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CRO/SPONSOR : The Value of Late-Phase Patient Reported Outcomes  Financial Simulation Modeling in Clinical Trials  TRIAL DESIGN : A Concise Look at Adaptive  LABS : Steps to Optimize Imaging  Also in this issue : New FDA Leadership Means Business, EU Works Together to Improve Trial Rules, Interoperability: A Reality or Just a Dream?, Social Media and Health Care

Applied Clinical Trials Digital Edition - October 2009

Like many industries, clinical research is no stranger to the allure of the global world. Its advantages are plenty, and for most, read like a memorized shopping list: lower costs, shorter timelines, more patients. But unlike other industries, going global with clinical trials raises red flags in many circles.    

"Pretty much everything out there is negative," says Todd Clark, referring to press covering the global expansion of trials. To get beyond this, what it calls anecdotal reporting, the Association of Clinical Research Organization (ACRO) commissioned Clark to do some research. The result is the white paper, The Case for Globalization: Ethical and Business Considerations in Clinical Research. 

When asked if any of the findings in the midsummer report surprised him, ACRO's Executive Director Doug Peddicord said there were two: the small size of the marketplace emerging countries currently constitute and how some act stricter than U.S. and EU bodies. 

Clark likened this strictness to paternal protection. "In Latin America, especially in Brazil," he said, "it is virtually impossible to do a placebo controlled trial...they think it's sort of excessive experimentation to some degree. And in India, you cannot do as a foreign sponsor a Phase I first-in-human trial." 

India also provides an example of what the white paper says may prove an additional layer of oversight in less developed countries: close relations. It cites one study in which 92% of Indian patients said they consulted with family or friends before enrolling in a trial, compared with just 62% of the Americans. 

Positive findings like this are heavily sprinkled throughout the 39-page pro-global report to support its thesis that "emerging countries play a vital role in the advancement of medical science." With them, it finds, years can be shaved off Phase III cancer trials via shorter enrollment times. Which means drugs get to patients, get to market faster—"In truth," notes the report, "the largest benefit of globalized trials." 

None of that matters, of course, if the quality isn't there. Which is a common criticism. How can a country with little experience ensure good clinical quality? The answer: with some help, which has come from industry and CROs. It seems the consensus view is that their growing global presence over the past 10 to 15 years has created a wider knowledge base. 

Both groups are at the forefront of education, says FDA Senior Advisor for Clinical Science David Lepay, MD, PhD. He told 

 that "It is rare for FDA to approach a country about capacity building without them talking about industry training programs taking place in their country." 

Clark credits sponsors for central Europe's rise to nearly being on par with western Europe. Their trials and financial investments in the region are behind its improvement, he says, and better global health care. 

Exposing developing countries to clinical research exposes their medical professionals to new equipment, new approaches, new patients. Clark describes it as a "technology transfer and knowledge transfer that improves the level of health services in these countries." 

Take Poland for example. According to Clark, 30% of cancer care in its hospitals come from clinical trials. What good would it do, he asks hypothetically, to take away this care because Poland is still an emerging country? That might make sense to globalization skeptics, but it doesn't to Clark. "It's really a case of letting the perfect be the enemy of the good," he says.—

News

Recent white paper from ACRO emphasizes the need for global trials.

Globalization Gets An A+

There is no doubt among health care professionals that the United States is experiencing an obesity epidemic. This epidemic cascades to the related diseases from increased weight, including Type 2 diabetes, hypertension, and lipid disorders, which include atherosclerosis and other cardiovascular problems. The epidemic is not confined to the United States, and is becoming a health issue in other developed countries.    

Obesity drugs have a long and storied history. In 1997, fenfluramine in the class of anorectics was withdrawn from the U.S. market after reports of heart valve disease and pulmonary hypertension. Fenfluramine was half of fen-phen or Pondimin and also in Redux, marketed by American Home Products, which became Wyeth. In 2008, rimonabant in the class of cannabinoid-1 receptor antagonists, was withdrawn in Europe after being available for two years. A review of postmarketing data showed a doubling of risk for psychiatric disorders in patients taking Acomplia, marketed by sanofi-aventis. And most recently, in late August, the FDA announced it was conducting a review of anti-obesity drug orlistat in the class of lipase inhibitors, marketed as Xenical and Alli by GlaxoSmithKline, for 32 reports of liver-related adverse events, 30 of which were reported outside of the United States and included six cases of liver failure. Xenical was approved as a prescription drug by the FDA in 1999 and Alli was approved for OTC in 2007. 

However, the development of obesity drugs is not eclipsed by the adverse events of these representatives in various drug classes. Decision Resources issued a report in mid-September predicting a six-fold increase of the obesity drug market from $512 million in 2008 to $3.2 billion in 2018. The market represents the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan. The authors of the report cite the drivers of the obesity drug market growth as novel therapies. The Decision Resources report found the pipeline had a dearth of cannabinoid receptor-1 antagonists, paving the way for the novel therapies and combination therapies. 

