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Applied Clinical Trials Digital Edition - August 2011, Supplement

CRO/SPONSOR : Clinical Contracting Efficiency Can Save Millions  REGULATORY : Common Technical Document Development - A Partnership Approach  Also in this issue : FDA Looks to Collaborate Overseas, EU Reviews, Clinical Trial Rules, Meaningful Web, Greater Trial Insight

Applied Clinical Trials Digital Edition - August 2011

The European Union is going ahead with the review of its clinical trials rules, and many of the key figures in the European clinical trials community are worried that time is running out for them to influence the way the debate on the new rules will shape up.  

Everyone agrees that some change is needed to the rules. The question is what sort of change, and how much of it. European Health Commissioner John Dalli has clearly indicated that he wants new rules: "If we want to continuously stimulate pharmaceutical innovation in Europe and give patients access to the most recent healthcare, we will need to revise our legislation on clinical trials," he said recently. He acknowledges that the current framework "has led to complicated procedures, in particular for multi-national trials." But he has not indicated how he aims to remedy this. 

Right now his staff is working on an assessment of different options for changes, and by early next year a legislative proposal is scheduled to appear. This will then go into the EU's legislative machinery, where it will be kicked about by the European Parliament and by national ministers of health meeting in the EU Council—who, between them, may accept, amend, or reject the proposal. 

Many in the clinical trials community in Europe are nervous that the deficiencies that they have suffered from since the current rules were adopted 10 years ago will not be fixed, and that the legislative process may deliver something not much better than the existing framework, or even make it worse. One of the main fears is that new rules will not prevent each country from continuing to insist on its national mechanisms, invoking "cultural differences" and similar arguments for ducking out of a European approach.  

This is why the European Forum for Good Clinical Practice (EFGCP) and the European Organization for Research into Treatments for Cancer organized a joint meeting of interested parties in Brussels in July. "We cannot afford this nationalism anymore if we want to rescue clinical research for Europe," said the background papers for the meeting. According to Ingrid Klingmann, the EFGCP chair, the resistance comes from the member states. The competent authorities and the ethics committees in particular are not keen on changes to the existing legislation. The approach favored by EFGCP is to initiate public discussion nationally and with the European Parliament before the new legislative proposal is on the table, so that once the draft text emerges, the debate will be more focused and more predictable.  

More than 100 clinical trials professionals from industry, CROs, academia, patient associations, the medical profession, ethics committees, and regulatory agencies convened to explore what they could usefully do to improve the prospects. Their discussions centered on optimizing the clinical trial approval system, developing a risk-based approach to clinical trial documentation, supervision, patient liability insurance, dealing with peculiarities in patient populations, and improving trial designs. As Kevin Loth of Celgene put it, "Success is dependent on a sufficient level of detail within the legislative framework." As his remarks implied, the right sort of detail was equally important. 

Angelika Joos of MSD outlined how a single submission with a coordinated assessment procedure might make the approval process more consistent across Europe, and accelerate the conduct of clinical trials while reducing administrative burdens. Subsequent discussions ranged across issues such as how to ensure access to the right expertise, or how to deal with disagreement with the assessment among the member states. A common submission dossier might force some standardization into applications, but could result in a very long list of requirements. 

Jacques Demotes of INSERM and ECRIN outlined some of the considerations in developing a risk-based approach to clinical trial rules. His tentative recommendations were for a stratified—top-down—approach through adopting a system based on risk categories, alongside a personalized—bottom-up—approach with a broad group of stakeholders generating guidelines that could be applied to individual protocols. 

Participants examined some of the questions raised by this debate—including how far new legislation should drive clinical research that is considered "meaningful for society" (a concept itself open to multiple interpretations), how far rules should distinguish between trials related to authorization and trials related to comparative effectiveness, and how to keep the focus on the patient.  

Detlef Niese of Novartis teased the audience with some provocative reflections on specific requirements for trials in emergency research in patients unable to consent, in research in children, and in conducting clinical trials in developing countries.  

In reflecting on clinical research in children, participants pointed to the potential psychological distress over and above any medical or physiological risks that clinical trials may expose children to. They agreed there is a need to consider methodologies of trials more intensely; to avoid unnecessary pain, fear, discomfort, and risks; and to define requirements more strictly. 

The discussion of developing countries noted the limited access to healthcare resources—and approved medicines—for a large proportion of the population, because of widespread economic deprivation. Deficiencies existed regarding the legal system and the protection of human rights, including, but not limited to, good clinical practice. Emphasis was placed on finding the right partner, and ensuring adequate understanding among researchers from developed countries about the legal and ethical framework and the local situation in developing countries. Involvement of civil society—patients groups and local communities—was recommended, especially for risk assessment and informed consent. 

There was wide support for clinical trials in developing countries applying the same principles as in the EU, with research participants being guaranteed the same level of protection, and for demonstration of the merits of a trial for the health needs of the local population. In the same vein, the principle of benefit sharing should apply so that there is access to the product if it is proven safe and effective. 

The disparate assortment of people that assembled for this meeting cannot yet be described as a coalition—although the participants indicated by a show of hands that they are ready to explore the creation or adoption of some formal personality to maximize their impact on the upcoming debates. 

Whatever the shape their lobbying exercise takes, they are going to have to shout loud and in unison to make their voices heard. They are going to have to do more than shout loud—they will have to make sure that what they are shouting is clear and simple enough for people who know nothing of clinical trials, and care even less. 

They focused their discussions on what they described as "areas of particular complexity for the new clinical trials legislation"—but for nearly everyone in the outside world, any area of clinical trials is already of particular complexity.  

They may not like the idea of resorting to vulgarized communications and memorable slogans, because such an approach is naturally alien to intellectually refined doctors, scientists, and industrialists. But the nature of public and political debate in Europe may make it necessary.  

