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The Internet and various services using it as a platform evolve at such a rapid pace that it is difficult to keep track of everything and to understand its significance to clinical trials.
The Internet and various services using it as a platform evolve at such a rapid pace that it is difficult to keep track of everything and to understand its significance to clinical trials. One of the key aspects to consider is access to the Internet. In 1995, there were 16 million Internet users or 0.4% of the world’s population. In just 17 years, this figure has grown to 2.4 billion and 34.3% adoption.1 At the current rate, each year, the penetration percentage sees a 2-4% growth. The distribution of these users is also important (see Figure 1 below). Most of the Western world is already very well connected with many countries in the high 90’s in terms of Internet penetration percent of total population. For example, Norway is near the top with 97.2%. Many services, such as banking, have moved towards online service models, shutting down branch offices. This has led to some countries, like Finland, for example, making access to broadband Internet a basic civil right. At the same time, other parts of the world have much lower figures. Even Asia, which accounts for 44.8% of total users, only has penetration of 27.5%.
What does this mean for clinical trials? It means that bias due to lack of Internet access is going to be far greater in some parts of the world. It also means that the same bias is going to be close to non-existent in the western world, where the penetration figures are starting to be close to literary rates of the population. It’s difficult to say how this bias will impact studies in practice, but for example, the Pfizer virtual trial pilot reported that the average age in their online trial was 10 years younger than it was in a similar paper-based trial.2 What was interesting was that the average age was still in the 50’s. This age bias is likely to get smaller in the future as more and more people will be used to using the Internet. This age bias is also likely to have a strong correlation with the therapeutic indication. The Pfizer trial was for overactive bladder, a condition that has been shown to correlate with increased age.3 Had the study been done with a condition that did not have this inherent age bias, the “digital bias” would also likely have been less evident.
Another significant change that is ongoing at the moment is the “mobile revolution.” The availability of low-cost smartphones and the increased usability of these modern devices keep lowering the bar for the users. The introduction of easy-to-use touch-screen phones and user interfaces enable these devices to be used without any previous training or computing background. This is far easier than having to master a keyboard and a mouse and be able to navigate a traditional desktop operating system. In many parts of the developing world, the Internet statistics are upside-down when compared to Europe or North America. For example, Egypt has 70% of its Internet users only using via mobile devices. Many other countries also have the majority of their Internet users be mobile-only, including India and South Africa. The United States, on the other hand, only has 25% of users mobile-only. While the desktop Internet still dominates in the developed world, it is highly mobile-enabled, with 3G penetration of 81% in the United States and 99% in Japan. In terms of infrastructure and access to devices, this change has made the use of this technology feasible practically anywhere in the world. Even more so, it has the potential to open access to populations that were difficult to reach in the past, as mobile technology can help extend the reach of trials to new areas.
Internet and health
A lot has been said about the e-patients and how they are changing the way healthcare is being provided. Some sophisticated services, such as patientslikeme.com, are practically eliminating the healthcare professional and allowing patients to share their symptoms and treatments directly with each other. Using the Internet to search for health information is incredibly popular. In 2010, 80% of adult Americans searched for health information online.4 This activity is about as common as searching for information about the weather (81%) and clearly more popular than activities like using social media (69%) or doing online banking (61%). It seems that at least in the United States, large populations of people across socio-economic and age ranges expect to find health information online. In fact, these populations that routinely expect online services may already be so large that not providing online engagement to this audience can affect their decisions whether to participate in a trial or not.
Affect on clinical trials
Many clinical trials can be quite a burden to patients. In fact, trial complexity and burden has increased significantly in recent years. For example, between 1999 and 2005, several changes occurred, as illustrated in Table 1.5
Based on this data, it appears that the increased burden may explain the decreased enrollment and retention rates of patients. Some of this burden can be decreased with the use of technology. Electronic patient reported outcomes (ePRO) technology, for example, can be used to complete questionnaires remotely. Even more advanced patient engagement technologies are emerging and these can further decrease the number of required site visits and make them more efficient. It is likely that using online/mobile technologies to conduct parts of a clinical trial will bias trials to some extent due to “technophobia,” but it is also likely that using paper will also bias them at the other end by excluding the people who do not want to deal with the burden of clumsy paper-based trials. The question is, which bias has a greater impact on the trial? In the future, as the tech-adoption barriers keep lowering, the biasing effect will increasingly favor trials that use online/mobile technologies to make the patient experience more satisfactory.