One obesity drug that recently went through two Phase III trials with positive results is Qnexa from Mountain View, CA-based Vivus. Qnexa, a combination of phentermine and topiramate, met all primary endpoints of demonstrating statistically significant weight loss in all three doses of the drug, which was evaluated in 3750 subjects at 93 sites for 56 weeks. The FDA requires that there be a 5% loss of body weight between the investigational drug and placebo. For Qnexa, the statistics showed this greater than or equal to 5% weight loss rate among 59% of those completing the trial for the low dose and 84% for the full dose in the first trial, and 75% for the mid-dose and 85% for the full dose in the second trial. 

Qnexa also showed a reduction in hypertension, diabetes, and dyslipidemia (lipid disorders). The side effect profile was also positive. Vivus completed a thorough QT prolongation (TQT) study to evaluate subjects. Monthly assessments for prospective psychometric evaluations showed no signals for suicidality risk, and moderate to severe depression or depressed mood adverse events were seen in less than 2% of the subjects. 

Another investigational drug that is in preclinical development for Type II diabetes addresses the cardiovascular safety problems found in previous diabetes drugs. Alize Pharma, based in France, is investigating AZP-01 in a new therapeutic class of compounds called growth hormone secretagogues. Alize cofounder and president Thierry Abribat, PhD, told 

 the company's goal is to move the compound out of the preclinical stage and to then partner with a larger company for regulatory and, hopefully, marketing. 

"We feel the compound is quite suited for the current need of the metabolic market because it targets reduced glucose," said Abribat. "The new rules and regulations in the field of Type II diabetes, with Avandia, and the risks with these products...it's not enough to lower HbA1c levels to have efficacy in diabetes, you have to have effects on cardiovascular also." The naturally secreted peptide found in AZP-01 has been shown to exhibit effects on endocrine pancreatic function, glucose metabolism, appetite stimulation, and the cardiovascular system, among others. 

The related co-morbidities of obesity, diabetes, and lipids create challenges for the clinical trial professional. Specifically in areas that include: 				

Overall, there has been an increase in protocols in drug design as noted in a 2007 report from the Tufts Center for the Study of Drug Development. From 1999-2005, the number of unique procedures increased 6.5%, the frequency of procedures was up 8.7%, and the execution burden on the site was up 10.5%. Also, as we reported in our June issue, "Raising the Bar on Subject Recruitment," FDA—just in the past three to five years—is requiring more data from the sponsors. 

More complex protocols require more resources. Protocols for the cardiometabolic drugs are also increasingly stringent, based particularly on the side effect histories presented above. More complex protocols require more resources. As noted in the Qnexa trials, both TQT evaluations and psychiatric assessments were necessary. In December 2008, the FDA published a guidance for industry to evaluate cardiovascular risk in new type II antidiabetic therapies. The guidance does not specifically mention the TQT tests, however, many CROs and service vendors provide TQT services including CareFusion, ERT and Quintiles. Protocol requirements then trickle down into inclusion/exclusion criteria, which impact the next area of subject recruitment. 

Inclusion/exclusion criteria on the drug protocol is increasingly difficult in recruiting subjects for clinical trials. In diabetes trials, the two most difficult barriers to recruitment are finding treatment naive patients or patients that have the right HbA1c levels. 

Sandra Chase, vice president of operations for HCG, told 

 in a podcast last year, that while genetics plays a role in Type II diabetes development, "Many times especially in Type II there is a lifestyle issue...and that can have co-morbidities which can be exclusionary." In addition, in the United States, most potential subjects have been treated with some kind of diabetes medication, making the treatment naïve more difficult to find. Said Chase, "Finding treatment naïve, means in many cases looking at the uninsured or underinsured or underserved populations that may be difficult to access." 

In the end, new retention and recruitment strategies will be necessary in order to find and keep the right subjects for the right cardiometabolic trials. 

For more information on cardiometabolic clinical trials, visit 

Special Report

Success and challenges for clinical trials that address these interrelated conditions.

Obesity, Lipids, and Diabetes

Top Related Articles: Two Decades of Change for PROs

Putting the "e" in FDA's Draft PRO Guidance 

 The growing need to establish a drug's safety and long-term efficacy in a given population has increased the number of late-phase studies performed by the pharmaceutical industry over the past decade. The competitive drug market has driven companies toward product differentiation and positioning, both of which may be determined through postmarketing studies. Strategic guidance in areas such as reimbursement, franchise development, and marketing is provided through late-phase studies.

