ETM: The Next Frontier

With all the attention being paid to new electronic data collection alternatives, or which clinical data management system should we migrate to, the stepchild of clinical research software, electronic trials management (ETM), continues to be underfed. This is not for a lack of trying: many sponsors have been working on their own systems for years or implementing vendor products, and CROs/SMOs are certainly aware of their need, but have been frustrated by the cost (in dollars and time) of implementing solutions which are ultimately unsatisfying.

At the recent Executive Forum on Electronic Trials Management, sponsors, vendors and service providers gathered to discuss these critical issues. The problems (or needs) fall into two buckets technology, and process. The former, it turns out, is always easier to fix than the latter.

In technology terms, current ETM software exhibits a lack of focus on who the true users are (and there are several, all different). The result is a hodgepodge of products which, when implemented, seem to serve the needs of a few and aggravate the many. The market’s frustration, expressed in many phone calls to us, is that be they sponsor or CRO or SMO, they can’t seem to find the right product for what they want to do. Part of the reason is that ETM is a very broad field, and probably needs products that are more modular and tailored.

Both sponsors and service providers appear evenly split between those who have gone to a vendor product and those who decide to write their own. There are strong arguments on both sides, but ETM can mean something so unique to a company that building your own makes sense. Any number of platforms are apparently equally effective Oracle, Notes, SAS, Microsoft.

What we heard at the Forum, and hear from customers repeatedly, is how critical it is for ETM functionality and data to be integrated with the other clinical research software components EDC, adverse event reporting, CDM, lab information, patient recruitment. Very few vendors even begin to offer such integration or know how to help you achieve it.

Process Issues at the Core

The people, political, and logistical obstacles to effective use of ETM are more problematic than the technology questions. Sponsor initiatives fail the most when the ETM program is designed to only feed information to upper management, without giving anything back to those down below entering the data. This is a surprisingly common error, producing powerful negative feedback. Upper management is pleased at the aggregated reports they are getting from the system, while those actually in the trial trenches say that those reports are inaccurate and out-of-date. Why? Because the application doesn’t provide the end user what they need in their daily work, greatly reducing their incentive to enter accurate data on a timely basis.

Another source of failure within large sponsors comes from the nature of the problem ETM is trying to solve to provide interdepartmental aggregated information. This means the application crosses the “silos” of clinical, monitoring, data management and safety. If your company’s silos have thick concrete walls, their willingness to participate in the successful design, implementation and use of ETM will be severely diminished.

These two problems, and many more like them, lead to a huge price tag in dollars and time for implementing an ETM application. Several sponsors report very high costs and years of effort. If the design and implementation of the application was seriously flawed, this is a embarrassing waste. And worst of all, if it takes too long, the application’s technology base will be obsolete by the time it’s implemented.

Service providers have some different challenges in adopting ETM. First, in many ways ETM is even more critical to them than to sponsors. Trials management means business management to a CRO or SMO, and so they are thinking about proposal management, billing histories and scheduling as much as they are about enrollment and data quality. The possibilities of value for a fully integrated application to a CRO or SMO are incalculable, and yet almost all such companies are reluctant to spend the money necessary to build a necessarily complex mission-critical application. Some public CROs still run their business on spreadsheets; it might work, but what’s being missed is enormous.

Why ETM Anyway?

Sounds like ETM is a difficult challenge: too many kinds of users with too many different needs. Why shouldn’t it stay a stepchild? Because ETM is at least as important to Time to Market as other research technology initiatives.

A month saved is a month saved, whether that month comes at the beginning of the project or at database lock. Knowing your progress in patient enrollment, the data quality level from different sites, where study drug supply should be and when, which monitors or CROs are underperforming, are critical to timely trial completion. This information needs to be known in as real time as possible, and only an electronic means can make that happen.

The lessons learned indicate that sponsors need to simplify their ETM efforts and ensure all users benefit; service providers need to spend enough money to get the value awaiting them. Both constituencies need to bring ETM out of the shadows and focus their creativity on using technology to gain control of their trial programs.

