Why the Paperless Clinical Trial



Target Health has always been, and will continue to be, committed to the paperless clinical trial. Why the “obsession?“


In today’s high speed world, there is a need for transparent transactions which minimize errors and maximize speed. Surely if we collect data on paper at any point in the drug/device development process, we fulfill none of the above since recording data on a piece of paper:


  • Is effectively “dumb data entry“ with no edit checks firing at the time of data entry
  • Delays the time that data can be seen
  • Only allows for transparency after the “data are cleaned“


Target Health provided the data entry solution 12 years ago with Target e*CRF and the eTMF solution 3 years ago with Target Document. And now, Target Health has software to address eSource for clinical trial data, as described both in the eSource FDA Draft Guidance and EMA Reflection Paper. Target e*CTR (eClinical Trial Record) is now being used in 2 studies under 2 INDs. The NDA submission is planned for Q4 2012.


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 www.targethealth.com


Antibiotic-Resistant Bacteria Have Evolved a Unique Chemical Mechanism

(Credit: National Institutes of Health)


For the first time, a detailed chemical picture has been painted of how a particular strain of bacteria has evolved to become 1) ___ to antibiotics. The study is a key step toward designing compounds to prevent infections by recently evolved, drug-resistant “superbugs“ that often are found in 2) ___, as well as in the general population. A paper describing the research, by a team led by Squire Booker, an associate professor in the department of chemistry and the department of biochemistry and molecular biology at Penn State University, was posted by the journal Science on its early-online Science Express site on 28 April.


The team began by studying a protein made by a recently evolved “superbug.“ Booker explained that, several years ago, genetic studies had revealed that Staphylococcus sciuri – a non-human bacterial pathogen – had evolved a new 3) ___ called cfr. The protein created by this gene had been found to play a key role in one of the bacterium’s mechanisms of antibiotic resistance. Later, the same gene was found to have crossed over into a strain of Staphylococcus aureus – a very common kind of bacteria that constitutes part of the flora living in the human 4) ___ and on the skin, and which is now the cause of various antibiotic-resistant infections. Because this gene often is found within a mobile DNA element, it can move easily from a non-human pathogen to other species of bacteria that infect 5) ___.


“The gene, which has been found in Staphylococcus aureus isolates in the US, Mexico, Brazil, Spain, Italy, and Ireland, effectively renders the bacteria resistant to seven classes of antibiotics,“ Booker explained. “Clearly, bacteria with this gene have a distinct 6) ___ advantage. However, until now, the detailed process by which the protein encoded by that gene affected the genetic makeup of the bacteria was unclear; that is, we didn’t have a clear 3D picture of what was going on at the 7) ___ level.“


To solve the chemical mystery of how such bacteria outsmart so many antibiotics, the study investigated how the Cfr protein accomplishes a task called methylation – a process by which enzymes add a small molecular tag to a particular location on a nucleotide – a molecule that is the structural unit of RNA and DNA. When this molecular tag is added by a protein called RlmN, it facilitates the proper functioning of the bacterial ribosome. Many classes of antibiotics bind to the ribosome, disrupting its function and thereby killing the bacteria. The Cfr 8) ___ performs an identical function as the RlmN protein, but it adds the molecular tag at a different location on the same nucleotide. The addition of the tag blocks binding of antibiotics to the ribosome without disrupting its function.


What had perplexed scientists is that the locations to which RlmN and Cfr add molecular tags are chemically different from all others to which tags routinely are appended, and should be resistant to modification by standard chemical methods. “What we’ve discovered here is so exciting because it represents a truly new chemical mechanism for methylation and a very clear chemical picture of a very clever mechanism for antibiotic resistance that some 9) ___ have evolved“ said Booker. Booker also said he believes the next step will be to use this new information to design compounds that could work in conjunction with typical antibiotics because the specific mechanism by which bacterial cells evade several classes of 10) ___ is known.