PHOTOGRAPHY: WESTEND61, PHOTOALTO/ERIC AUDRAS, GETTY IMAGES    ILLUSTRATION: PAUL A. BELCI 

Late-phase trials are postmarketing studies and classified as Phase IIIb or IV. The term Phase IIIb is used by the industry to describe additional therapeutic exploratory and confirmatory studies conducted after the primary regulatory dossier has been submitted by the manufacturer. They are typically conducted on marketed drugs to look for a new indication. Ziprasidone hydrochloride (Geodon), a commonly used antipsychotic introduced to the market for the treatment of schizophrenia in February 2001, received approval for treatment of bipolar mania in August 2004 as a result of Phase IIIb research.

Phase IV studies are typically conducted to capture physician prescription patterns, evaluate adherence to treatment guidelines, and conduct safety surveillance after the approval of a drug. Phase IV postmarketing research has evolved into patient registries, risk management programs, postmarketing surveillance programs, observational studies, disease management programs, and care quality improvement initiatives.

  The Phase IV research environment is largely driven by the changing regulatory environment, increasing safety concerns of new medicines, and the need for real-world data on the marketed drugs' safety and efficacy.

  The association between long-term combination Hormone Replacement Therapy use and a heightened risk of breast cancer was discovered during a Phase IV trial partially funded by Wyeth and conducted by the National Institutes of Health.      

Figure 1. Some of the main factors that lead to treatment ineffectiveness. 

Decision-making by health care professionals in the United States is primarily based on patient visits, is highly decentralized, and driven by professional autonomy to a large extent.

  The prevailing model of health care delivery is complicated, comprised of layers of processes and handoffs that result in slow and expensive health care. The system often fails to consider the importance of tailoring care based on patients' needs. While health care delivery needs to be timely and safe, the overall effectiveness of treatment can be optimized through patient-level feedback. 

Some of the main causes for treatment ineffectiveness have been described in Figure 1. Patient noncompliance, driven in part by lowered treatment satisfaction, has emerged as one of the leading causes for treatment inefficacy. High patient noncompliance leads to annual economic losses of up to $100 billion in the United States. Studies have shown that noncompliance causes 125,000 U.S. deaths annually, and hospital costs due to noncompliance have been estimated to be $8.5 billion annually.

Since the 1990s, studies have shown that systematic attention to patient feedback on health care outcomes and behavioral change lead to improved treatment outcomes.

  According to an IBM publication on health care in the 21st century,

  a patient-centric approach would ensure an improvement in health; a reduction in costs and premiums by payers; improvements in the efficiency, quality, and safety of care; and a reduction of the financial burden in the industry.  

Outcomes that matter to patients following treatment can be gauged most accurately using patient-reported outcomes (PRO) measures. The term PROs has evolved to include any endpoint derived from patient reports, whether collected in the clinic, using a diary or by other means, including single-item outcome measures, event logs, symptom reports or longer questionnaires. PROs are typically used to measure health-related quality of life (HRQoL), health status, symptoms, adherence, and treatment satisfaction.

 The selection of appropriate PRO instruments depends on the study design, nature of the intervention, and the target population. 

Results from psychometrically validated PRO measures can help us learn about overall patient treatment satisfaction, treatment effectiveness, and the impact of the drug on patients' day-to-day lives (see Figure 2). Physicians can gain useful feedback on prescribed treatments and could alter their course of treatment to improve the care delivered. 

The recent FDA and EMEA guidelines providing clarifications on the use of PRO endpoints from clinical trials to support label claims have resulted in a significant increase in the use of PRO measures in clinical studies.

  While PRO measures used in early-phase studies evaluate a drug's safety and efficacy in a small group of patients, PRO measures in late-phase studies are used on a larger patient population and in real-world settings. Compared to the controlled settings used in early-phase studies, the data provided in late-phase research, particularly related to PROs, has better external validity. The observational nature of most late-phase studies requires following patients through their normal course of treatment, which enables better determination of the factors leading to treatment ineffectiveness.  

Figure 2. Mediators contributing to improving treatment effectiveness and safety. 

Since early-phase studies are designed to specifically address drug safety, efficacy, and dose adjustment issues, they do not allow for head-to-head comparisons between drugs. Late-phase studies provide more comprehensive data about overall treatment satisfaction and patient HRQoL in real-world settings (see Table 1). 

A study designed to investigate the scope of HRQoL data from oncology studies showed that more than 80% of oncologists believed that HRQoL information collected prior to the commencement of treatment would improve overall treatment outcomes.

  Health-related quality of life data from late-phase studies can set the stage for physicians to tailor treatment regimens based on patient needs and ensure the provision of timely safe and high-quality health care. 

However, care must be taken to make study design adjustments in the context of observational studies or registries, where patient assessment using a PRO measure has the potential to alter routine clinical care.  

Table 1. Examples of why to use PROs and the different ways the data can be captured. 

Provider attitudes, decision-making, and health care delivery styles can influence treatment outcomes to a great extent. Physician characteristics such as lower practice volume, previous primary care or interviewing training, satisfaction with personal autonomy, and physician specialty are associated with higher doctor/patient participatory decision-making style ratings.