EDC is Off the Back Burner: Is the Right Dish Being Cooked?

For those of us who have worked for many years to help the industry redefine clinical data processing, it is highly gratifying to see substantial interest in electronic data collection (EDC) not only spreading broadly across the industry, but also creating an air of “inevitability” for EDC use. As we sit down to our holiday dinners, I worry that now that EDC is off the back burner, do its purchasers think of it as the grand turkey in the center of the table, or the acorn squash in the corner that only the more adventurous health nuts make room for?

Do companies now laying plans to adopt EDC really understand what EDC is, and what it really allows them to do?

Understandably, EDC acquisition or use decisions are usually made by, or involve, clinical data managers, IT personnel and regulatory staff. These folks usually bring to the table a structural picture in their mind of clinical data processing — a picture which is “CDM-centric”. In this picture, EDC is only a moon orbiting the CDM sun, along with other moons, like trials management and adverse event systems, and asteroids like drug supply logistics and site communications.

This approach will set back the adoption of EDC many years. Why? For at least 5 key reasons:

Today’s EDC tools are moving closer to full CDM and ETM (electronic trials management) functionality.

As EDC use increases (and its functionality broadens), CDM’s usefulness is increasingly marginalized.

A CDM-centric approach, to have any logic at all, would require study designs to be built in the CDM application, none of which are designed to take advantage of the process and usability improvements EDC applications bring.

Dramatic improvements in drug development depend entirely on sponsors becoming Site-centric, which a continuing focus on CDM prevents.

Clinical staff, and sites themselves, must become equal, if not greater, partners in the design of any sponsor’s next clinical data processing system.

What is the basis for my concern? Recent industry meetings, while gratifyingly filled with EDC stories, indicate sponsors are using it marginally, without applying adequate resources, or assuming it should be limited to a handful of trials, or show a reluctance to use EDC technologies which stray more than a step or two from paper.

I am also concerned for the vendor community. Our recent report on the EDC market, now available to the industry as a whole, reveals dozens of groups attempting to provide sponsors with an “off-the-shelf” solution for EDC, but even those who “deserve” to survive cannot possibly do so if sponsors think of their offerings as a side dish.

A picture for the future of clinical data processing would look more like the following: A data warehouse underlies all clinical development applications, whose interfaces to all users share a common look-and-feel. The dominant application sitting on top of this warehouse is electronic data collection (now encompassing many traditional CDM functions, including study design and CRF standards, coding dictionaries, query management, and even a path for entry off of paper CRFs). This EDC application is wrapped in an ETM envelope, deriving data from EDC and sister applications, feeding the data warehouse, so that management can have a single integrated view of the progress and quality of the trial, the danger signs, the unexpected good and bad news. In this picture something akin to traditional CDM remains, but is used only for specific, limited, reporting and export functions feeding analysis and submission.

Why should sponsors hang this new picture in their dining room? Because it is only through focusing on what happens at the site, and involving the clinical operations staff in accelerating that activity — recruitment, evaluable patients, rapid identification of problem enrollment or poor CRF design, keeping to the study schedule, and real-time data cleaning which will lead to rapid database lock, timely decision-making, and compressed development timelines. EDC is the catalyst (not the answer in itself) to this crucial process change.

It is in this context that a sponsor’s strategy for adopting EDC must be considered, and potential vendors subsequently evaluated. To view EDC as a satellite to CDM will hobble EDC’s contribution to accelerating drug development and lead to inevitable disappointment in its ROI. To view EDC where it belongs, as the trigger to a clinical data processing re-design, is the key to realizing the benefits that have long been promised but rarely realized.

Make sure you give electronic data collection and trials management the right opportunity to shine at your table. It is the main dish: prepare it correctly and you will feast on the results.