ANSWERS: 1) resistant; 2) hospitals; 3) gene; 4) nose; 5) humans; 6) evolutionary; 7) molecular; 8) protein; 9) bacteria; 10) antibiotics

Cystic Fibrosis


Cystic fibrosis has an autosomal recessive pattern of inheritance



Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned “Wehe dem Kind, das beim Kuss auf die Stirn salzig schmekt, er ist verhext und muss bald sterbe“ or “Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die,“ recognizing the association between the salt loss in CF and illness.


In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner. In 1936, Guido Fanconi published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis. In 1938 Dorothy Hansine Andersen published an article, “Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study,“ in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952 Paul di Sant’ Agnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade.


In 1988 the first mutation for CF, deltaF508 was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF. Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene. Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping techniques were then used to identify and sequence the gene. In 1989 Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics.


These pictures were sent by Dennis Bunyan from Petrolia, Ontario, Canada. He was about 6 years old at the time, in 1963. The first one is how his mother did therapy on him back them. No fancy therapy boards like now! The second one show extra large bottles of Cotazyme pills, of which he says he eventually had to take 50-60 of at each meal. Sounds like a meal in itself! Only the older PWCF will remember Mist Tents, which we had to sleep is back then…not really as fun as camping. You would wake up pretty soggy in the morning! Also, notice the “contraption” at the bottom of the page which served as a compressor. Not too fancy, hunh? But that’s how it was back then, you did what you could with what you had. It permitted many to survive…


Lucentis and Avastin for Neovascular Age-Related Macular Degeneration



The following article explains clearly why the pharmaceutical industry needs to redefine itself and focus primarily on healthcare rather than on sales.


Clinical trials have established the efficacy of ranibizumab (Lucentis) for the treatment of neovascular age-related macular degeneration (AMD), while bevacizumab (Avastin) is used off-label to treat AMD, despite the absence of similar supporting data.


As a result, a multicenter study, single-blind, noninferiority study, published online in the New England Journal of Medicine on 28 April 2011 and funded by the National Eye Institute, was performed to evaluate the comparative effectiveness of the two treatments in neovascular AMD. The study randomly assigned 1,208 patients to receive intravitreal injections of Lucentis or Avastin on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.


Results showed that Avastin administered monthly was equivalent to Lucentis administered monthly, with 8.0 and 8.5 letters gained, respectively. Avastin administered as needed was equivalent to Lucentis as needed, with 5.9 and 6.8 letters gained, respectively. Lucentis given as needed was equivalent to its treatment monthly, although the comparison between Avastin as needed and monthly Avastin was inconclusive. The mean decrease in central retinal thickness was greater in the Lucentis-monthly group than in the other groups (P=0.03). Rates of death, myocardial infarction, and stroke were similar for patients receiving either treatment. The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Lucentis (24.1% vs. 19.0%; risk ratio, 1.29), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.


According to the authors, at 1 year, Avastin and Lucentis had equivalent effects on visual acuity when administered according to the same schedule. Lucentis given as needed with monthly evaluation had effects on vision that were equivalent to those of Lucentis administered monthly. Differences in rates of serious adverse events require further study.


5-Minute Screen Identifies Subtle Signs of Autism in 1-Year Olds



Identifying autism at an early age allows children to start treatment sooner, which can greatly improve their later development and learning. However, many studies show a significant delay between the time parents first report concerns about their child’s behavior and the eventual of autism spectrum disorder (ASD) diagnosis, with some children not receiving a diagnosis until well after they’ve started school.


According to an article published online in the Journal of Pediatrics (29 April 2011), a five-minute checklist that parents can fill out in pediatrician waiting rooms may someday help in the early diagnosis of ASD. The study’s design also provides a model for developing a network of pediatricians to adopt such a change to their practice.


For the study, recognizing the need to improve early ASD screening, Karen Pierce, Ph.D., of the University of California, San Diego, and colleagues established a network of 137 pediatricians across San Diego County. Following an hour-long educational seminar, the pediatricians screened all infants at their 1-year, well-baby check-up using the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist, a brief questionnaire that detects ASD, language delay, and developmental delay. The questionnaire asks caregivers about a child’s use of eye gaze, sounds, words, gestures, objects and other forms of age-appropriate communication. Any child who failed the screen was referred for further testing and was re-evaluated every six months until age 3.