PRO measures from observational studies can provide useful information on the effect of physician attitudes on patient outcomes. Researchers agree that low levels of treatment satisfaction among gastroesophageal reflux disease patients are often a result of inadequate communication between physicians and patients, and believe that an understanding of a patient's HRQoL during the course of the disease would help address this problem.

PRO measures have been used to establish long-term treatment effectiveness and the negative impact of treatment on patients' HRQoL. The Prostate Cancer Outcomes Study (PCOS) was initiated in 1994 in collaboration with six cancer registries that were part of the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Their aim was to obtain information on specific diagnostic procedures, clinical status, and details of treatments using patient surveys, medical records, and registry data.

HRQoL measures such as the SF-36 were used to obtain information on patient treatment satisfaction and disease symptoms. The PCOS generated over 25 publications, and one of the study findings was that with aggressive treatment there was a reduction in absolute risk of dying from prostate cancer but at the cost of a significant decrease in disease-specific HRQoL.

 PRO endpoints in late-phase trials support treatment benefit claims that describe a patient's symptoms or ability to function.

  They can help establish secondary indications for an approved product label. 

Porfimer was approved for a second indication of endobronchial cancer based on two randomized Phase IIIb studies comparing the safety and efficacy of porfimer versus laser therapy alone for the reduction and palliation of symptoms in the patients. Patient symptoms were evaluated using a PRO, the pulmonary symptom severity scale. 

 The most efficacious combination of drugs can often vary among patient populations, and it becomes necessary to conduct the assessment from the patient's perspective, using PRO measures. 

The postmarketing ADORE trial studied the relative efficacy of etanercept alone versus combination therapy of etanercept and methotrexate for patients with rheumatoid arthritis. It established that both treatment options were effective in reducing symptoms associated with rheumatoid arthritis and improving general patient health, by using endpoints from PRO measures like the EQ-5D, the VAS, and the Stanford Health Assessment Questionnaire.

 Treatment modifications, symptom control, and side-effect prevention techniques can be evaluated in late-phase clinical trials using PRO data. 

For example, an open-label observational study used the Short Form-12 (SF-12) to evaluate changes in symptomatology for patients whose antihypertensive drug therapy was modified due to tolerability issues.

  Instruments used in osteoporosis studies, such as the Osteoporosis Functional Disability questionnaire, were developed to assess disability in patients with osteoporosis and back pain due to vertebral fractures. This has led to interventions using fracture prevention techniques in clinical practice.

 PRO-reported side effects can present a comprehensive picture of drug-related safety. Health care researchers use PRO instruments to study side effects in late-phase studies, and experts believe the combined use of side-effect questionnaires with health status instruments could yield a broader understanding of treatment outcomes. 

The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) is comprised of over 1000 individual items related to specific adverse events based on their degree of severity, and has been mandated for identifying toxicity-related symptom burden from chemotherapy patients.

  While the CTCAE was designed for clinician reporting, the rating scale was adapted by researchers for patient self-reporting and to evaluate the efficiency of the electronic collection of PROs.

Online patient reporting was demonstrated to be a feasible strategy for chemotherapy toxicity symptom monitoring, and could improve overall treatment safety and satisfaction with care. Another questionnaire, the Side Effect and Life Satisfaction inventory was useful in the evaluation of side effects among epilepsy patients.

  PRO data in real-world settings assessing side-effects often form the basis for dose modifications or the introduction of supportive medications. 

 Health care researchers and policymakers can use PRO data from late-phase trials to study the burden of disease on the targeted patient population. 

Resource allocation, drug costs, and premium reductions can be made through the extraction of information from postmarketing surveillance data. Using short-term data from the late-phase PROactive trial, a health outcome model was updated to project long-term clinical and cost outcomes associated with pioglitazone versus placebo in patients with type 2 diabetes.

  However, for modeling HRQoL based on Quality-Adjusted Life Years, health state utilities derived from another source was modeled into the event data from the PROactive trial. 

In the future, late-phase studies could incorporate simple preference-based PRO measures such as the EQ-5D to enable researchers to directly obtain information on HRQoL without the need to use multiple data sources. 

While manufacturers and researchers use late-phase clinical trials as instruments to corroborate the safety and long-term effectiveness of their drug, incorporating PRO endpoints could ensure focus on patient-centered health care delivery. PRO data from late-phase trials should percolate through the layers of the health care system to support the industry's growing commitment to patient-centric health care and reinforce the principles of safety, effectiveness, timeliness, efficiency, and equity in health care delivery. 

1. I.F. Moodie, "Emerging Role of Postmarketing Clinical Research," 

Strategic Research: A Practical Handbook for Phase IIIB and Phase IV Clinical Studies

3. D. Polygenis and G. Radulescu, "The Changing Face of Post-Marketing Research," Bioscienceworld, 

http://www.bioscienceworld.ca/TheChangingFaceOfPostMarketingResearch

Feature Article

Patient-level feedback from later studies provides a multitude of valuable answers to all stakeholders.