Preparing for the Tsunami

As I write this, Armageddon is the top summer movie, high-profile drug withdrawals are calling into question whether our industry is doing enough pre-market testing, and the rapid changes in drug discovery mean that, in the words of a top FDA official, we are facing a “tsunami” of new therapeutic candidates. We seem to be at the forefront of the latest fashion for end-of-the-millennium disasters. Are you ready for this?

This is a serious question for all players in the development phase of the pharmaceutical industry. We are familiar with the statistics showing how the number of trials, patients in trials, and trial complexity have already been rising rapidly, accelerating the cost of clinical testing. This creates a feedback loop of questionable business strategy: companies are driven to find the blockbuster candidate, as quickly as possible, because who can afford to test a drug that will make “only” $100 million a year? They can’t all be blockbusters, and some important therapies that people need will never generate blockbuster revenues.

The recent market withdrawals highlight the gap between testing drugs in “real” use situations, as distinct from “artificial”, or what we would call “scientific”, controlled use conditions, and they also highlight the increasingly impossible task of testing for all possible drug interactions. Pfizer did not anticipate the need for a Phase IIIb study of Viagra in 80-year old men with heart conditions. And as more and more of us are taking more and more drugs, on a daily basis (our lipid-lowerer, our half-an-aspirin, our bone-loss inhibitor, our St. John’s Wort), the “normal” patient using a drug in real life will not be taking it in a vacuum. How do we anticipate the potential for problems?

Press attention will blow over, but the wave of discovery candidates will only build higher. Add genomics and pharmacogenetics to combinatorial chemistry and high-throughput screening, and not only are we pumping out many more potentially active substances, but we may end up developing 8 flavors of the same SSRI or COX-2 inhibitor instead of one. Are clinical development teams going to be faced with doing a suite of trials on all the flavors? Even without genetic tailoring, almost every company talks about significantly increasing the number of NDAs to be filed each year.

The first group to be hit will be the preclinical departments, a world until now relatively immune from re-engineering, time pressures, and the spotlight. But they are living right on the shoreline where discovery’s waves break. Will we be doing rats and dogs for the rest of our lifetimes, or will the very nature of drug discovery, at the molecular and gene level, enable us to devise preclinical testing methodologies radically different, faster and more productive than today?

Managing Armageddon

There are numerous implications for drug development in these trends we have described. Drug interaction dilemmas can be greatly served by improved use of safety surveillance procedures and technologies which already exist. Numerous schemes are available for electronic transmission, including Web transmission, of medWatch forms, for instance who and how do we get physicians to use them? A major initiative among industry, government and healthcare providers is needed to take this issue more seriously.

Preclinical will need to wake from its slumber and confront the changing demands it will be facing. Sponsors are likely to take the lead in blurring the line between late discovery and early nonclinical development in order to filter the volume of candidates to a more manageable size. Nonetheless, we will need to expand the capabilities of pre-human testing, and the implication of the blockbuster business strategy is that we must speed the results and analysis of preclinical testing to accelerate decision-making. Enhanced computer-based reporting tools will be critical to make this happen.

I think a new area of clinical research will have to open up: “real use” trials. In the foreseeable future we can imagine this becoming a regulatory advantage, if not a requirement. What are the implications? Will this be where organized healthcare providers demonstrate their unique contribution to clinical research, be they PPMs or SMOs or some new useful combination? How will we reconcile real, dirty data, with the controlled research model at the heart of our traditional research? New statistical models, and information technologies which make real use data collection easier, will be required.

And more than ever, we will need to continue to change the fundamentals of the clinical research process. We must push forward on processes and technologies which slash study startup time, accelerate enrollment, and eliminate paper: get the data right the first time, accelerate locking a clean database, and simplify electronic submission.

There’s no going back to an “easier” time. Public and business pressures are likely to increase. Even the causes of change are not what we thought they would be a few years ago. So continuous improvement in our processes, and creative application of ideas and information technology, will be essential to keep up with this spiral of change. Let’s keep the tsunami on the movie screen.

