best possible protection of patient personal information and the prevention of unfair commercial use of data, particularly outside the EU.

It should be once again clearly stated that the EMA has publicly recognised the potential benefits for public health of re-analyses of data for marketed drugs by independent academics and researchers, and acknowledged that regulators do not have a monopoly on science.

The policy on publication of the clinical board was discussed at the Management Board meeting on June 12, 2014. According to the minutes published at the EMA webpage, the Management Board endorsed the general approach, and also the proposal to include a more user-friendly solution for academic and non-commercial research purposes.

The draft policy will be discussed again at the Management Board meeting in October 2014. If approved, the policy will serve as a complementary tool preceding the implementation of the new clinical trials regulation foreseen to come into force earliest in May 2016.

References:

European Medicines Agency policy on access to documents (related to medicinal products for human and veterinary use). EMA, November 30, 2010.

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/11/WC500099473.pdf

Publication and access to clinical-trial data (draft for public consultation). EMA, June 24, 2013.

www.ema.europa.eu/docs/en_GB/document_library/Other/2013/06/WC500144730.pdf

European Medicines Agency agrees policy on publication of clinical trial data with more user-friendly amendments. EMA, June 12, 2014.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/06/news_detail_002124.jsp&mid=WC0b01ac058004d5c1

Release of data from clinical trials. EMA.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000555.jsp&mid=WC0b01ac0580607bfa

Minutes of the 84th meeting of the EMA Management Board held in London, 12 June 2014.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/08/event_detail_000740.jsp&mid=WC0b01ac058004d5c3

Eichler H-G, Abadie E, Breckenridge A, Leufkens H, Rasi G (2012) Open Clinical Trial Data for All? A View from Regulators. PLoS Med 9(4): e1001202.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001202

Difficulties in recruiting patients

One of the biggest problems in conducting clinical trials successfully is patient recruitment. Another challenge is assuring diversity in clinical trials enrolment which is essential for eliminating health disparities as low enrollment and participation of racial/ethnic minorities and underserved patients affects the generalisability of research results for these groups (Baquet). Many factors affect enrolment into clinical trials such as race, socioeconomic status, access to healthcare, and cultural beliefs (Baquet). How the pharmaceutical industry is viewed along with participating healthcare professionals is also a major factor. According to Shavers-Hornday et al., and Harris et al., limited access to information on available trials by the general public, a lack of understanding and knowledge of the role of clinical research in the development of interventional treatment, coupled with existing attitudes toward research, including mistrust of researchers or research institutions, perpetuate existing fear, influence participation off African American patients in the US. Transposed to Eastern Europe, especially in those countries with history of conflict between state and the people, those fears are palpable and may play a role in the enrolment of patients into clinical trials.

Being culturally sensitive

Since the majority of large pharmaceutical companies are based in the West, practices are generally created to suit those Western countries. For example, in Western countries the initial stages of investigator identification, selection and recruitment are often automated and no contact is made with any person until the data from the Investigators’ online questionnaires are analyzed. In contrast, the process in Eastern Europe typically involves interaction with people from start to finish, over the telephone and in person, in the language of the land (Niedzielska).

Educating patients and healthcare professionals

Therefore, creating a culturally appropriate enrolment system of communication and education for pharmaceutical companies, health practitioners and patients is key to improving the buy-in from patients to overcome any issues stopping people taking part in clinical trials. Ideas and techniques can be garnered from those implemented in Western countries. A holistic approach involving patients, their families’, clinical specialists, nurses, surgeons, social workers, and primary care providers in the recruitment process will ultimately improve patient participation. Educating patients and their families about the benefits and risks of relevant clinical trials are essential to overcoming any fear-based barriers. Ensuring that healthcare professionals’ are involved from the start plays a big part in patient confidence.

Using modern technology

Educating people via all popular channels of communication, and involving all parties throughout the recruitment process will help build relationships. Since culture is evolving in tandem with advancing technology, the role of social media is taking on a more prominent role, with infomercials on YouTube, that are shared over Facebook and Twitter for example. Coupled with traditional forms of communication such as word of mouth, advertisements, and relationships throughout communities, this combination can be very powerful. Consequently, a holistic but personalised approach will help improve the rate of patients enrolling and committing to clinical trials until completion.

References:

Shavers-Hornaday VL, Lynch CF, Burmeister LF, Torner JC. Why are African Americans under-represented in medical research studies? Impediments to participation. Ethn Health. 1997;2(1-2):31–45.

Baquet CR. The Role of State Legislation and Policy in Addressing Disparities in Clinical Trials. Eliminating Disparities in Clinical Trials (EDICT). http://www.bcm.edu/edict/PDF/State_Legislation.pdf

Harris Y, Gorelick PB, Samuels P, Bempong I. Why African Americans may not be participating in clinical trials. J Natl Med Assoc. 1996;88(10):630–4.

D L Niedzielska. The Reality of Clinical Trials in Central and Eastern Europe. Journal of Clinical Research Best Practises. Vol. 9, No. 5, May 2013