Late Phase Patient Reported Outcomes

The new leadership at the Food and Drug Administration is wasting little time in taking steps to erase the charges of incompetency and ineffectiveness that have plagued the agency for several years. FDA is announcing new rules and policies almost daily and strengthening enforcement of research, manufacturing, and marketing requirements to show industry it means business.      

FDA Commissioner Margaret Hamburg began by reorganizing her immediate office to emphasize the importance of food safety and scientific integrity and to encourage speedy compliance with rules. There will be a new "food czar"—a deputy commissioner of food overseeing the Center for Food Safety and Nutrition and the Center for Veterinary Medicine. An expanded office of external affairs will improve communications with the media, health professionals, and interest groups. Several cross-cutting activities—bioresearch monitoring, combination products, orphan drugs, and pediatrics—will be managed by the Office of Special Medical Programs. 

Budget development will shift to the policy office to improve the agency's ability to explain to Congress how FDA spends its resources and why it may need additional funding. Hamburg is benefiting from a record $3 billion budget for the coming year (including some $600 million in user fees), but will be hard-pressed to further expand resources. 

A prominent addition is the Center for Tobacco Products, authorized by Congress in June and launched by FDA in record time. The Center is headed by Lawrence Deyton, an MD with experience in academia and public health and successful in revitalizing smoking cessation programs as a top health official at the Department of Veterans Affairs. The tobacco legislation charges FDA with enforcing tobacco marketing restrictions, regulating ingredients, and reducing youth smoking; leeway for FDA to promote smoking cessation could stimulate development of new nicotine replacement products. 

Hamburg is intent on positioning FDA as a science-based regulatory agency where politics doesn't override medical judgment in making regulatory decisions. She hopes to deal effectively with internal disputes over product safety and approvals and to avoid public controversies, such as that which delayed approval of an over-the-counter version of the Plan B emergency contraception pill. 

At the August meeting of FDA's Science Advisory Board, Hamburg highlighted the need to strengthen regulatory science as a field, noting that it has atrophied compared to the surge in biomedical research investment by the National Institutes of Health. She emphasized the importance of "revitalizing and reenergizing" support for FDA's Critical Path Initiative and acknowledged concerns about the slim pipeline for new drugs and medical products. 

Efforts to make the FDA review process as efficient as possible can benefit R&D, she commented, while the current lack of transparency about FDA programs can be "very stifling to innovation." Here Hamburg echoed opinions expressed by biotech companies and venture capitalists at a recent meeting organized by FDA and the White House Office of Science and Technology Policy to address innovation and transparency. 

One sign of the times is Hamburg's decision to appoint a new head of the Center for Devices and Radiological Health (CDRH). Veteran FDA official Dan Schultz resigned in August as CDRH director in the wake of several high-profile device safety cases, plus internal complaints about management ignoring staff concerns regarding safety and efficacy testing of new products seeking market approval. 

Under the Hamburg regime, FDA Chief Scientist Jesse Goodman has the task of ensuring scientific integrity in agency deliberations, along with encouraging research and innovation. Goodman will head up a new office for resolving scientific disputes within the agency, coordinate responses to charges of inappropriate action, manage appeals, and oversee advisory committees. 

Another assignment is to coordinate FDA's involvement in counter-terrorism and emerging threats, which involves managing the agency's response to the influenza pandemic as well as other diseases that threaten public health. Goodman's office will facilitate access to effective medical countermeasures, authorize emergency use of needed therapies, and oversee FDA counter-terrorism and pandemic planning. 

Chief Scientist Goodman also will make the case for FDA support of high-quality scientific projects as head of the Office of Science and Innovation. That will involve expanding Critical Path, encouraging personalized medicine, and promoting comparative effectiveness research. FDA hopes to tap into data resources that can identify patient populations likely to benefit from certain treatments. Such information, says Goodman, should help design studies that can produce useful information on how medical products should best be used to yield benefits and avoid harm. 

In addition to these organizational changes, FDA is rolling out new programs and policies important to drug development and research. One set of new rules aims to expand patient access to investigational medicines by finalizing proposals made in 2006 and long sought by patient advocates. The policy aims to make it easier for seriously ill individuals to obtain unapproved drugs under the treatment IND policy, or to have early access to an approved drug for an unapproved indication. And it provides sponsors with additional clarification on when they may charge patients for an experimental drug outside a clinical trial. 

FDA also has issued a proposed rule requiring electronic submission of postapproval adverse event (AE) reports for drugs, biologics, and medical devices. Most of drug AEs (80%) already are submitted to the agency online or in digital media. FDA is establishing a new Web portal that aims to make it easier for small companies and individuals to report safety problems. There are no changes in the scope and timing of AE filings, and therefore fairly easy for sponsors to comply. However FDA estimates it will save $2.4 million a year and, more importantly, will gain access to safety information much faster. 