Jimmy Durante Was Right

Jimmy Durante had a repertoire of famous phrases (“ha cha cha” comes to mind), but in thinking about clinical research, the phrase that recurs is “Everybody’s gettin’ inta the act!” Our industry is both blessed and plagued with new businesses every month new SMOs, new CROs, new software players, new service or product niches we didn’t know we needed.

We are blessed because sometimes these companies represent at least the possibility of innovation, in a business sorely in need of new ideas. (Actually, there are plenty of new ideas; we need people to start applying at least some of them.) We are plagued by these new companies sometimes, often by their evanescence, and almost always by their incompleteness. They can be incomplete in their thoughtfulness (as evidenced by products or services brought out too early or with too many holes), in their business infrastructure (they are usually undercapitalized, under-staffed and overpromising), and in their market understanding (for which, while annoying, we can be more forgiving, because they will learn quickly or die).

One of the curses of the state of software today, for instance, is one of the most important developments in that industry: tools for rapid application development (RAD). To some extent, this leads to a situation in software development not unlike the curse of desktop publishing tools or consumer video cameras. The tools are “so easy” to use that anyone can use them, and unfortunately, anyone does. The results in document design and home videos are known to us all; in software, the “ease” of RAD leads to products in tradeshow booths whose flaws may be less obvious.

What this means to the clinical research professional is that ever more care and diligence must be taken in examining new technologies to serve us a fact that co-exists with our ever accelerating need to adopt information technology to improve our trials processes. Those of you specializing in studying these technologies for your institution will play an increasingly critical role as you help sift through the new products and services being offered.

Internet-related products will certainly be a focus in the coming months for this kind of hopefulness and appropriate skepticism. Many vendors or CROs are hurrying to bring out “Web-enabled” versions of their products, reports, communication tools, or other services. Many sponsors are equally guilty of exhorting their staff to “do something with the Internet” this. Some of these products and services will be very valuable; others will be only “web-dressing”. How do you tell the difference? By following the same analytical means described in earlier columns:

Consider your needs first; not the vendors’ features

Examine the vendors’ vision and intent as much as their products

Study their business infrastructure as much as their brochures

Test their flexibility in working for your needs

Test their understanding of how their product or service will impact the daily work of your organization.

Can SMOs Afford to be SMOs?

I have similar concerns about service providers as I do about software vendors. Site Management Organizations (SMOs), in theory, should be able to offer significant advantages to the clinical research process: accelerating study startup, simplifying contracting and communication, ensuring more professional sites and thereby cleaner data, and more. Not the least benefit of SMOs should be the pressuring of CROs out of their complacency and into a clearer definition of their unique value to the process.

But these benefits are not yet obvious to the bulk of the sponsor community. Success stories are isolated or sometimes harbored for competitive advantage; in other instances, the benefits objectively have not been demonstrated. Meanwhile, it remains uncertain how SMOs make money, and how they will find their way to a business model able to reward the aggressive expectations of their investors.

This relates directly to information technology. SMOs are operating in a narrow space between investigators, CROs, sponsors and investors, and only by proving their value will their companies gain in value. One of the most important values an SMO can bring to the clinical research process is the creative application of information technology for trials management, patient recruitment, study documentation, and clinical data capture. By being an administrative layer intimate with the site the heart of clinical research the SMO can gather and deliver information of unprecedented usefulness to create sorely needed efficiency in trial conduct and project decision-making.

But very few SMOs are making the commitment to information technology to make this happen. They talk about it, sometimes sincerely, but have been hard pressed to make the investment. It does cost something to create the IT infrastructure that brings this value. And considering the economics of trials as managed today, we have to ask, “can SMOs afford to be SMOs?” Can they afford to deliver the value they have in their grasp? The answer to this is critical for sponsors to understand, and for all those forming the latest SMO-of-the-month.