The discussions among the participants are still a long way from clarity of agreement or of presentation, and if they really want to intervene to influence this debate, they need to move pretty fast to get up to speed. For instance, the meeting displayed a desire for "more professionalism in ethics committees—but not professional ethics committees." Some difficulties in persuading unsympathetic audiences of the merits of such highly refined positions can well be expected. 

The coming weeks will make clear whether the distinct component groups in the clinical trials community are ready to make the compromises in their own positions that will allow the confection of a message that is simple and clear enough for public debate. 

One of the challenges will be to generate some enthusiasm for public discussion of a subject so remote from most people's (and most politicians') knowledge base. Since it is very hard to win (or even make) an argument on a subject that no one knows about (and therefore automatically doesn't care about), this loose coalition seeking more effective clinical trial rules is going to have to get the guardians of the public (politicians, officials, diplomats, ministers) on their side. This can be done more effectively if, even before the lobbying exercise commences, the profile of clinical trials—the positive aspects of clinical trials—is raised significantly. Only then, on that basis, is there a real chance of being able to argue a case. Without investment in such energetic efforts, the clinical trials community may remain merely unheard victims amid the hubbub of voices expressing diverse—and often contrary—views.

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

View from Brussels

A meeting in July to discuss changes to the old rules explored the need for compromise across the industry.

Change the CT Rules, but to What Precisely?

Information provided to clinical trial participants during the consent process is lengthy and difficult to understand—or at least that's the common belief. There's an urgent need to improve the information supplied and work out how sponsors, researchers, and subjects can work together to influence law, policy, and ethics and hence change these regulatory requirements and current culture. 

Brussels will be the location for the EFGCP’s annual conference on informed consent.			

This is the crux of the latest message from the European Forum for GCP (EFGCP), which has pledged to focus its efforts on reforming the consent process over the coming months. 

"It has long been recognized by all groups that the information for potential participants is not fit for its purpose—to explain a research study to someone considering whether to join. The current regulations and culture that demand 'Information by Volume' do not lead to informed consent," noted the EFGCP in a press release dated July 7. "It's time for change, but how can we bring this about?" 

At its annual conference, to be held on January 24-25, 2012 in Brussels, Belgium, EFGCP is concentrating on improving information and empowering patients. It will address the questions: What do patients want and need to know? What are the barriers to change? Can a risk-based strategy help? Who should be persuaded of the need to change? Can ethics committees ensure adequate and complete information? How can you deal with trials in emergencies and unconscious patients? 

The delay from consent rituals in emergency situations has important consequences and results in avoidable mortality and probably morbidity in participants in the trial, noted Prof. Ian Roberts of the Clinical Trials Unit, London School of Hygiene and Tropical Medicine, in a letter published in 

"Far from protecting the interests of patients participating in research, requirements for written informed consent and the resultant delay in starting treatment could be lethal," he wrote. "The delay in starting treatment can obscure a real treatment benefit from the administration of a time-critical treatment." 

The need for an urgent trial treatment excludes the possibility of fully informed consent, even in patients who are conscious and whose relatives are available, according to Roberts. Informed consent procedures, like other well-intentioned public health interventions, should be assessed rigorously, he pointed out. 

Roberts and his colleagues studied data from the Medical Research Council's CRASH Trial, a multicenter randomized controlled trial of corticosteroid administration in acute severe head injury, which provides an estimate of the delay associated with the requirement for written consent. On average, compared with hospitals that waived the need for consent, initiation of treatment was delayed by one to two hours in hospitals where written consent from relatives was required. This delay would not occur if the treatment was given (or withheld) outside the context of a clinical trial, in normal clinical practice, they wrote. 

At the EFGCP meeting, workshops will discuss how technology can improve the consent process, how to teach investigators to better inform participants, and experiences with national differences in information package constitution. Plenary sessions will address the cultural aspects (particularly in developing countries), the challenges in ensuring that patients are truly informed in the ICH regions, and what ICH regions can learn from the informed consent process in developing countries. 

EFGCP intends to publish a report for wider dissemination, and aims to change the regulatory requirements and current culture. EFGCP is a non-profit organization established by and for individuals with a professional involvement in the conduct of biomedical research. Its purpose is to promote good clinical practice and encourage the practice of common, high-quality standards in all stages of biomedical research throughout Europe. 

For more details on the annual conference, contact 

Global News

The EFGCP annual conference in January aims to improve information and empower patients.

EFGCP Advocates Change to Consent Process

My newspaper didn't arrive this morning, so I had to view it on my iPad. As a result, I read it much more quickly, since it was easier to focus only on what I found truly interesting.  The print version has been wasting away over the past year anyway, a mere shadow of its former self, denuded of most of the ads that used to comprise much of the printed bulk. This week's printed 

 was a tad more than a pamphlet, though it appears much more substantial in the iPad app, which doesn't readily betray how thin the printed content would be. 

We've been paying our bills online for some time now, though a number of our creditors still insist on sending us a paper invoice. I can't remember the last time I saw someone use a leather-bound day-timer either—unless it included a pocket for their smartphone. Then there are those bulky yellow pages books—which we threw right into the recycling last time since it's so much easier to look up phone numbers on Google. 

My employer has an automated app for just about every administrative business process from training, to performance reviews, to expense reports. In fact, expense reports are pretty much the only things that still involve paper—for receipts, which I need to scan. I much prefer getting e-receipts sent right to my e-mail address, since they save me part of that effort. 

Then there's my toxic wasteland of a desk. Whenever I search for anything on my computer, odds are I'll find what I want. But I can't tell you how many scraps of paper on my desk I've lost. I have a friend whose desk is always clean. Every time he gets a scrap of paper, he either moves it to disk or just chucks it.  I've never searched through his computer, but his office is as pristine as an operating room table.  