Hamburg's most high-profile initiative is to streamline the process for issuing warning letters and for taking enforcement actions against companies that violate agency rules. 

Many serious violations "have gone unaddressed for far too long," including problems in product quality and false and misleading labeling and advertising, Hamburg commented at an August meeting sponsored by the Food and Drug Law Institute. The Commissioner wants to limit all the back-and-forth wrangling with regulated companies that delays compliance and says that FDA may implement recalls or seizures if serious health and safety issues are not corrected promptly. 

In addition to establishing tighter time frames for issuing warning letters following field inspections that uncover quality control issues, FDA is taking steps to respond quickly to companies that address cited problems. If violations are corrected promptly, FDA will issue a formal close-out letter indicating that the firm is back in compliance. If failings are not fully addressed, FDA says it won't just issue another warning letter, but may seize products or impose additional penalties. 

This campaign to step up enforcement extends to ensuring compliance with good clinical practices (GCPs), according to FDA officials. The agency issued new policies in August to speed up procedures for disqualifying and debarring clinical trial investigators who violate the rules, instead of allowing such proceedings to drag on for years. FDA also is making debarment and disqualification information more visible so that sponsors can avoid hiring individuals debarred from conducting regulated studies. 

Even before announcing these changes, FDA officials were expanding enforcement efforts. 

An analysis by the Center for Drug Evaluation and Research reveals an increase in warning letters (from 10 in 2006 to more than 20 this year) related to violation of rules governing trial conduct or human subject protection. While it's less common for FDA to cite sponsors for GCP violations, in August the agency sent a strong letter to Johnson & Johnson citing numerous deficiencies and failure to monitor a problematic investigator at a site conducting research on a new treatment for skin infections, ceftobiprole. 

Hamburg expects to see such an increase in warning letters initially, but anticipates that the volume will level off as industry recognizes that strong compliance programs are good for business and for consumers. FDA's success in spurring compliance "should be measured not by the number of warning letters or injunctions or seizures," she said, but by "our impact on the health and welfare of the public." 

Failure to meet FDA standards means that a company is "putting the public at risk" and also "jeopardizing the public's confidence in your industry." Alternatively, speedy corrective efforts by companies and broader compliance throughout industry will increase public confidence in FDA and better educate consumers about potential risks in medical products. 

View from Washington

Stiffer enforcement of research standards aims to restore the public's confidence in agency actions.

FDA Promotes Integrity and Compliance

ICH GCP has revolutionized clinical trials by improving the quality of clinical data and assuring patient safety during the past 13 years. The guidelines should not undergo radical changes, but there are some areas where further clarification is required. 

That is the consensus view among members of the Institute of Clinical Research (ICR), who were asked whether they thought ICH GCP should be reviewed. The initial online poll, conducted in June 2009, found that 84% of the 90 respondents believe the guidelines should be updated. ICR then undertook a qualitative survey, asking its members what elements should be updated and/or what should be added. 

"Although the ICH GCP guidelines don't have any direct legal status, its principles set the tone for how most people conduct clinical research," said Sue Fitzpatrick, education manager at ICR. "The opinion expressed by our members was that some areas of ICH GCP should remain unchanged, however, certain amendments would be welcomed and would ensure the guidelines are still meeting the needs of the industry." 

Since ICH GCP was introduced in 1996, the guidelines have never been updated. Other guidelines, such as the Declaration of Helsinki, have been revised several times during the past decade, she added. 

"I think this discussion is overdue and very relevant," Paul Chester, PhD, visiting researcher at the Oxford Centre for Diabetes Endocrinology and Metabolism, UK, told ICR's publication, 

. "Whenever I talk about GCP, I feel it is important to point out that ICH GCP is now 13 years old and getting older every day, so it must be read in light of new regulation and guidance." 

According to Arun Bhatt, president of ClinInvent Research India in Mumbai: "The current ICH GCP guidelines are too broad and general to proactively manage today's scientific and ethical issues. There is a need to make ICH GCP more explicit, specific, and stringent. There are also new concerns [to be met by ICH GCP], such as the use of poor illiterate populations from developing countries as trial subjects." Not everyone agrees, however. 

"I do not think that ICH GCP guidelines need to be changed. They have stood the test of time and remain perfectly reasonable," said David Hutchinson, visiting professor at the University of Surrey, UK. "They are a global standard and seem to fit the practices in most parts. They present clear requirements for sponsors, investigators, and ethics committees." 

Furthermore, ICH GCP's dominance has been ended, in Europe at least, by EU directives and national legislation that call for the guidelines principles to be taken into consideration but shy away from giving it any direct legal force. 

Other respondents voiced concerns about the potential for differing interpretations that can lead to local variations, bureaucracy, and confusion. Additionally, in the area of clinical pharmacology, there is a need to integrate the guidance on first-in-man studies developed after the TGN-1412 incident. Rapid progress in personalized health care and biologics must also be taken into account. 

