FDA Draft Guidance on Risk-Based Monitoring


Congratulations to FDA on encouraging the Industry to run clinical trials in a more productive manner. The recently published Draft Guidance for Industry entitled: “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring will permit the Industry to replace labor-intensive, minimally productive procedures with currently available technologies and approaches to improve the quality of clinical trials and the safety of patients participating in these trials.


Target Health wants to acknowledge the hard work of the dedicated members of the Clinical Trial Transformation Initiative, under the leadership of Dr. Judith Kramer (Duke University School of Medicine) and Dr. Briggs Morrison (Pfizer) for their contributions to some of the thinking behind the draft guidance. This was recognized within the draft guidance where FDA stated that “A survey conducted through the Clinical Trials Transformation Initiative (CTTI) indicates that a range of practices has been used to monitor the conduct of clinical trials.” Target Health is also honored that 2 of the references cited in this draft guidance were co-authored by Dr. Jules T. Mitchel, President of Target Health.


The guidance is intended to assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for investigational studies of medical products, including human drug and biological products, medical devices, and combinations thereof. The overarching goal of this guidance is to enhance human subject protection and the quality of clinical trial data. This guidance is intended to make clear that sponsors can use a variety of approaches to fulfill their responsibilities related to monitoring investigator conduct and the progress of investigational new drug (IND) or investigational device exemption (IDE) studies. This guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively. For example, the guidance specifically encourages greater use of centralized monitoring methods where appropriate.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at


On 9/11/2001, out of our office windows on the 25th floor on Madison Avenue, Target Health Inc. staff witnessed the days’ catastrophic sequence of events. An historical nightmare, never to be forgotten.    Joyce Hays



Ground Zero: Complete Devastation
September 12, 2001




In the wake of the 10th anniversary of the September 11th attacks, research published in the Journal of Traumatic Stress reveals how the attacks impacted the 1) ___ processes of those not directly exposed to the event. The study, which focused on college students in Massachusetts, found that even those who were not directly connected to New York or Washington showed increased stress responses to run of the mill visual images.


“Other studies have shown that the 9/11 attacks resulted in a wave of stress and anxiety across the United States,” said Ivy Tso from the University of Michigan. “8-10 percent of the residents of New York City reported symptoms consistent with PTSD 2) ___ ___ ___ and depression while 40% of Americans across the country experienced significant symptoms of 3) ___ related to the attacks.”


Tso and her colleagues’ study, which took place within one week of the attacks, assessed a sample of 31 university students in Boston, Massachusetts who were not directly connected to the attacks in New York and therefore represented the wider American 4) ___. The participants were shown a series of 90 pictures, 30 of which contained images of the attacks while the others were defined as either ‘negative’ but not related to the attacks, or ‘neutral’. The team then measured the 5) ___ activity of the participants to detect signs of anxiety and stress. “The results of our study indicate that participants’ brainwave responses during processing of the images deviated from 6) ___ in proportion to their self-report distress level directly related to the 9/11 attacks,” said Tso.


These stress-related neural deviations are analogous to the clinical phenomena and abnormal cognition observed in individuals with PTSD (e.g., diminished attention, hypervigilance, suppression of unwanted thoughts). “This finding is significant as our participants were young, unmediated, highly functional individuals and while their distress was clearly below clinical threshold, their brain responses to 7) ___ information were affected the same way, though not to the same degree, as in PTSD,” concluded Tso. “This makes us rethink whether distress reactions should be considered a spectrum of severity, rather than simply divided into normal vs. clinical categories.”


ANSWERS: 1) psychological; 2) post-traumatic stress disorder; 3) stress; 4) public; 5) brain; 6) normal; 7) emotional




September 11, 2001


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Homo Erectus and the Art of Cooking


A diorama in National Museum of Indonesia, Jakarta, depicting the life size
model of a Homo erectus family living in Sangiran about 900,000 years ago.



While haute cuisine would appear to be a modern human trait, new research suggests that the art of cooking could well go back almost 2 million years. A paper published in the PNAS (doi: 10.1073/pnas.1107806108) week by Harvard scientist Chris Organ and his colleagues examines the relationship between molar tooth size and time spent eating amongst humans and other extant primates.