Now, let's segue to clinical research. Thanks to HITECH and other global initiatives, more and more physicians are implementing electronic healthcare record systems, and entering patient data as well as prescriptions directly into the system. Lab tests are conducted by devices, with reports output electronically. Regulatory-relevant documents are almost always created on a computer, and submitted to regulators in pdf and xml electronic formats. Yet CRF data is still typically first recorded on some sort of paper source document before being entered into a system. So why exactly do we still feel a need to use so much paper in clinical research? 

Paper's more secure, some say. Well, except in the rubble of an unexpected disaster, or when you just lose it. And what about those disturbingly confidential patient lab reports that are somehow mistakenly sent to my home fax several times a week? 

Paper's better for audits, others feel. Yet how difficult is it to edit a document and print out as many variations of it as you need to address various tiny issues? Even before the days of image enhancement tools, a touch of Wite-out and a copy machine were able to do wonders to tweak a paper document. 

Paper's necessary to meet regulatory requirements, many persist in believing. But 21 CFR 11 is over a decade old, and ICH e6 Guidelines for Good Clinical Practice don't include a single reference to paper—though there are some 40 references to "records" which might be electronic or not.  

So does source data and regulated information really have to be on paper? Or does it just have to be able to meet some of the same requirements as paper documents in a credible fashion? In other words, can we reproduce the digital version of such information on demand for review, and can we verify who authored it, when, and that it wasn't changed—without a paper crutch?  

To find paper, we need to index and file it. But a physical piece of paper can only be filed in one place at a time, whereas a digital piece of information can be linked in many ways to many different catalogs, or even concepts. Digital information can also be broken down to items, elements, and things that can be linked with many other things. 

Which brings us to the semantic web and its role in clinical research. The semantic web is already all around us—the number of available data sources in the semantic web has been doubling every 10 months since 2007. But we just don't always notice it when we interact through web browsers to access it. The World Wide Web is a way to link and access documents (which we characterize as containing unstructured data), which is fine for many purposes, but not usually sufficient for working in depth with structured data. Relational databases are one way to work with structured data, but they don't handle the unstructured stuff so well, and they tend to be confined in organizational silos and esoteric in design unless they are represented in common formats, organized around common models, and populated with common vocabularies that are consistently understood.  

The semantic web, which is sometimes referred to as Web 3.0 or the Meaningful Web, is a way to deal with this. It makes it possible for both computers and people to find things or objects on the web—and know what they mean. In some ways it's reminiscent of artificial intelligence—once objects can describe themselves with rich context and relationships it's possible that computers will begin to develop understanding heretofore limited only to the human brain. As such, it's one practical path forward to what Ray Kurzweil describes as singularity. 

The fundamentals of the semantic web seem simple enough: data objects are represented in triples in subject-verb-predicate form, and each of these data elements is tied to uniform resource identifiers (URIs) which can be looked up on the web and linked (hence becoming linked data or hyper data). These triples are often described as graph objects, much like a diagrammed sentence. A particularly useful link is the Same As link, which allows equivalent concepts or objects to be connected. But it quickly gets more complicated after that—and far beyond this author's level of understanding. There are plenty of resources on the web to consult for the details, and one well known example of the semantic web in action is the DBpedia project, which is a community effort to extract information from Wikipedia and make it available through the semantic web. DBpedia illustrates how you can access the collective knowledge of the web about a particular object of interest instead of relying on an individual database.  

But maybe we don't need to worry about the details of the semantic web ourselves—we should first concentrate on the information that belongs there. 

Now the semantic web may not be the best solution for everything—but it's ideally suited for persistent data and especially metadata that are likely to be reused or referenced by the broader research community as an ongoing source of knowledge via the web. In the world of clinical research, this would apply to research and clinical concepts that are translated into data elements in protocols or on CRFs. Ideally every instance of every trial would access a single, gold standard repository to describe each aspect and procedure of a protocol, formulate each question on a CRF, and represent each data item in the same way, so that it would be finally possible to combine, compare, and study the vast wealth of information we collect in a consistent and scientifically meaningful way. Representing metadata and vocabularies this way becomes even more impactful once we as an industry begin to embrace cloud computing, with the promise of all information stores being accessible over the net (to properly authorized users of course). 

We've used standard vocabularies to describe some of the concepts used in healthcare such as general clinical terminology (SNOMED), adverse events (MedDRA, and before that COSTART), diagnoses and procedures (ICD-9, CPT), and many others. Unfortunately, different vocabularies are used for different purposes by different organizations, and it's not always easy to translate one into another. What's more, the complex information that comprises healthcare can't be fully expressed in a manner that allows for an unambiguous computer understanding. There's a lot of hard work to identify and define concepts, organize and map across different terminologies and ontologies, and specify data elements and values.   

Now the medical informatics community has been discussing these matters for years, and many current initiatives are in progress to help define medical and clinical concepts so that computers can understand them. This goal is being pursued through multiple initiatives, including the ONC SHARP AREA 4 program, CDISC SHARE, HL7 Fresh Look initiative, the ISO/CEN Detailed Clinical Models (DCM), the European Innovative Medicines Initiative knowledge management programs, and others. Of course, it would be helpful if all of these activities converged to form a single international gold standard of concepts that could provide services to all in a semantic web infrastructure, but this might be expecting too much all at once.  

We can all contribute to becoming digital by vowing to forego paper, treating electronic information with control, and using available standards, vocabularies, and metadata before inventing our own. And we should begin to explore the potential of the semantic web for supporting such a universal knowledge repository that we'll all need eventually. 

 is Senior Director, Life Sciences Product Strategy at Oracle Health Sciences. He can be reached at 

Technology Viewpoint

The positives of "going digital" are becoming more and more apparent for clinical research.

Digital Data, the Semantic Web, and Research

(Bucks, UK) has announced the addition of 

as Vice President. Grupp will also head up the organization's recently launched Philadelphia office which opened in May. 

 as a biotechnology expert to its Board of Directors.  

 has joined the executive management team as Vice President of Sales and Marketing and will be responsible for global business development efforts. 