Barbara Hepworth-Jones, PhD, principal education advisor at the GSK Academy of Pharmaceutical Medicine, thinks that ICH GCP is woefully lacking in data protection requirements. The growing sophistication of electronic data systems and the potential for misuse of personally identifiable information mean that there is a real need for this to be added. 

"In many countries there are data protection laws, and inspectors and auditors can use those to supplement GCP, so in practice it can be covered. But if it is not covered in GCP, then subjects' rights and well being are not totally protected by GCP," she noted. 

				The whole research team, rather than just the principal investigator, should be considered more in ICH GCP, said Jacqueline Briggs, clinical trials unit manager at Bristol Haematology and Oncology Centre, UK.—

Global News

The ICH GCP guideline continues to age and while members of the Institute of Clinical Research voice the need for its revision, industry debates whether changes are necessary.

Pressure Mounts for ICH GCP Revisions

 (Cambridge, UK) for many years, the current vice president of business operations for 

, will become the new Chairman for the organization. 

•Now the new vice president of project management for 

 will hold the responsibility of globally implementing and delivering the company's project assurance methodology, which will include developing and executing strategic plans to enhance customer service.

 (Fargo, ND), who will now manage operations, sales, and finance divisions of the company, the role of chief executive officer has been given to 

, who will now focus on business strategies and growth opportunities, including development of on-demand packaging and labeling. 

, MD, will gain the responsibility of providing clinical insight and site experience to clients and internal staff, as well as provide therapeutic training, industry white paper leadership, speak at industry conferences, and represent the company's special interest groups. 

 (West Lafayette, IN) has expanded its business development team in the United States with 

 now representing the company in Canada and the Western United States, including California, Oregon, Washington, Idaho, Nevada, Utah, Montana, Arizona, and Wyoming. 

•The former founding executive, president, and chief scientific officer of 

, PhD, is now the chief operating officer of 

Professor So Iwata, an Imperial College London scientist, accepting his Â£2 million Diamond Fellowship from the Biotechnology and Biological Sciences Research Council. 

' (New York, NY) Medidata Rave EDC solution, 

 (Basel, Switzerland) will deploy its software as its core EDC system in a phased, multiyear approach across its five disease biology areas.

As a new collaboration to support Phase I cardiac safety clinical trials, 

 (Portland, OR) Ambulo 2400 ambulatory blood pressure monitoring (ABPM) systems into its suite of offerings.

 (Redwood Shores, CA) clinical data management platform, 

 (Philadelphia, PA) has recently implemented the company's enhanced EDC application, Oracle Remote Data Capture Onsite 4.5.3.

 (Newark, DE) has entered into an alliance with 

Taiwan's Development Center for Biotechnology

 (Xizhi City, Taiwan) to provide biopharmaceutical companies with comprehensive drug development services ranging from preclinical through clinical services.

Upon a three-year agreement signed with the 

 (Philadelphia, PA) will enhance or upgrade its software products already in use at the agency as well as provide maintenance and support.

To cover such employment gaps as seasonal fluctuations, and maternity or holiday leave and to provide an additional resource option, 

 (Birmingham, UK) to implement a UK-wide temporary staff Recruitment Process Outsourcing solution.

 and his academic research group of Leuven, Belgium, and 

 (Leiden, The Netherlands) will now come together to combine their efforts in Alzheimer's research to develop a potential treatment for the disease.

 (Boston, MA) to enhance its capabilities of processing and analyzing medical images for central nervous system and oncology trials.

To support the development of its pipeline of biologics for immune-related disorders, 

 (New York, NY) Trial Planning product suite, after already utilizing the company's Grants Manager and CRO Contractor.

(Denver, CO) training programs to a wider audience, 

 (Highland Ranch, CO) has entered into an agreement to manage its sales and marketing.

 (Redwood Shores, CA) Health Science Award for "Accelerating Interests for Better Health" was awarded to 

 (Cincinnati, OH) for their continuous collaboration with Oracle Health Sciences Global Business Unit.

, has been awarded the first ever Diamond Professorial Fellowship from the Biotechnology and Biological Sciences Research Council, which is worth about £2 million.

, has announced the establishment of the 

, a charitable trust in Northern Ireland.

 (Tokyo, Japan) has become the first Asia-based contract research organization to reach the most advanced level of 

 (New York, NY) Aspire to Win program, Rave Accredited Plus.

Following its recent performance recruiting for the JUPITER trial, 

 (Manchester, UK) has succeeded in the recruitment of 1221 patients across seven UK-based sites, and a total of 3273 patients were recruited worldwide across 87 sites for another global study.

 (Philadelphia, PA) has engaged in an aggressive hiring campaign in which it has hired 150 professionals in the past month, bringing its U.S. workforce to about 900, and is currently recruiting to fill 70 additional positions in the Philadelphia area.