Results showed that out of 10,479 infants screened, 32 were identified as having ASD. After excluding for late onset and regression cases, this is consistent with current rates that would be expected at 12 months of age. When including those identified as having language delay, developmental delay, or some other form of delay, the brief screen provided an accurate diagnosis 75 percent of the time.


Following the screen, all toddlers diagnosed with ASD or developmental delay and 89% of those with language delay were referred for behavioral therapy. On average, these children were referred for treatment around age 17 months. For comparison, a 2009 study using data from the Centers for Disease Control and Prevention found that, on average, children currently receive an ASD diagnosis around 5.7 years (68.4 months) of age, with treatment beginning sometime later.


In addition to tracking infant outcomes, the study also surveyed the participating pediatricians. Prior to the study, few of the doctors had been screening infants systematically for ASD. After the study, 96% of the pediatricians rated the program positively, and 100% of the practices have continued using the screening tool.

NIH Researchers Create Comprehensive Collection of Approved Drugs to Identify New Therapies for Rare and Neglected Diseases



This is how we should excel in healthcare delivery as part of the redefinition of the pharmaceutical industry.


Drugs that receive regulatory approval have been demonstrated to be reasonably safe and effective in the treatment of a specific disease or condition. When such drugs are used in large populations, new benefits or adverse effects can be discovered. Subsequently, the use of approved drugs can be expanded beyond what a drug was originally approved for to treat other health conditions. Since creating a new drug is expensive, recouping the investment can be difficult for rare diseases, due to the small number of patients with the disease or, in the case of tropical neglected diseases, the limited ability of patients to pay for treatments. Today, therapies are available for less than 300 rare diseases.


Thalidomide is an example of repurposing a drug with serious adverse effects in one condition to treat another disease. In the 1950s, it was used as a sedative and as a treatment for morning sickness during pregnancy. It was later withdrawn because it was found to cause severe birth defects. Thalidomide was then repurposed for use against leprosy, an infectious disease causing skin lesions and multiple myeloma, a cancer of plasma cells, which are a type of white blood cell present in bone marrow. Based on the drug’s new application, the FDA approved thalidomide for the treatment of leprosy in 1998 and for multiple myeloma patients in 2006.


More recently, a team lead by Daniel Kastner, M.D., Ph.D from the National Human Genome Research Institute (NHGRI) used a similar approach, examining patient blood samples to see what gene and protein networks were active in a syndrome called periodic childhood fever associated with aphthous stomatitis, pharyngitis and cervical adenitis – or PFAPA. PFAPA causes monthly flare-ups of fever, accompanied by sore throat, swollen glands and mouth lesions. The team detected overactive genes in the patient’s immune response, including interleukin-1, a molecule that is important in triggering fever and inflammation. From these data, it was hypothesized that anakinra, a drug that prevents interleukin-1 from binding to its receptor, could be therapeutic. A study was then performed where anakinra was injected into five children on the second day of their PFAPA fevers and all showed a reduction in fever and inflammatory symptoms within hours.


Another approach that does not require a complete knowledge of a disease or drug mechanism uses high-throughput drug screening technologies that screen drugs for biological activity in cell-based models of disease.  Drugs that record an activity are known as hits and can be further studied for their therapeutic potential by researchers in animal models of the disease and eventually in human clinical trials.


NCGC already has screened the approved drug collection against more than 200 cell-based models of disease. In every screen, NCGC characterizes the pharmacology of each compound over a wide range of concentrations using its signature quantitative high-throughput screening approach. All of the data from NCGC screens will be published and made publicly available.


In addition to repurposing drugs, the NCGC plans to screen the collection as part of the Tox21 initiative to better predict and model adverse effects associated with approved drugs. Drug toxicity is one of the primary reasons that approved drugs are removed from the marketplace and the ability to predict toxicity would dramatically improve the efficiency of drug development.