Jimmy Durante also used to say, with a tip of his hat and a gleam in his eye, “You ain’t seen nothin’ yet!”. To a disappointing degree, we’ve seen a lot of nothing from new companies (or new products from old companies). Let’s hope Jimmy was right, and we will see real value being offered, and have the wit to recognize it when we see it.

You Are Misunderstood

You are a CRC or CRA. You are swamped with paper. Your life is paper. Charts, CRFs, Labs, Reports, Queries. Pharmaceutical companies ¡© the people paying for the clinical research which is your livelihood ¡© think you are afraid. They think you prefer to work with all that paper rather than be faced with that “frightening” contraption, the computer. They think you won’t use it. That you can’t use it. That you’re not smart enough, or creative enough, or innovative enough. They don’t realize you are already using computers in your home, office or site. They don’t realize that among yourselves, you are imagining your own computer solutions ¡© drawing dreams on a paper napkin, or programming your own applications with a spreadsheet or word processor. They don’t realize that, in fact, many of the most active research sites have already used EDC tools, and depend on computers for study tracking, and are willing to use their computers more, if only the software was improved. Pharmaceutical companies have convinced themselves that you are too busy, too rigid, or too disinterested to learn how to use technology to replace the paper covering your desk. You are misunderstood.

You are ignored. You are a site director or investigator. When a pharmaceutical company is considering the design, acquisition or implementation of a new computer application for clinical research, you are ignored. Yes, you will be expected to use it, and they will be impatient when you find it hard to use or make errors, but you will not be asked about it while they are building or buying it. Several informal surveys of pharmaceutical company application projects, whose use involved the investigative site, have found that despite months of meetings, planning and design debate, no site was ever invited in to comment on the application, explain the work environment, or communicate their ideas for how computers can improve their daily real-life work. You need to make yourself heard ¡© in conferences, in meetings with your clients, in your professional associations.

You are mistrusted. You are a clinical project manager, whose responsibility to your company is to get this new drug out on time, on budget, or kill it before you spend too much time on a dead end. The site mistrusts you for checking up on them all the time, and for your obsession with the timetable instead of the drug. Your data management colleagues think you don’t appreciate them, and that you will try to go around them to use new technologies, or use a new CRO, just to avoid them. But you hold more power than anyone to change things, and many of the improvements in the process have come from the vision and innovation of individual project directors.

You are resented. You are the clinical data manager, the protector of the data, the data upon which the sponsor’s submission will succeed or fail. You established detailed SOPs, you enter the data from the CRFs, and enter it again. You check the data over and over, spending hours ensuring cleanliness, proper procedure, and rigorous security. You struggle with outdated computer systems, with code held together with gum and rubber bands, and yet you get the job done every time, and the submissions are completed. Through it all, you raise concerns and push back on vague ideas for improvement that have holes in them like craters. You protect the data against unproven technologies for the sake of the company. But the world is not standing still around you, and if technologies or processes are inadequate you must nurture those vendors or colleagues who can join with you to help.

You are in the middle. You are the CRO, that extra staff, the outsider brought in to carry the load the sponsor cannot handle themselves. You see the clinical research process with an outsider’s eyes, yet you get your work from someone asking only for performance, not innovation: “Do it for me, my way, as fast as you can.” You hear the misunderstood study coordinator, you see the ignored site, you get your work from the clinical project director, you understand the concerns of the clinical data manager. Somehow, you have to make sure all these players work together so that your project is a success. In fact, many CROs have proven their value-added in just this manner, achieving success where the sponsor alone could not.

We all need to understand. We all need to respect each other’s responsibilities, and yet not be stalemated into inaction by our sensitivity. The clinical research process is serious flawed; proper use of enabling technologies is critical to improving this process. Too often, technologies are not adopted because key users are ignored, or key staff erect obstacles based on sincere professional beliefs. The consensus to move forward, which senior management so wishes it could find, remains elusive. This is fatal. Understanding each other’s perspective is an important first step to joining together for change. We all must trust each other, to change together, to step off the line and move, with enthusiasm and mutual respect.