 MD, as Medical Director of Pediatrics, where he will be responsible for maintaining the scientific integrity of the CRO's pediatric clinical trials and providing medical oversight and therapeutic training to its project teams in the United States.  

 (Bannockburn, IL) has made several new additions including 

, PhD, to its leadership team as Executive Vice President, Scientific and Medical Affairs, and 

 as Senior Director of Business Development. 

 President of Allscripts, has been elected to 

 MD, as Vice President, Oncology Medical Affairs. 

(EMA) (London, UK) Management Board has nominated 

as new Executive Director of the Agency. Rasi has been Director-General of the Italian Medicines Agency since 2008, and a member of the EMA's Management Board since 2010. The management board also elected 

, Chief Executive of the Medicines and Healthcare Products Regulatory Agency of the United Kingdom, as chair for a three-year mandate. 

• With more than 20 years of leadership experience in the life sciences, medical, pharmaceutical, and biopharmaceutical sectors, 

, MD, its new President and Chief Executive Officer and a member of the board.   

, PhD, has been appointed to the editorial board as Statistical Editor of the 

 (Princeton, NJ) subsidiary, PharmaNet Canada and 

and its research center have agreed to collaborate and conduct pharmacokinetic studies in patients with impaired renal function.

(Princeton, NJ) is collaborating with the 

(CITN) (Seattle, WA) in order to help identify trials with immunotherapy agents prioritized by the CITN as having high potential for cancer therapy.

 (Dublin, Ireland) has formed a strategic partnership with 

(New York, NY) which will see it serve as one of two preferred providers of clinical trial implementation services. The partnership will enable Pfizer to focus internally on its core capability in clinical trial design, while leveraging the strengths and scale of ICON to implement clinical development programs with greater efficiency and rigor.

 (Cranford, NJ) has committed to use their technologies for another global clinical trial, their sixth of 2011. ExpeData partner writeresult is a provider of data management solutions for clinical research to the pharmaceutical/life sciences industry, and is automating the process of capturing patient-reported outcomes during clinical trials with digital pen and paper technology. 

 (Newton, MA) have formed an alliance to jointly offer their services to pharmaceutical companies and other industry stakeholders interested in enhancing patient recruitment and retention for ongoing and upcoming clinical research studies.  

 (Raleigh, NC) as the 13th partner to join its Technology Partner Program, for solution providers that have leveraged Medidata products for data sharing with their clinical systems. 

 (Cheshire, UK) eDiary technologies have been selected by 

(New York, NY) as part of the first ever Participatory Patient-Centered trial.

(Lincoln, NE) clinical research operations in Belfast, Northern Ireland, and its clinical research and bioanalytical services operations in Lincoln have been certified by the Brazilian National Health Surveillance Agency (ANVISA). ANVISA provides regulatory approval for drugs and other products seeking to enter the Brazilian market.  

 (Research Triangle Park, NC) has announced President and CEO 

 is a 2011 Ernst & Young Entrepreneur of the Year Award Carolinas winner. The awards celebrate entrepreneurs who transform economies, drive innovation, and change communities.

(New York, NY) announced that it is conducting the first-ever randomized clinical trial under an investigational new drug application that manages study participation entirely using electronic tools and allows patients to participate in the clinical trial regardless of their proximity to clinical sites. The pilot project uses mobile phone and web-based technology to collect  the necessary data for the trial without clinic visits. 

(Bloomington, IN), a contract solutions provider for the life sciences industry, celebrated its fifth year of operations recently. BioConvergence expanded its facilities after one year, and strives to create an environment where its employees and its clients collaboratively plan new product development. 

(New York, NY) has been selected to conduct a Phase II clinical research study of an investigational medication in patients with Major Depressive Disorder.

 (Minneapolis, MN) has recently invested in its Central Laboratory, servicing pharmaceutical, biotechnology, and medical device industries.

(Souderton, PA) Clinical Services business unit have increased its presence in the Asia Pacific region. It has extended its reach by adding five new depots located in Japan, Thailand, Hong Kong, and Taiwan to its extensive global depot network.  

Laboratory Corporation of America Holdings

 (Burlington, NC) has entered into a definitive agreement to acquire 

 (Toronto, Canada). The transaction, which is subject to customary closing conditions, is expected to close in the second quarter of 2011. 

 (Austin, TX) to expand its clinical trials outsourcing footprint and expertise in Australia, New Zealand, and India. Under the terms of the agreement, Trident will become a wholly owned affiliate of INC Research and will operate as Trident Clinical Research, an INC Research company, through its offices in Sydney, Brisbane, Melbourne, Adelaide, Auckland, and Mumbai. 

 (Chicago, IL) has added a Scientific and Medical Affairs Division to its core client offerings. New divisional service offerings include Pharmacovigilance, Regulatory Affairs, Clinical Pharmacology/Translational Medicine, Medical Monitoring, and Quality Assurance. 

, an eClinical and Biostatistical service provider headquartered in Louvain-la-Neuve, Belgium, has opened a new office in Houston, TX to enable access to clients on both the East and West coasts. 

 (Dublin, Ireland) announced that its medical imaging division has made MIRA, ICON's medical image review and analysis software, available to clients in an Application Service Provider (ASP) model. ICON Medical Imaging is the first medical imaging provider to offer clients an ASP solution for their image management needs. 

(Pittsburgh, PA) announced the availability of DiaryPRO Web, its Web-based electronic PRO data collection solution. DiaryPRO Web provides all of the scientific design and ease-of-use features necessary for capturing valid, reliable patient data in a web interface.

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update August 2011

A decade ago, Steve Cummings, MD, developed a truly innovative idea: patient-facing clinical trials. And he did one with a nutriceutical product. The trial didn't require an IND, but it went well. However, considering the industry 10 years ago—one only at the beginning of discovering EDC—this untraditional idea never progressed. Then 18-months ago, in early discussions with Pfizer, Cummings realized the idea now could blossom into a true business and founded Mytrus on the anticipation that it was an idea whose time has come. 