To help ensure that the cancer center community can fulfill the new registration requirements for the U.S. National Cancer Institute (NCI) Clinical Trials Reporting Program, 

 (Fremont, CA) has provided new capabilities and functions in its eResearch platform.

Upon a successful UK MHRA Good Manufacturing Practices audit, 

 (Melbourn, UK) is expanding its facilities with the creation of a suite of rooms specific for early stage formulation development.

 (Dublin, Ireland) bioanalytical and immunoassay capabilities is the company's acquisition of 

, a provider of biomarker laboratory services.

 (Princeton, NJ) interactive voice and Web response services business for $10 million by 

 (Waltham, MA) has also led to a multiyear marketing agreement mandating that Phase Forward market InForm EDC solution and Clarix interactive response technology solution to Covance clients.

 (Chicago, IL) has acquired the pharmaceutical development division from 

 (Wilmington, NC), renaming it AAIPharma Services Corp., and has also committed $75 million to expand the businesses' capabilities.

To support a growing American client base, 

 (Nottingham, UK) has opened a U.S. office in River Hills, SC.

In acknowledgement of an increasing interest in outcomes research, 

 (Cincinnati, OH) has opened a new office in Raleigh, NC, to support biostatistics and outcomes research.

 (Philadelphia, PA) will move from their current location in Bridgewater, NJ, to the company's new headquarters located in Philadelphia, PA.

 (Raleigh, NC) has relocated its corporate headquarters to the Brier Creek Corporate Center, which will provide larger office space and more amenable facilities for staff and customers. 

Community

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

Business and People Update October 2009

The ongoing din of debate about health care reform and the associated transition to electronic health care records continues to influence clinical research and regulatory strategies. It's hard to dispute the belief that these two worlds should converge—the typical processes in clinical data collection are antiquated and redundant, and unnaturally separated from the process of data collection within health care itself.       

To some extent, recent demonstrations of health care data connecting with research cast a positive light on the use of data standards in general—since standards are so fundamental to the harmonization of these parallel worlds of health care and clinical research. On the other hand, it's a little premature to bet the ranch on a future utopia at the expense of other, albeit lesser alternatives that may provide benefits that are already available today. 

The vision for fully realizing the ultimate potential of health care standards centers on the nirvana-like goal of semantic interoperability (or, more accurately, computer semantic interoperability—the ability for computer systems to unambiguously exchange information and meaning). Wikipedia calls this "the ability of computer systems to communicate information and have that information properly interpreted by the receiving system in the same sense as intended by the transmitting system." Too many existing standards in common use are primarily syntactic in nature—they provide a way to represent the structure and format of data, but do not sufficiently convey context or meaning. Thus, data sent in such a standard may consist of perfectly well-formed sentences that don't make any sense to the person who receives them. 

The lack of semantic interoperability has been a criticism sometimes made of CDISC standards. The CDISC Study Data Tabulation Model (SDTM), for example, provides a way to represent the vast majority of commonly collected clinical trial data. But it breaks down around the edges for questions not explicitly described in the SDTM Implementation Guide and especially for data unique to a specific therapeutic area, leaving lots of room for creativity among individual implementers. A recent research project that is seeking to repurpose and pool clinical trials data from a group of different sponsors in the hope of achieving treatment breakthroughs for two catastrophic diseases illustrated the consequences of such creativity. Everyone was using the same CDISC SDTM domain model, but somehow, none of the data quite looked the same or fit together in the same way. 

We can help close such gaps with experience and with increased effort on the content standards that would be used to populate the SDTM—what some call the common data elements. CDISC is directly pursuing a project, CSHARE, to build a repository to collect the metadata associated with the thousands of individual questions that can be asked on Case Report Forms—and, hopefully, eventually find a way to harmonize the many different expressions of similar concepts. 

And as such information is made available, reviewed, mapped, and put in use, and we begin to adopt the same set of questions with the same terminologies within the same syntax, we can move in the desired direction toward semantic interoperability. 

But how far? Even in the absence of such tools as CSHARE, should we postpone using helpful but imperfect standards like SDTM entirely until the promise of full semantic interoperability can be achieved? Of course not. SDTM has shortcomings, but also offers many tangible benefits. Using SDTM gives companies a common reference point to begin with, and SDTM will be incrementally improved as more terminologies (including those in CSHARE), examples, and improved syntactical representations are made available. 

Is computer system interoperability for clinical data an impending reality or just a dream?

Applied Clinical Trials-10-01-2009

Applied Clinical Trials Digital Edition - October 2009

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Late Phase Patient Reported Outcomes

FDA Promotes Integrity and Compliance

Pressure Mounts for ICH GCP Revisions

Business and People Update October 2009

The Semantics of Health Care Interoperability

Operation Adaptive

Financial Simulation Modeling

Working Toward a Better Future

A Canary in a Coal Mine?

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Emerging Pharmas and CROs Need Each Other