Humans spend only about a tenth of the time eating that they “should” compared with other similarly-proportioned primates. We also have far smaller molar teeth than we “should.” The reason is that we eat a significantly superior diet of cooked food compared with our close ape cousins. This means that food needs less chewing, it takes less time to eat and we can extract far more calories from each meal. Consequently, despite maintaining a large body, we can afford to eat relatively infrequently.


So what about our ancestors? Intriguingly, delving back about 2 million years into the hominid fossil record to the time of Homo erectus, we see similarly shrunken molar teeth like our own beginning to appear and being carried into Neanderthals too. These changes are too dramatic to be accounted by merely by an altering body shape so must have a functional significance.


Organ and his colleagues think it’s down to food preparation and in particular, cooking, which unleashed the caloric potential and cut the disease risk of many more foods, helping make humans such a success. According to study co-author Zarin Machanda, “Energy is a currency that animals work with, so the more calories you have the more energy you have. And if you can increase energy that can give you an evolutionary advantage. We think that’s why every modern human culture cooks its food.” TheNakedScientists.com (CambridgeUniversity)


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Study Finds Two Doses of HPV Vaccine May Be As Protective As Full Course


Worldwide, approximately 500,000 new cases of cervical cancer are diagnosed every year, with about 250,000 deaths. An overwhelming majority of these new cases and deaths occur in low-resource countries. Virtually all cases of cervical cancer are caused by persistent infection with the human papillomavirus (HPV). Cervarix (GSK) is one of two vaccines approved by the FDA to protect against persistent infection with two carcinogenic HPV types, 16 and 18, which together account for 70% of all cervical cancer cases. The vaccine is intended to be administered in three doses given over the course of six months. To date, investigators have observed up to eight years of protection from persistent HPV infection with the vaccine. Studies are ongoing to determine the maximum length of protection.


The cost of the vaccine as well as the logistical difficulties of administering 3 doses to an adolescent population in resource-poor countries is greater than administering 2 doses. Even in wealthier countries such as the US, few adolescent females complete the entire course of 3 vaccinations. According the CDC, although approximately 49% of American girls ages 13 to 17 received one dose of the vaccine in 2010, only 32% received all three doses. In the US, the predominately used HPV vaccine is Gardasil (Merck), which has a different formulation than Cervarix. Gardasil also protects against up to 90% of genital warts because it targets HPV strains 6 and 11 as well as 16 and 18.


According to an article published online in the Journal of the National Cancer Institute (9 September 2011), 2 doses of Cervarix were shown to be as effective as the current standard 3-dose regimen after four years of follow-up. The results of the study, based on data from a community-based clinical trial of Cervarix in Costa Rica.


The NCI-sponsored Costa Rica Vaccine Trial was designed to assess the efficacy of Cervarix in a community-based setting. Women ages 18 to 25 years were randomly assigned to receive the HPV vaccine or a Hepatitis A vaccine as the control treatment. Although the investigators intended to administer all 3 doses of the assigned vaccine to all 7,466 women in the study, about 20% of the participants received only one or two doses of the HPV or control vaccine. A third of women did not complete the vaccine series because they became pregnant or were found to have possible cervical abnormalities, reasons that would not likely bias the findings.


The study found that, after 4 years of follow up, 2 doses of the vaccine conferred the same strong protection against persistent infection with HPV 16 and 18 as did the full 3-dose regimen. From just a single dose, they also observed a high level of protection, but they are cautious about the long-term efficacy of a single dose because other vaccines of this type usually require a booster dose. Additional studies are needed to evaluate the efficacy of a single dose, as well as the duration of protection for both one and two doses.


The authors emphasized that findings from this study of the Cervarix vaccine in women in Costa Rica may not be relevant for all populations, such as those in which HIV infection, malnutrition, or endemic diseases may influence the immune response. In addition, it is not known whether the same results would be obtained with the other FDA-approved HPV vaccine, Gardasil, because the vaccine formulations are different.


It is important to note that regulatory agencies have approved the HPV vaccine based on prevention of cervical precancers, not persistent infections. From studying the natural history of HPV and cervical cancer, experts know that persistent infections are first steps toward precancer. Furthermore, vaccine recommendations take into consideration many factors and studies. In the US, the CDC’s Advisory Committee on Immunization Practices determines federal recommendations regarding vaccination.