Anthony Costello, Chief Operating Officer at Mytrus, relates this as background to Mytrus' role in the latest breakthrough in clinical trial process since EDC. With Pfizer at the sponsor-helm, it introduced the "virtual" clinical trial concept in early June. The first-ever randomized clinical trial under an IND is assessing the safety and efficacy of Pfizer's Detrol LA, a treatment for overactive bladder. The study is specifically designed to test the methodology of the virtual trial concept, to determine if it can replicate the results of the previously completed Phase IV Detrol LA trial. This will then validate the patient-centered approach to the trial. The trial itself is called REMOTE, or Research on Electronic Monitoring of OAB Treatment Experience. 

REMOTE is stirring a lot of interest and comment. Not only is the trial virtual, it also is truly patient facing. There are four vendors providing the various tools in the chain. Mytrus serves as the single coordinating center for patients, recruitment, the principal investigator, sub-investigator, and the coordinators. Its portal is designed for patients and all the materials they need to read, fill out, or sign including the recruitment process, informed consent, case report forms, and safety data. The other vendor participants in REMOTE are Exco InTouch, providing ePRO via Nokia cell phones; Perceptive Informatics, providing IVRS; and Greenphire, providing subject payments.  

In the REMOTE trial, the lead PI is based at the University of California, San Francisco (UCSF), and works with the site staff—employees of Mytrus—that include the sub-PI and the coordinators. Said Costello, "There has always been on clinical trials the thought-leader principal investigator and this will continue into the future. But all other centralized staff are employees of Mytrus." However, not all of the trials follow or will follow the Pfizer model. Costello said the company has other trials with multiple PIs. In fact, there are other differences from the REMOTE trial and how the Mytrus' patient-facing trials will work in the future. 

Currently, the company is working on its own ePRO tools, apps for smartphones, and IVRS technology so that it can avoid the endless integration cycle. "We want to give patients a unified interface that has all the tools they need," Costello said. "Whether it's the iPhone or iPad or something else, we want a patient with any mobile device to have the same look and feel and have the access and visibility into the trial."  

This visibility into the trial comes with extra effort on the regulatory side.  For the REMOTE trial, Costello told 

 that it involved discussions directly with FDA and approval from multiple IRBs. Western IRB located in Olympia, WA, approved the materials that support all of the states. However, the institutional IRB at UCSF also needed to approve the trials. Historically, institutional IRBs don't have the greatest reputation for speed, but in this instance the approval process went extremely well. "IRBs look at everything that is patient-facing, typically the informed consent, advertisements, and such," explained Costello. "But everything on this trial is patient-facing, so every piece of it had to go through the IRB, which was a substantial increase in volume. But we have not had any significant slow-downs or pushback. In fact, they were quite excited to be working on this and seeing the whole trial for a change."  

Mytrus recruits through Google, Facebook, Craigslist, and banner ads on several health information sites such as WebMD and everydayhealth. Mytrus also used hybrid approaches that include partnering with EHR companies or medical foundations to access available patients via e-mail blasts or enewsletters. Another partner website Costello discussed was the WEGO Health site targeted at health activists who may want to help patients find clinical trials.  

Currently, enrollment for the trial is ongoing and can be found at 

, identifier NCT01302938. The enrollment estimation is 283 and trial completion is expected in 2012. 

In addition to the much-discussed Pfizer trial, Mytrus has many other studies starting up, including Phase II through Phase IV studies. Even large Phase III oncology studies that require a long-term follow up may convert to the Mytrus model at the end of the study for the follow-up portion.  

Mytrus has developed the following videos for patients to learn about the trial: 

http://www.youtube.com/watch?v=0fEx5V45zp4

News

Patient-facing clinical trials are finally implemented a decade later.

An Idea Whose Time Came

Food and Drug Administration officials recently acknowledged that its established system for ensuring the quality and safety of medical products cannot cope with significant changes in today's global medical market. More reliance on foreign producers and contractors increases the potential for diversion and fraud and weakens the ability of regulatory authorities to monitor product quality and adherence to standards. 

These developments require major changes to how FDA does business. Instead of sending out inspectors to scrutinize foreign facilities, agency officials seek to collaborate more with other regulatory authorities to make greater use of third-party auditors and to establish global information networks that can better alert officials to potential safety hazards.  

The call for a new approach to food and drug regulation will have a notable impact on FDA field inspections and compliance operations, as seen in changes at the Office of Compliance (OC) in FDA's Center for Drug Evaluation and Research (CDER) that increase its focus on imports and supply chain issues. At the same time, pharma companies are supporting new collaborative efforts to ensure the quality of supplies and to prevent drug theft, diversion, and distribution of counterfeit products around the world.  Increasingly tight resources at FDA and other government agencies and healthcare organizations, moreover, necessitate new approaches, as FDA faces sizeable cuts in its budget for fiscal year 2012.  

Major difficulties in ensuring the safety and quality of imported food and medical products in a world of increasingly blurred lines between domestic and foreign production are outlined in the "Pathway to Global Product Safety and Quality," which Commissioner Margaret Hamburg unveiled in June. While the report contains few really new proposals for overseeing food and drug imports and outsourced production, the document is noteworthy for providing a comprehensive overview of the forces reshaping the global economy and biopharmaceutical product development.  

To cut costs and increase productivity, FDA documents how pharma companies are shifting manufacturing and clinical testing to new locations. US pharma companies now import 80 percent of active ingredients, and contract manufacturing has more than doubled over the past decade to an estimated $46 billion business in 2010. More complex, high-risk biologics and vaccines are coming from emerging nations, instead of Western Europe. In addition, more R&D is shifting overseas; India and China already have more than 30% of the world's drug master files, and more clinical trials are taking place outside the United States and Europe. These developments make it "difficult to identify the 'source' of a product and to ensure that all players along the supply chain meet safety and quality responsibilities," the report states.  