Currently, researchers have begun screening the first definitive collection of thousands of approved drugs for clinical use against rare and neglected diseases. They are hunting for additional uses of the drugs hoping to find off-label therapies, for some of the 6,000 rare diseases that afflict 25 million Americans. The effort is coordinated by the National Institutes of Health’s Chemical Genomics Center (NCGC).


The researchers assembled the collection of approved drugs for screening based on information from the NCGC Pharmaceutical Collection browser. This publicly available, Web-based application described in a paper appearing in the April 27 issue of Science Translational Medicine (2011;3:80ps16), provides complete information on the nearly 27,000 active pharmaceutical ingredients including 2,750 small molecule drugs that have been approved by regulatory agencies from the United States, Canada, Europe and Japan, as well as all compounds that have been registered for human clinical trials.


The NCGC Pharmaceutical Collection (NPC) browser provides users with the ability to explore drugs by name, chemical structure, approval status and indication. Groups interested in developing their own screening collections can leverage the supplier and catalog information provided in the browser. The browser, which is an ongoing effort, also includes entries on investigational drugs. The ultimate goal is to collect all of the more than 7,500 compounds that have been tested in man and which present potential jump-start development of treatments for rare and neglected diseases.


The current focus is on collaborating with disease foundations, industry, and academic investigators with disease-relevant assays to screen against the approved drug collection acquired by NCGC. Any new therapeutic use of an approved drug would require additional studies including clinical trials in that disease, approved by the FDA. Given the cost and limited quantities of the drugs in the collection, each partnership to screen the NPC will be evaluated based on the quality of each disease-related assay and its scientific merit.


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



The “Off-Label“ Conundrum

by Mark L. Horn, MD, MPH, CMO, Target Health Inc.



It is impossible to work in the Pharmaceutical industry without being aware of the controversies and risks that surround the off-label use of medicines. Many companies have paid significant fines and suffered public embarrassment due to marketing medicines for unlabeled uses. Additionally, while physicians are operating entirely within the bounds of their professional authority and discretion when prescribing approved medicines for unlabeled uses, media coverage has made these usually entirely proper, and sometimes clinically critical decisions, seem somewhat tawdry.


Given this complex dynamic, it was unusual to read last week in an editorial by Philip J. Rosenfeld, published on-line by the New England Journal of Medicine and cited above, that “Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label?“


What has happened to provoke this sentiment?


A controversy has emerged in the treatment of age-related macular degeneration, a significant cause of loss of visual acuity in the elderly caused by proliferation and leakage of blood vessels in the retina. Bevacizumab (Avastin), a drug approved to treat various cancers, and its newer cousin, ranibizumab (Lucentis), designed and labeled specifically for ophthalmologic use, both ameliorate this vascular pathology. The controversy: there is an enormous cost differential favoring Avastin which has prompted doctors, patients, (and presumably some payers), to opt for the unlabeled therapy.


The question has been called by the publication of the Comparison of AMD Treatment Trials (CATT) study which, while unable to answer certain important long term safety questions, provides support for the use of either treatment. Coupled with the enormous cost differential of approximately $2,000 vs. $50/dose, it is clear why there will likely be pressure from multiple sources to cover the off-label treatment. While this may seem like a “no-brainer“ to many, and any efforts of the innovator company to advocate that reimbursement be limited to the product specifically developed – at considerable cost – for ophthalmologic use disingenuous, this situation presents complex and difficult questions.


If limiting off-label prescribing and reimbursement for, (especially expensive), products used for unlabeled indications is clinically appropriate, is it acceptable to circumvent these restrictions as a cost saving measure, especially when there are unresolved safety questions? Additionally, if we want innovators to make investments in clinical development programs, generating valuable condition and cohort specific data, those data sets must confer economic value for the innovator.


Of course, at the same time we must control health spending, and utilizing cheaper, equally effective medicines, seems an ideal tool.


This controversy is evolving and for On-Target readers it warrants attention; the impact on drug discovery and development may be significant.


For more information about our expertise in Medical Affairs, contact Dr. Mark L. Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.


Target Health has developed a full suite of eClinical Trial software including:


1) Target e*CRF® (EDC plus randomization and batch edit


2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials).


Target Health’s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.






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