One of the key reasons that come up in the literature about patient motivators is altruism, the willingness to help others. It fairly consistently ranks among the top three reasons for participation. Another important reason is patients’ interest in the medical condition or research in general, and they expect to learn more by participating in the study. Of course, many patients have some expectation for personal health gain (e.g., access to new or free treatment). Some other reasons, such as financial gains are not anywhere near the top of the list of motivators.
The question is, how well do clinical trial professionals understand and address these motivators as part of their trial planning? For many patients, clinical trials may seem like a “black box,” where their data goes in, but nothing ever comes out and they often do not have a good picture of the overall trial objectives and their role in it.
Given that altruism is one of the main reasons for participation, it would seem logical to assert that providing controlled distribution of information to patients on the trial and their important contribution towards the completion of the trial would motivate them to stay compliant with the study protocol. Providing this information to the patients has to be done carefully in order to not bias their behaviour towards what they think would be a positive outcome of the study.
In a vacuum of information, there is a risk that patient volunteers will seek out information — and potentially find that information — from fellow study subjects, therefore compromising the integrity of the study.
Providing even generic clinical trial information online to raise public awareness may help. In a study of 1,013 U.S. adults, only 34% had even heard of clinical trials.6 Certainly more could be done to better educate participants about the clinical trial process in general. There are patient-friendly generic materials available online, which can be a great help to an organization wanting to promote awareness. Instead of spending considerable effort in creating new material, it is likely to be far easier to simply make sure patients have easy access to this information (e.g., by web links, embedded YouTube videos, etc.).
Motivators represent one side of the story and barriers for participation another. There are several reasons patients cite that prevent them from participating in clinical trials, including:6
While many of the patient concerns are well founded, many are based on myths or due to lack of information. For example, not all clinical trials use placebo and its use is governed by the Declaration of Helsinki and its amendments, with the purpose of ensuring ethical use of placebo in clinical trials.
Physicians are often the main gatekeeper for patient participation and, thus, serve a crucial role. However, physicians can also be barriers to patient entry for various reasons. There are some misconceptions regarding clinical trials with physicians as well that might influence whether they talk to their patients about clinical trials. Physicians are also often unaware of trials in their area.6
It is clear that more information for both patients and physicians would help alleviate some of the concerns and better promote clinical trial awareness. Trying to educate patients only via physicians/investigators might not be the best strategy, as patients may be unwilling to ask questions about a study despite trusting their doctor. Many physicians also state that they do not have enough time to spend with patients to better educate them.7
Once these motivators and barriers are understood, they can be better addressed. To support the altruistic or information motivations of patients, they can be provided with patient-friendly materials that support these needs. During the recruitment process, this information can be provided using pre-recorded online presentations or videos that specifically target these needs with topics like “Why is this research important?” It is also important to reinforce the messaging during the study to help engage the participants with the research. This can be efficiently done via online newsletters or a study webpage with relevant news about the disease, the treatment, or the study itself. At the end of the trial, patients appreciate being informed of the results.8 In a study from 2008, 89.3% of patients had “complete or high satisfaction” with a phone call from the study site regarding the study results. Patients were also very satisfied (82.1%) with a teleconference that was organized for the patients. These proactive methods were clearly better received than the press release from the sponsor (50% satisfaction). Electronic methods, such as simply emailing a link to a video or a website, can make delivering this information to patients even more efficient and less intrusive.
Finding and recruiting patients is only the beginning of the clinical trial process. At times, it is often more important to retain the patients already in the trials than to recruit new ones. Study dropouts cause difficulties in data analysis due to missing data. These patients also use up the study’s resources without always providing data that can be reliably analyzed. Some of the most common reasons for study dropouts are:
Perhaps some of these issues could be avoided by ensuring that patients are better informed about the study in the first place. Most trials can anticipate some of the expected side effects, and these can be explained to the patient. Unexpected new symptoms can be a cause of concern, but if a particular side effect is known from the start, then it may be more acceptable to the participant. Healthy volunteers lack the motivational factor of an active disease that requires constant treatment and attention, as they have no health-related expectations for themselves. The same effect may apply to individuals who experience a beneficial treatment effect and feel better. The efficacy of the investigative product might in some cases take the treatment off the top of the list of things to do with these participants. Explaining the mechanism of the treatment might help keep these participants motivated to stay engaged with the study until the end.
The problem often is that the Patient Information Sheet has turned into a legal document rather than something the patients can easily absorb. Perhaps it is time to rethink the way study information is delivered to the patient to make sure they are properly informed without burdening the site and expecting it to summarize the key information to the patients.