With more foreign operators to monitor, FDA concedes that it's not viable to scale up its current regulatory model, even if it had the resources to do so. The average cost of a foreign inspection is $52,000, more than twice the $23,000 outlay for a domestic site visit. More than 54 percent of foreign drug facilities went uninspected from 2002 to 2007, and the record is even worse for medical device operations overseas. Clinical site inspections dropped in 2010, compared to the previous year, particularly for foreign investigators and for drugs and biologics.  

These developments also raise the specter of encouraging economically-motivated abuse, such as drug counterfeiting, fraud, and intentional adulteration. For many novice operators, the "temptation of economic gain is greater than any concern for risk to human and animal health," the FDA report observes. Americans feed these actions by purchasing more pharmaceuticals online, often from unknown sources and without appropriate oversight and safeguards. The nation already has suffered the consequences of adulterated heparin and counterfeit glucose monitoring strips, and low-quality counterfeit medicines are widely available, particularly in developing countries.  

In response, FDA is looking to rely more on regulatory counterparts and to implement third-party inspection programs and international cooperative activities to bolster oversight of medical products. FDA officials envision drug regulators adopting a more collaborative approach, somewhat along the lines of the International Civil Aviation Organization, which promotes global standards for aviation safety. Another model is the information sharing by Interpol, the International Criminal Police Organization. Access to international data on manufacturers, contractors, and regulatory operations will help FDA identify signals and warnings of potential risks that can be monitored and addressed before they lead to public harm. 

Although FDA has been engaging foreign regulatory counterparts in collaborative initiatives such as the International Conference on Harmonization (ICH) and the Pharmaceutical Inspection Co-operation/Scheme, these "are not sufficient" to deal with an increasingly complex global environment, the report concedes. What is needed are "global coalitions of regulators" that allow countries to maintain sovereignty in standards and decisions, but rely more on the work of counterparts and pool resources for managing the global biomedical inventory.  

More collaboration already is emerging in Asia and other regions. Mexico and Costa Rica are accepting FDA medical device review decisions. FDA recently put a company on import alert based on an inspection report from a European agency. The European Medicines Agency (EMA) has long relied on "qualified persons" employed by drug manufacturers to verify the quality and safety of all approved drug batches, and that model is worth looking at, says OC Director Deborah Autor. She also is open to initiatives involving third-party audits for drugs, an option already authorized at FDA for medical devices and food imports.  

FDA and EMA have extensive information-sharing activities involving new drug applications, drug safety reports, orphan medicines, and field inspections for active drug ingredients. A joint good clinical practices (GCP) initiative launched in September 2009 has been particularly successful, according to a June report on EMA-FDA interactions through September 2010. The two parties have exchanged GCP inspection plans, applications, and inspection outcomes to help target inspections and oversight. In addition, there have been seven joint and four observational inspections, which encourage further discussion on interpretations of findings.  

Broader Third-World adoption of ICH standards for drug quality, efficacy, and safety also has gained support from pharma companies and regulatory authorities in the United States, Europe, and Japan as a way to promote global collaboration. When ICH was established in 1990, most pharmaceutical R&D and manufacturing took place in those three regions. The pharma world has changed greatly in the last 20 years, and "the continued success and relevance of ICH," said Justina Molzon, CDER Associate Director for International Programs, "will depend on a much broader use of ICH guidelines and standards." 

To this end, ICH began inviting other regulatory authorities to participate in expert working groups several years ago and now is opening the way for them and Regional Harmonization Initiatives to become regular expert working group participants. In addition, the ICH Global Cooperation Group now transmits ICH deliberations and decisions to all interested parties. 

The expansion of drug manufacturing and clinical research activities overseas and at home has prompted the transformation of CDER's Office of Compliance into a "super" office better equipped to deal with global issues. The reorganization will help OC officials manage a staff that has grown to 300 people, up from 118 in 2005, explained OC Deputy Director Ilisa Bernstein at the PDA pharmaceutical supply chain conference in June. The change also puts OC on a par with CDER's Office of New Drugs, Office of Pharmaceutical Science, and Office of Surveillance and Epidemiology.  

Under the new organization, a string of top aides will oversee risk assessment, policy and strategic planning, and a broader range of compliance-related activities, directly under OC Director Autor. A new Office of Drug Security, Integrity & Recalls now oversees import operations, recalls, and a range of supply chain issues such as product authentication, intentional adulteration, and theft.  

The Office of Scientific Investigations (OSI), which monitors clinical trial operations, bioequivalence testing, and patient protections, now has a new division of safety compliance to oversee postmarketing activities, including adverse event reporting and Risk Evaluation and Mitigation Strategies implementation. Autor considers this a logical move because these programs require an interface with the clinical side of drug approval, and OSI has a large number of MDs who can take a hard look at the clinical significance of issues related to adverse event reports.   

A significant reason for the OC reorganization, Autor comments, "is to recognize the challenges of globalization" and to be able to focus more on international collaboration and data mining and risk analytics. "It fits together nicely and it's the right direction for us to move in." 

 At press time FDA announced a major reorganization of the Commissioner's office: Autor was named FDA Deputy Commissioner for Global Regulatory Operations and Policy; Ilisa Bernstein, OC Acting Director. 

View from Washington

Pharmaceutical testing and production overseas spurs call for more reliance on counterparts.

FDA Seeks New Approach to Global Challenges

A consistent theme that I hear from clinical study teams is the desire to have greater visibility and insight into clinical trials. Whether it's the status of site activation, overall patient recruitment, or some other view of important trial data, study teams are desperately trying to find the path to this intelligence. 

I was reminded of this theme when I attended a clinical outsourcing conference in London earlier this year where sponsors, CROs, and other members of the clinical trial community discussed the challenges and approaches related to strategic outsourcing. All the conversations showed that the foundational elements of transparency—trust and collaboration—are seen as critical elements of a successful outsourcing relationship.  