Association Between Serum Cathepsin S and Mortality in Older Adults



In the immune and inflammatory responses, Cathepsin S is a cysteine protease involved in major histocompatibility complex class II antigen presentation and in intracellular and extracellular proteolysis. Moreover, a causal interplay between cathepsin S activity and inflammatory activity has been proposed. Current data regarding factors that influence circulating levels of cathepsin S are scarce. Previous studies have reported higher circulating levels of cathepsin S in patients with obesity, diabetes, or cardiovascular disease. It also has been reported that weight loss reduces circulating levels of cathepsin S. Furthermore, higher circulating levels of cathepsin S have been shown to be associated with increased inflammatory activity. As a result, a study published online in the Journal of the American Medical Association (29 August 2011) was performed to investigate associations between circulating cathepsin S levels and mortality in elderly men and women.


This prospective study used 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1009; mean age: 71 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 987; 50% women; mean age: 70 years). Serum samples were used to measure cathepsin S. The main outcome measure was total mortality.


Results showed that during follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 P = .009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03; P = .04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62; P = .01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05; P = .01).


According to the authors, among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. However, the authors added that additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

The Association of LRRK2 Exonic Variants with Susceptibility to Parkinson’s Disease


Genes such as the leucine-rich repeat kinase 2 gene (LRRK2) harbors highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson’s disease (PD) has not been assessed systematically. As a result, a study published online in Lancet Neurology, Early Online Publication (31 August 2011), was performed to assess the frequency of LRRK2 exonic variants in individuals with and without PD, and to investigate the role of the variants in PD susceptibility.


For the study, LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson’s Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.


The study included assessment of 121 exonic LRRK2 variants in 15,540 individuals: 6,995 white patients with PD and 5,595 controls; 1,376 Asian patients and 962 controls; and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43; p=0.0012) and Asian individuals (A419V, 2.27; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73; p=0.0026), but no association was noted for R1628P (0.62; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48; p=0.012).


According to the authors, the results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk, and that LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. The authors added that these results will help discriminate those patients who will benefit most from therapies targeted at the mutated LRRK2 gene.


The study was funded by the Michael J Fox Foundation and National Institutes of Health.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.



FDA Approves Xalkori With Companion Diagnostic For Non-Small Cell Lung Cancer




Target Health congratulates our colleagues at Abbott Molecular Diagnostics for this breakthrough approval in the area of personalized medicine.


The FDA has approved Xalkori (crizotinib) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene.


Xalkori is being approved with a companion diagnostic test that will help determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such targeted therapy approved by the FDA this year.


This ALK gene abnormality causes cancer development and growth. About 1% to 7% of those with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically non-smokers. Xalkori works by blocking certain proteins called kinases, including the protein produced by the abnormal ALK gene. Xalkori is a pill taken twice a day as a single-agent treatment.


According to Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug and that targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects.”


Xalkori’s safety and effectiveness were established in two multi-center, single-arm studies enrolling a total of 255 patients with late-stage ALK-positive NSCLC. A sample of a patient’s lung cancer tissue was collected and tested for the ALK gene abnormality prior to study enrollment. The studies were designed to measure objective response rate, the percentage of patients who experienced complete or partial cancer shrinkage. Most patients in the studies had received prior chemotherapy.


In one study, the objective response rate was 50% with a median response duration of 42 weeks. In another, the objective response rate was 61% with a median response duration of 48 weeks.


Xalkori was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients. The program is designed to provide patients with earlier access to promising new drugs, followed by further studies to confirm the drug’s clinical benefit.


Xalkori and the companion Vysis ALK Break Apart FISH Probe Kit were approved ahead of the drug’s September 30, 2011, FDA review goal date and the companion diagnostics’ September 28, 2011 review goal date.


The most common side effects reported in patients receiving Xalkori included vision disorders, nausea, diarrhea, vomiting, swelling (edema), and constipation. Vision disorders included visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects. Xalkori use has also been associated with inflammation of the lung tissue (pneumonitis), which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with Xalkori. The drug should not be used in pregnant women.


In July 2011, FDA issued a draft guidance industry on the agency’s policy for reviewing a companion diagnostic and the corresponding drug therapy. The guidance is currently available for public comment.


Xalkori is marketed by New York City-based Pfizer. The Vysis ALK Break Apart FISH Probe Kit is marketed by Abbott Molecular Inc. of Des Plaines, Ill.



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