Electronic methods can improve this process in several ways. First, information can be provided in richer format, using images, video, and hyperlinked content, which make it is easier for patients to find the information they are looking for. Information can also provided in different levels; for example, the study can be summarized in short format using a structure that the patient can expand to find more specifics.
Information delivery is one part of the equation, but the most important aspect is the result. With electronic tools, the informed consent is easy to make performance-based, where the participants are presented with a quiz at the end of each section or at the end of the process. Getting some of the answers wrong does not mean the participant fails, but it provides very valuable information for the study site to address when they next see the patient. Electronic informed consent can also track behavior automatically, and the site staff can be provided with not only the quiz results, but also information on how much time the participant spent reading (or not reading) each section. Sites can then address the gaps during the visit, thus ensuring that the participant has an adequate level of understanding before signing the informed consent form.
Enrollment and retention
Once a potential patient is interested in a study, the next step often is to check if the patient is suitable for the trial and meets the inclusion/exclusion criteria. Study protocols can be fairly complicated and restrictive in this matter and considerable effort is required to screen and qualify patients. Automating even parts of this process with technology in order to save the burden from the sites and subject candidates can yield significant efficiencies. In one example, a study used a call center to pre-qualify patients (see Figure 2). They were then sent to complete a questionnaire via an interactive voice response (IVR) system, and if qualified, only then were they sent to the study site to complete the screening process.9
Had the original 33,000 patients been screened by the sites first, the costs and time would have been astronomical. On average, the effort to screen a patient has been estimated to cost between $129 and $336, depending on study phase. If an average of $232 is used and applied to the example above, the savings at the site-level could be estimated at more than $7 million. Operating the call center and the IVR system have costs associated with them as well, but by centralizing these functions and using the right technology, it can make for a far more efficient and user-friendly approach. Further, user convenience and cost efficiencies could be achieved by utilizing a suitable online system for pre-screening.
Once a participant has been successfully enrolled into the study and they have been appropriately informed about the trial procedures, the actual study can start. Patients are typically sent home with a binder of information regarding the activities expected of them between the visits. This can be a problem, as the patient might have misunderstood some of the procedures. They might not be taking the medication as instructed, or filling in their diaries as regularly as they should. It can be difficult to even remember when the next visit is and how to prepare for it. Post hoc evaluation of completed FDA Phase III trials have reported protocol violations ranging from 15.6% to 24.9% in all enrolled patients.10 This number could be reduced by keeping closer track of the patients and allowing them a convenient channel to stay engaged with their study site between visits. For example, replacing paper binders with a more sophisticated electronic system that is study-protocol aware can be advantageous. Some electronic tools, such as electronic diaries for clinical outcomes assessments (eCOA), allow near real-time visibility of the patient’s activity for the sites and enables proactive, on-time intervention that can prevent small issues from becoming protocol violations. Just the fact that the participants know they are being monitored is likely to increase their compliance; many eCOA systems report an average diary compliance rate of more than 90%.
Technology and innovation
Some sponsors have already proven that the virtual study model is feasible. However, it does not mean that all studies should go completely virtual right away. Technology usually only works when the right solutions are applied to the right problems. That is particularly important in clinical development, an environment that requires significant change-management efforts. Applying technology without reconsidering the processes where it is applied often means that the expected returns on the investment are not achieved.
New technologies are emerging to support patient recruitment and engagement in clinical trials. Some services help patients find suitable trials in their area, while some companies produce solutions for electronic informed consent. Electronic data collection directly from patients has been routinely deployed in many kinds of trials for several years. While many systems do have integration capabilities, it can still be quite a puzzle to put all these systems together. Sometimes the different systems have overlap between each other and sites might need to key in the same patient information into several systems. One of the most frequent complaints from the sites is that they already have too many systems to work within a single trial. Many centers and staff work with several trials at the same time, all of which can use different systems. The needs and requirements of patients and sites should be taken into account, as well as the existing technology infrastructure in place at the sponsor or study sites. Change management is likely to be the key to ensuring buy-in of all parties and is an important factor of overall success.
Technology by itself is certainly not going to solve these challenges. Considering the current obstacles with paper-based methods, it does promise improvement, especially for sites and patients. It is likely that in the near future there will be technology options that will provide an improved user experience for both site personnel and patients. By focusing on providing the sites and patients with the right tools to perform well in their trials, the sponsor companies will ultimately benefit in terms of faster recruitment, better visibility, and higher quality data for their analysis. No matter how good the technology is, it needs to be used in the right way. Doing so often requires some process re-engineering, training, and monitoring in order to get the best results.
Kai Langel, Principal Consultant, Co-Founder, and Director, eClinicalHealth Ltd., [email protected]