Related to this, a recent Gartner report by Steven Lefebure summarized the results of a clinical study best practices survey and identified "real-time visibility" as one of the best practices. Forty-five percent of survey respondents rated "near real-time line-of-site visibility to all trial activity" as highly effective in trial execution, analysis, and submission. Based on additional findings, Gartner also concluded that simply "having additional data, in and of itself, is not sufficient to achieve value. The information must be acted on." 

Knowledge is power, but power is of no value if you don't exercise it. In order to do that, you need to be able to analyze information and draw conclusions to make the best decisions and take appropriate action. So, how do you get away from the mess of paper that for example, is involved in clinical study management, to a state of empowered enlightenment?  

As a first step, think about the end goal and work backwards. In order to take action, teams need access to data that will allow them to analyze situations and make decisions. This, in turn, is reliant on visibility into real-time process status. Finally, in order to have visibility, the process needs to be centralized and standardized to enable a comprehensive view.  

Simply stated, the roadmap to success is: centralize, standardize, automate, monitor, and act. 

These tenets are not new, but change is difficult. Just think how long it took for EDC to be widely adopted. eClinical abilities, however, now need to extend beyond capturing data to capturing the whole process. Think about the mountains of physical paper exchanged between sponsors and sites for a single study. Although the prospect of centralizing this activity for all global studies is daunting, the technology exists to do it. Web-based, or cloud computing, solutions are literally changing the way business gets done.  

Available 24/7/365 via an internet connection, cloud solutions are breaking down the barriers of technology adoption and time zones. Companies are now able to centralize business processes online via secure, controlled document exchange, workflow, and collaboration. What was once manual, paper-based, and "untrackable" becomes centralized, standardized, and automated, allowing for real-time monitoring. Clinical teams can gauge the status of a process, such as how many sites have been activated for a new trial, who has received and reviewed information about a serious adverse event, or who has outstanding tasks that need to be completed. This new insight empowers study teams to take action to ensure milestones are hit, resulting in faster, smarter clinical trials.  

 Vice President of Life Sciences Product Marketing IntraLinks 

A Closing Thought

Knowledge is power, but power is of no value if you don't exercise it.

In Pursuit of Enlightenment

Standard of Care in Clinical Study Budgeting

Although the exact cost is debated, recent estimates suggest that bringing a new drug to market costs between $500 million and $2 billion, depending on the therapy and the developing company.

  These costs continue to rise each year.

  Greater competition, more expensive trial technologies, increasingly complex clinical trial protocols,

  among several other factors, all combine to contribute to the increased, and ever-increasing, development costs. 

In order to thrive in the competitive market of drug development, companies must find means to increase revenues and decrease costs, without sacrificing safety. By increasing clinical contracting efficiency during the clinical trial process, drug development companies can do both.  

To understand how, companies must first understand the life span of typical drugs so that the cost of delays, even as early as the clinical trial contracting phase, can be fully appreciated. Once the costs, and causes, of delays are appreciated, companies can correctly emphasize the importance of clinical contracting efficiency and work with qualified legal counsel to implement the suggestions outlined in this article to potentially save millions of dollars in expenses and lost potential revenues. 

 If a new drug is patented, the company inventing it will have the exclusive right to exclude others from making, using, or selling the patented invention for 20 years from the date of the patent application. For the duration of the patent, the drug enjoys market exclusivity and the drug's price can be set at a level that maximizes its profitability. But following the expiration of a drug's patent, manufacturers of generic versions of the drug are often able to reverse engineer the branded drug and provide low priced bioequivalents that do not need to be priced to recoup the costs and risks associated with drug development and clinical trials. The generic drugs quickly erode the sales of the branded drug, which means the vast majority of a drug's value lies in the period between marketing approval and patent expiry.  

A company usually spends seven to 12 years performing safety and efficacy tests, conducting clinical trials, and seeking marketing approval for a new drug before the drug can be marketed.

  Thus, during this seven- to 12-year period, a company spends hundreds of millions of dollars on a drug but generates no sales revenues from it.  

Unfortunately, by the time a drug is patented (which at best takes two to three years after the patent application is first submitted) and receives marketing approval, only six to 10 years remain in its patent life. An extension to the drug's patent life of up to five years may be available to enable a company to recoup a fraction of the time spent seeking regulatory approval,

  but such extensions are relatively uncommon. Instead, after receiving marketing approval for a new drug, the typical company has only an eight- to 13-year period of market exclusivity to earn back the immense amount of money spent on the drug's research, development, and clinical trial costs before generic competitors can enter the market and capture a vast majority of the market share. 

 By subtracting the costs expended for research and development, clinical trials, marketing approvals, and commercialization efforts from the revenue generated by a drug, discounted to reflect the time value of money and risk, the net present value (NPV) of the drug can be approximated. As an equation, NPV equals aggregate revenues, less aggregate costs, plus a terminal value, discounted for the time value of money and discounted for the risk of failure in reaching the market. All other things being equal, if the period during which revenue is generated can be increased by reducing the time to marketing approval, the NPV will increase as well (Figure 1). 

 Because companies have a limited period to generate the majority of the profits that are needed to recoup the substantial sum of money expended to bring a drug to market and make a profit, companies should appreciate that any delay with regard to clinical trials postpones potential marketing approval, resulting in both increased expenses and decreased revenues. This combination of increased expenses and decreased revenues costs drug companies, on average, $1.3 million for each day of delay.

 Industry research indicates that contract and budget negotiation and approval causes 38% of clinical trial delays, and that legal review causes another 24%. These two factors together constitute "clinical contracting," which cause the majority of trial delays;

  delays that result in millions of dollars in cost-overruns and lost potential revenues (Figure 2). 

Fortunately, such delays and their associated costs can be minimized, and sometimes even avoided, by improving one simple, overlooked step in the clinical trial process: clinical contracting efficiency. To minimize drug development costs, companies that sponsor clinical trials, in particular, and the medical research industry, in general, must find ways of minimizing potential trial delays. By focusing on clinical contracting efficiency, sponsors can:   More readily identify investigational sites and investigators interested and capable of timely conducting clinical trials.   Avoid sites and investigators that historically introduce avoidable delay, whether due to low patient recruitment/retention or difficulty reaching definitive agreements.  Select sites and investigators with a proven track record of timeliness and reliability. Negotiate, review, and approve clinical trial agreements (CTAs) with sites more quickly.  

The first opportunity to improve clinical contracting efficiency occurs even before the inception of the clinical trial protocol. All CTAs have certain provisions in common (e.g., confidentiality, rights to publish clinical results, indemnification, ownership of clinical data, ownership of inventions, choice of law, etc.). Although the common provisions appear in all CTAs, each provision can be drafted so as to give rise to several different rights and obligations of the parties.  

As just one example, the provision regarding ownership of inventions could be drafted so that:   

The sponsor will own the rights to all inventions created by the site relating to the trial.  

The site will own the rights to all inventions created by the site relating to the trial. 

The site and sponsor will jointly own all the rights to inventions created by the site relating to the trial.  

Each of these three positions will be further negotiated before both the sponsor and the site are typically able to agree (e.g., the site may own the rights to the inventions but provide the sponsor with a right of first refusal to license the rights to such inventions; alternatively, the sponsor may own the rights to the inventions but permit the site to retain the right to use inventions for the site's internal research and educational purposes).  

Summarizing all the potential starting positions and compromise positions for the common provisions of CTAs would require a treatise and such a comprehensive summary is not provided here. Needless to say, the potential positions are nuanced and virtually limitless, which is exactly why CTA negotiation, review, and approval causes so many trial delays. 

 Before ever contacting a site, sponsors should work with their legal counsels to identify the sponsor's fundamental position and acceptable fallback positions for the common provisions in CTAs. Then, each such position should be codified in a "CTA playbook." Additionally, the sponsor should clearly identify to its counsel the appropriate sponsor contact who can authorize a deviation from the playbook if a deviation ever becomes necessary.  

A good playbook simplifies and narrows the issues that must be considered during negotiation and review, thereby streamlining the contracting process and minimizing back-and-forth between sponsors and their legal counsel. A good CTA playbook also ensures conformity and consistency of legal rights and obligations, helping the sponsor keep track of and abide by its legal obligations when working with numerous sites (Table 1). 

 Next, the "CTA template" can quickly be generated by selecting the appropriate provisions from the playbook and organizing them into a coherent CTA. Typically, the fundamental position should be selected for the first CTA draft that will be exchanged with a site, but, in certain circumstances, fallback positions may be more appropriate in order to facilitate faster review and approval. 

Sites will usually request revisions to the template, but because virtually all of the CTA language that a site may request will have been drafted while preparing a proper playbook, revising the template and approving the final CTA becomes a rapid process that consists primarily of choosing from alternative, pre-approved provisions and then ensuring that the CTA is internally consistent. 

 Lastly, a "CTA checklist" should be prepared summarizing each of the provisions (but not positions) of the template. Then, once a CTA is negotiated and approved by both parties, the checklist can be used to ensure that the CTA includes all necessary and desired terms (Table 2). 

The checklist can also be used to note any deviations from the playbook language. Although most language that a site may request can be predicted and included in the playbook and template, occasionally a site will refuse the fundamental and fallback positions that are anticipated in the playbook or propose a provision that is not anticipated in the template. When this happens, the at-issue provisions should be negotiated by the site and sponsor's legal counsel and then highlighted for the sponsor's consideration upon final review.  

After any new provisions are approved by the sponsor, the deviations from the playbook/template should be noted in the checklist, along with a summary of the rationale underlying such changes. The checklist can then be filed with the executed CTA in the sponsor's legal records to provide a concise summary of all the sponsor's legal obligations with atypical provisions clearly identified. This summary helps to simplify the sponsor's future compliance with its contractual obligations. The checklist can also be used to expedite future negotiations with a particular site by providing a documented history of prior negotiations and deviations to the template that were required prior to the CTA being executed with such site. 

 Notice that the playbook, template, and checklist can be prepared at any time, so sponsors have an incentive to complete them long before a drug is ready to be used in clinical trials. By completing these three documents prior to the initial exchange of the CTA with a site, clinical contracting efficiency will be improved and potential delays during the CTA negotiation, review, and approval process will be minimized. 

The execution of the CTA is often delayed by time spent waiting for responses from the other party. When a sponsor exchanges the initial draft of the template with a site, the sponsor should express its urgency that the CTA quickly be reviewed, negotiated, and approved. Then, to reinforce that urgency, the sponsor should follow-up with the site frequently. If three business days pass without a response, a courteous follow-up is in order.   

It is not only important to follow-up with the site. A survey of sites indicated that 75% of the time spent waiting for responses is spent waiting for the sponsor who drafted the CTA.

  Therefore, it is equally important for the sponsor to follow-up internally to ensure that the contracting process progresses in a timely manner.  

To assist with the management of communications with multiple sites, sponsors should consider developing new or adapting existing software to track when the template was sent to or received from each site, when the last communication occurred, how many times the CTA has been exchanged, whom to contact at each site, etc. Ideally, the software will also include a customizable "alarm" that can remind the sponsor when it is time to follow-up with each site and/or with the sponsor's internal team again. Although potentially annoying for the sites and the sponsor's internal team, frequent follow-ups will help to keep clinical trials on schedule.  

Acquire and maintain industry knowledge. 

Many sites and sponsors are repeat players in the clinical trial industry. Accordingly, a careful observer can identify certain patterns and reputations that play a critical role in clinical contracting efficiency. Knowing the industry and the industry's players, institutionalizing that knowledge, and capitalizing on it will save a significant amount of time and frustration. 

A simple but overlooked way to save millions of dollars during new drug development.

Applied Clinical Trials-08-01-2011